Biochemistry

An introduction

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Contents
Articles
Cells and water 1
Biochemistry 1
Cells 10
Water 21

Structural Biochemistry 43

Nucleic acids 44
Nucleic acid 44
RNA 47
DNA 55

Proteins and amino acids 79

Protein 79
Amino acid 93
Properties of the twenty amino acids 108
Myoglobin 118
Hemoglobin 124

Enzyme mechanisms 141

Enzyme catalysis 141

Enzyme kinetics 148

Enzyme kinetics 148

Lipids and membranes 163

Lipid 163
Biological membrane 174
Membrane protein 175
Cell membrane 179

Carbohydrate structure 186

Carbohydrate 186
Polysaccharide 193
Intermediary metabolism 200

Metabolism 201
Overview of metabolism 201

Carbohydrate metabolism 221

Glycolysis 221
Gluconeogenesis 234
Glycogen 237
Pentose phosphate pathway 241

Citric acid cycle 245

Citric acid cycle 245

Oxidative phosphorylation 253

Oxidative phosphorylation 253

Photosynthesis 269
Photosynthesis 269

Lipid metabolism 283

Fatty acid synthesis 283
Lipogenesis 290
Acetyl-CoA carboxylase 292
Fatty acid degradation 299
Beta oxidation 301

Nitrogen metabolism 305

Nitrogen fixation 305
Amino acid synthesis 310
Nucleotide 313
Urea cycle 318

Integration of metabolism 322

Hormone 322
Signal transduction 326
Diabetes mellitus 335

Informational Macromolecules 349

DNA synthesis and repair 350
DNA replication 350
DNA repair 358
Oncogenes 370

RNA synthesis and processing 374

Transcription 374
Regulation of gene expression 380

Protein synthesis and modifications 385

Translation 385
Posttranslational modification 389
Proteolysis 393
Proteasome 395

References
Article Sources and Contributors 409
Image Sources, Licenses and Contributors 420

Article Licenses
License 427
 1

Cells and water

Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms,
including, but not limited to, living matter. Biochemistry governs all living organisms and living processes. By
controlling information flow through biochemical signalling and the flow of chemical energy through metabolism,
biochemical processes give rise to the incredible complexity of life. Much of biochemistry deals with the structures
and functions of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules
—although increasingly processes rather than individual molecules are the main focus. Over the last 40 years
biochemistry has become so successful at explaining living processes that now almost all areas of the life sciences
from botany to medicine are engaged in biochemical research. Today the main focus of pure biochemistry is in
understanding how biological molecules give rise to the processes that occur within living cells, which in turn relates
greatly to the study and understanding of whole organisms.
Among the vast number of different biomolecules, many are complex and large molecules (called biopolymers),
which are composed of similar repeating subunits (called monomers). Each class of polymeric biomolecule has a
different set of subunit types.[1] For example, a protein is a polymer whose subunits are selected from a set of 20 or
more amino acids. Biochemistry studies the chemical properties of important biological molecules, like proteins, and
in particular the chemistry of enzyme-catalyzed reactions.
The biochemistry of cell metabolism and the endocrine system has been extensively described. Other areas of
biochemistry include the genetic code (DNA, RNA), protein synthesis, cell membrane transport, and signal
transduction.

History
It once was generally believed that life and its materials had some essential property or substance distinct from any
found in non-living matter, and it was thought that only living beings could produce the molecules of life. Then, in
1828, Friedrich Wöhler published a paper on the synthesis of urea, proving that organic compounds can be created
artificially.[2] [3]
The dawn of biochemistry may have been the discovery of the first enzyme, diastase (today called amylase), in 1833
by Anselme Payen. Eduard Buchner contributed the first demonstration of a complex biochemical process outside of
a cell in 1896: alcoholic fermentation in cell extracts of yeast. Although the term “biochemistry” seems to have been
first used in 1882, it is generally accepted that the formal coinage of biochemistry occurred in 1903 by Carl Neuberg,
a German chemist. Previous to this time, this area would have been referred to as physiological chemistry. Since
then, biochemistry has advanced, especially since the mid-20th century, with the development of new techniques
such as chromatography, X-ray diffraction, dual polarisation interferometry, NMR spectroscopy, radioisotopic
labeling, electron microscopy, and molecular dynamics simulations. These techniques allowed for the discovery and
detailed analysis of many molecules and metabolic pathways of the cell, such as glycolysis and the Krebs cycle
(citric acid cycle).
Another significant historic event in biochemistry is the discovery of the gene and its role in the transfer of
information in the cell. This part of biochemistry is often called molecular biology. In the 1950s, James D. Watson,
Francis Crick, Rosalind Franklin, and Maurice Wilkins were instrumental in solving DNA structure and suggesting
its relationship with genetic transfer of information. In 1958, George Beadle and Edward Tatum received the Nobel
Prize for work in fungi showing that one gene produces one enzyme. In 1988, Colin Pitchfork was the first person
Biochemistry 2

convicted of murder with DNA evidence, which led to growth of forensic science. More recently, Andrew Z. Fire
and Craig C. Mello received the 2006 Nobel Prize for discovering the role of RNA interference (RNAi), in the
silencing of gene expression.

Starting materials: the chemical elements of life

Around two dozen of the 94 naturally-occurring chemical elements are essential to various kinds of biological life.
Most rare elements on Earth are not needed by life (exceptions being selenium and iodine), while a few common
ones (aluminum and titanium) are not used. Most organisms share element needs, but there are a few differences
between plants and animals. For example ocean algae use bromine but land plants and animals seem to need none.
All animals require sodium, but some plants do not. Plants need boron and silicon, but animals may not (or may need
ultra-small amounts). Just six elements—carbon, hydrogen, nitrogen, oxygen, calcium, and phosphorus—make up
almost 99% of the mass of a human body (see composition of the human body for a complete list). In addition to the
six major elements that compose most of the human body, humans require smaller amounts of possibly 18 more.[4]

Biomolecules
The four main classes of molecules in biochemistry are carbohydrates, lipids, proteins, and nucleic acids. Many
biological molecules are polymers: in this terminology, monomers are relatively small micromolecules that are
linked together to create large macromolecules, which are known as polymers. When monomers are linked together
to synthesize a biological polymer, they undergo a process called dehydration synthesis.

Carbohydrates
Carbohydrates are made from monomers called monosaccharides. Some of these
monosaccharides include glucose (C6H12O6), fructose (C6H12O6), and deoxyribose
(C5H10O4). When two monosaccharides undergo dehydration synthesis, water is
produced, as two hydrogen atoms and one oxygen atom are lost from the two
monosaccharides' hydroxyl group. A molecule of sucrose (glucose +
fructose), a disaccharide.

Lipids
A triglyceride with a glycerol molecule
on the left and three fatty acids coming
off it.
Lipids are usually made from one molecule of glycerol combined with other
molecules. In triglycerides, the main group of bulk lipids, there is one
molecule of glycerol and three fatty acids. Fatty acids are considered the
monomer in that case, and may be saturated (no double bonds in the carbon
chain) or unsaturated (one or more double bonds in the carbon chain).
Lipids, especially phospholipids, are also used in various pharmaceutical
products, either as co-solubilisers (e.g., in parenteral infusions) or else as drug
carrier components (e.g., in a liposome or transfersome).
Biochemistry 3

Proteins
Proteins are very large molecules – macro-biopolymers – made from monomers called
amino acids. There are 20 standard amino acids, each containing a carboxyl group, an
amino group, and a side-chain (known as an "R" group). The "R" group is what makes
each amino acid different, and the properties of the side-chains greatly influence the
overall three-dimensional conformation of a protein. When amino acids combine, they
form a special bond called a peptide bond through dehydration synthesis, and become a The general structure of an
α-amino acid, with the
polypeptide, or protein.
amino group on the left and
In order to determine whether two proteins are related, or in other words to decide the carboxyl group on the
right.
whether they are homologous or not, scientists use sequence-comparison methods.
Methods like Sequence Alignments and Structural Alignments are powerful tools that
help scientists identify homologies between related molecules.
The relevance of finding homologies among proteins goes beyond forming an evolutionary pattern of protein
families. By finding how similar two protein sequences are, we acquire knowledge about their structure and
therefore their function.

Nucleic acids
Nucleic acids are the molecules that make up DNA, an extremely
important substance that all cellular organisms use to store their
genetic information. The most common nucleic acids are
deoxyribonucleic acid and ribonucleic acid. Their monomers are
called nucleotides. The most common nucleotides are adenine,
cytosine, guanine, thymine, and uracil. Adenine binds with
thymine and uracil; Thymine binds only with adenine; and
cytosine and guanine can bind only with each other.

Carbohydrates
The function of carbohydrates includes energy storage and
providing structure. Sugars are carbohydrates, but not all
carbohydrates are sugars. There are more carbohydrates on Earth
than any other known type of biomolecule; they are used to store
The structure of deoxyribonucleic acid (DNA), the
picture shows the monomers being put together.
energy and genetic information, as well as play important roles in
cell to cell interactions and communications.

Monosaccharides
The simplest type of carbohydrate is a monosaccharide, which among
other properties contains carbon, hydrogen, and oxygen, mostly in a
ratio of 1:2:1 (generalized formula CnH2nOn, where n is at least 3).
Glucose, one of the most important carbohydrates, is an example of a
monosaccharide. So is fructose, the sugar commonly associated with
the sweet taste of fruits.[5] [a] Some carbohydrates (especially after
Glucose
Biochemistry 4

condensation to oligo- and polysaccharides) contain less carbon relative to H and O, which still are present in 2:1
(H:O) ratio. Monosaccharides can be grouped into aldoses (having an aldehyde group at the end of the chain, e.g.
glucose) and ketoses (having a keto group in their chain; e.g. fructose). Both aldoses and ketoses occur in an
equilibrium (starting with chain lengths of C4) cyclic forms. These are generated by bond formation between one of
the hydroxyl groups of the sugar chain with the carbon of the aldehyde or keto group to form a hemiacetal bond.
This leads to saturated five-membered (in furanoses) or six-membered (in pyranoses) heterocyclic rings containing
one O as heteroatom.

Disaccharides
Two monosaccharides can be joined together using dehydration
synthesis, in which a hydrogen atom is removed from the end of one
molecule and a hydroxyl group (—OH) is removed from the other; the
remaining residues are then attached at the sites from which the atoms
were removed. The H—OH or H2O is then released as a molecule of
water, hence the term dehydration. The new molecule, consisting of
two monosaccharides, is called a disaccharide and is conjoined Sucrose: ordinary table sugar and probably the
together by a glycosidic or ether bond. The reverse reaction can also most familiar carbohydrate.

occur, using a molecule of water to split up a disaccharide and break

the glycosidic bond; this is termed hydrolysis. The most well-known disaccharide is sucrose, ordinary sugar (in
scientific contexts, called table sugar or cane sugar to differentiate it from other sugars). Sucrose consists of a
glucose molecule and a fructose molecule joined together. Another important disaccharide is lactose, consisting of a
glucose molecule and a galactose molecule. As most humans age, the production of lactase, the enzyme that
hydrolyzes lactose back into glucose and galactose, typically decreases. This results in lactase deficiency, also called
lactose intolerance.

Sugar polymers are characterised by having reducing or non-reducing ends. A reducing end of a carbohydrate is a
carbon atom that can be in equilibrium with the open-chain aldehyde or keto form. If the joining of monomers takes
place at such a carbon atom, the free hydroxy group of the pyranose or furanose form is exchanged with an
OH-side-chain of another sugar, yielding a full acetal. This prevents opening of the chain to the aldehyde or keto
form and renders the modified residue non-reducing. Lactose contains a reducing end at its glucose moiety, whereas
the galactose moiety form a full acetal with the C4-OH group of glucose. Saccharose does not have a reducing end
because of full acetal formation between the aldehyde carbon of glucose (C1) and the keto carbon of fructose (C2).

Oligosaccharides and polysaccharides

When a few (around three to six) monosaccharides are joined together,
it is called an oligosaccharide (oligo- meaning "few"). These
molecules tend to be used as markers and signals, as well as having
some other uses. Many monosaccharides joined together make a
polysaccharide. They can be joined together in one long linear chain,
or they may be branched. Two of the most common polysaccharides
Cellulose as polymer of β-D-glucose
are cellulose and glycogen, both consisting of repeating glucose
monomers.

• Cellulose is made by plants and is an important structural component of their cell walls. Humans can neither
manufacture nor digest it.
• Glycogen, on the other hand, is an animal carbohydrate; humans and other animals use it as a form of energy
storage.
Biochemistry 5

Use of carbohydrates as an energy source

Glucose is the major energy source in most life forms. For instance, polysaccharides are broken down into their
monomers (glycogen phosphorylase removes glucose residues from glycogen). Disaccharides like lactose or sucrose
are cleaved into their two component monosaccharides.

Glycolysis (anaerobic)
Glucose is mainly metabolized by a very important ten-step pathway called glycolysis, the net result of which is to
break down one molecule of glucose into two molecules of pyruvate; this also produces a net two molecules of ATP,
the energy currency of cells, along with two reducing equivalents in the form of converting NAD+ to NADH. This
does not require oxygen; if no oxygen is available (or the cell cannot use oxygen), the NAD is restored by converting
the pyruvate to lactate (lactic acid) (e.g., in humans) or to ethanol plus carbon dioxide (e.g., in yeast). Other
monosaccharides like galactose and fructose can be converted into intermediates of the glycolytic pathway.

Aerobic
In aerobic cells with sufficient oxygen, as in most human cells, the pyruvate is further metabolized. It is irreversibly
converted to acetyl-CoA, giving off one carbon atom as the waste product carbon dioxide, generating another
reducing equivalent as NADH. The two molecules acetyl-CoA (from one molecule of glucose) then enter the citric
acid cycle, producing two more molecules of ATP, six more NADH molecules and two reduced (ubi)quinones (via
FADH2 as enzyme-bound cofactor), and releasing the remaining carbon atoms as carbon dioxide. The produced
NADH and quinol molecules then feed into the enzyme complexes of the respiratory chain, an electron transport
system transferring the electrons ultimately to oxygen and conserving the released energy in the form of a proton
gradient over a membrane (inner mitochondrial membrane in eukaryotes). Thus, oxygen is reduced to water and the
original electron acceptors NAD+ and quinone are regenerated. This is why humans breathe in oxygen and breathe
out carbon dioxide. The energy released from transferring the electrons from high-energy states in NADH and quinol
is conserved first as proton gradient and converted to ATP via ATP synthase. This generates an additional 28
molecules of ATP (24 from the 8 NADH + 4 from the 2 quinols), totaling to 32 molecules of ATP conserved per
degraded glucose (two from glycolysis + two from the citrate cycle). It is clear that using oxygen to completely
oxidize glucose provides an organism with far more energy than any oxygen-independent metabolic feature, and this
is thought to be the reason why complex life appeared only after Earth's atmosphere accumulated large amounts of
oxygen.

Gluconeogenesis
In vertebrates, vigorously contracting skeletal muscles (during weightlifting or sprinting, for example) do not receive
enough oxygen to meet the energy demand, and so they shift to anaerobic metabolism, converting glucose to lactate.
The liver regenerates the glucose, using a process called gluconeogenesis. This process is not quite the opposite of
glycolysis, and actually requires three times the amount of energy gained from glycolysis (six molecules of ATP are
used, compared to the two gained in glycolysis). Analogous to the above reactions, the glucose produced can then
undergo glycolysis in tissues that need energy, be stored as glycogen (or starch in plants), or be converted to other
monosaccharides or joined into di- or oligosaccharides. The combined pathways of glycolysis during exercise,
lactate's crossing via the bloodstream to the liver, subsequent gluconeogenesis and release of glucose into the
bloodstream is called the Cori cycle.
Biochemistry 6

Proteins
Like carbohydrates, some proteins perform largely structural roles. For
instance, movements of the proteins actin and myosin ultimately are
responsible for the contraction of skeletal muscle. One property many
proteins have is that they specifically bind to a certain molecule or class of
molecules—they may be extremely selective in what they bind. Antibodies
are an example of proteins that attach to one specific type of molecule. In
fact, the enzyme-linked immunosorbent assay (ELISA), which uses
antibodies, is currently one of the most sensitive tests modern medicine uses
to detect various biomolecules. Probably the most important proteins,
however, are the enzymes. These molecules recognize specific reactant
A schematic of hemoglobin. The red and
molecules called substrates; they then catalyze the reaction between them. By blue ribbons represent the protein globin;
lowering the activation energy, the enzyme speeds up that reaction by a rate the green structures are the heme groups.
of 1011 or more: a reaction that would normally take over 3,000 years to
complete spontaneously might take less than a second with an enzyme. The enzyme itself is not used up in the
process, and is free to catalyze the same reaction with a new set of substrates. Using various modifiers, the activity of
the enzyme can be regulated, enabling control of the biochemistry of the cell as a whole.

In essence, proteins are chains of amino acids. An amino acid consists of a carbon atom bound to four groups. One is
an amino group, —NH2, and one is a carboxylic acid group, —COOH (although these exist as —NH3+ and —COO−
under physiologic conditions). The third is a simple hydrogen atom. The fourth is commonly denoted "—R" and is
different for each amino acid. There are twenty standard amino acids. Some of these have functions by themselves or
in a modified form; for instance, glutamate functions as an important neurotransmitter.
Amino acids can be joined together via
a peptide bond. In this dehydration
synthesis, a water molecule is removed
and the peptide bond connects the
nitrogen of one amino acid's amino
group to the carbon of the other's
Generic amino acids (1) in neutral form, (2) as they exist physiologically, and (3) joined
carboxylic acid group. The resulting
together as a dipeptide.
molecule is called a dipeptide, and
short stretches of amino acids (usually,
fewer than thirty) are called peptides or polypeptides. Longer stretches merit the title proteins. As an example, the
important blood serum protein albumin contains 585 amino acid residues.

The structure of proteins is traditionally described in a hierarchy of four levels. The primary structure of a protein
simply consists of its linear sequence of amino acids; for instance,
"alanine-glycine-tryptophan-serine-glutamate-asparagine-glycine-lysine-…". Secondary structure is concerned with
local morphology (morphology being the study of structure). Some combinations of amino acids will tend to curl up
in a coil called an α-helix or into a sheet called a β-sheet; some α-helixes can be seen in the hemoglobin schematic
above. Tertiary structure is the entire three-dimensional shape of the protein. This shape is determined by the
sequence of amino acids. In fact, a single change can change the entire structure. The alpha chain of hemoglobin
contains 146 amino acid residues; substitution of the glutamate residue at position 6 with a valine residue changes
the behavior of hemoglobin so much that it results in sickle-cell disease. Finally, quaternary structure is concerned
with the structure of a protein with multiple peptide subunits, like hemoglobin with its four subunits. Not all proteins
have more than one subunit.
Biochemistry 7

Ingested proteins are usually broken up into single amino acids or dipeptides in the small intestine, and then
absorbed. They can then be joined together to make new proteins. Intermediate products of glycolysis, the citric acid
cycle, and the pentose phosphate pathway can be used to make all twenty amino acids, and most bacteria and plants
possess all the necessary enzymes to synthesize them. Humans and other mammals, however, can synthesize only
half of them. They cannot synthesize isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan,
and valine. These are the essential amino acids, since it is essential to ingest them. Mammals do possess the enzymes
to synthesize alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine, the
nonessential amino acids. While they can synthesize arginine and histidine, they cannot produce it in sufficient
amounts for young, growing animals, and so these are often considered essential amino acids.
If the amino group is removed from an amino acid, it leaves behind a carbon skeleton called an α-keto acid.
Enzymes called transaminases can easily transfer the amino group from one amino acid (making it an α-keto acid) to
another α-keto acid (making it an amino acid). This is important in the biosynthesis of amino acids, as for many of
the pathways, intermediates from other biochemical pathways are converted to the α-keto acid skeleton, and then an
amino group is added, often via transamination. The amino acids may then be linked together to make a protein.
A similar process is used to break down proteins. It is first hydrolyzed into its component amino acids. Free
ammonia (NH3), existing as the ammonium ion (NH4+) in blood, is toxic to life forms. A suitable method for
excreting it must therefore exist. Different strategies have evolved in different animals, depending on the animals'
needs. Unicellular organisms, of course, simply release the ammonia into the environment. Likewise, bony fish can
release the ammonia into the water where it is quickly diluted. In general, mammals convert the ammonia into urea,
via the urea cycle.

Lipids
The term lipid comprises a diverse range of molecules and to some extent is a catchall for relatively water-insoluble
or nonpolar compounds of biological origin, including waxes, fatty acids, fatty-acid derived phospholipids,
sphingolipids, glycolipids, and terpenoids (e.g., retinoids and steroids). Some lipids are linear aliphatic molecules,
while others have ring structures. Some are aromatic, while others are not. Some are flexible, while others are rigid.
Most lipids have some polar character in addition to being largely nonpolar. In general, the bulk of their structure is
nonpolar or hydrophobic ("water-fearing"), meaning that it does not interact well with polar solvents like water.
Another part of their structure is polar or hydrophilic ("water-loving") and will tend to associate with polar solvents
like water. This makes them amphiphilic molecules (having both hydrophobic and hydrophilic portions). In the case
of cholesterol, the polar group is a mere -OH (hydroxyl or alcohol). In the case of phospholipids, the polar groups are
considerably larger and more polar, as described below.
Lipids are an integral part of our daily diet. Most oils and milk products that we use for cooking and eating like
butter, cheese, ghee etc., are composed of fats. Vegetable oils are rich in various polyunsaturated fatty acids (PUFA).
Lipid-containing foods undergo digestion within the body and are broken into fatty acids and glycerol, which are the
final degradation products of fats and lipids.

Nucleic acids
A nucleic acid is a complex, high-molecular-weight biochemical macromolecule composed of nucleotide chains that
convey genetic information. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Nucleic acids are found in all living cells and viruses. Aside from the genetic material of the cell, nucleic
acids often play a role as second messengers, as well as forming the base molecule for adenosine triphosphate, the
primary energy-carrier molecule found in all living organisms.
Nucleic acid, so called because of its prevalence in cellular nuclei, is the generic name of the family of biopolymers.
The monomers are called nucleotides, and each consists of three components: a nitrogenous heterocyclic base (either
Biochemistry 8

a purine or a pyrimidine), a pentose sugar, and a phosphate group. Different nucleic acid types differ in the specific
sugar found in their chain (e.g., DNA or deoxyribonucleic acid contains 2-deoxyriboses). Also, the nitrogenous bases
possible in the two nucleic acids are different: adenine, cytosine, and guanine occur in both RNA and DNA, while
thymine occurs only in DNA and uracil occurs in RNA.

Relationship to other "molecular-scale" biological sciences

Researchers in biochemistry use specific techniques
native to biochemistry, but increasingly combine these
with techniques and ideas from genetics, molecular
biology and biophysics. There has never been a
hard-line between these disciplines in terms of content
and technique. Today, the terms molecular biology and
biochemistry are nearly interchangeable. The following
figure is a schematic that depicts one possible view of
the relationship between the fields:

• Biochemistry is the study of the chemical substances

and vital processes occurring in living organisms.
Biochemists focus heavily on the role, function, and
structure of biomolecules. The study of the
chemistry behind biological processes and the
synthesis of biologically active molecules are
Schematic relationship between biochemistry, genetics, and
examples of biochemistry.
molecular biology
• Genetics is the study of the effect of genetic
differences on organisms. Often this can be inferred by the absence of a normal component (e.g., one gene). The
study of "mutants" – organisms with a changed gene that leads to the organism being different with respect to the
so-called "wild type" or normal phenotype. Genetic interactions (epistasis) can often confound simple
interpretations of such "knock-out" or "knock-in" studies.
• Molecular biology is the study of molecular underpinnings of the process of replication, transcription and
translation of the genetic material. The central dogma of molecular biology where genetic material is transcribed
into RNA and then translated into protein, despite being an oversimplified picture of molecular biology, still
provides a good starting point for understanding the field. This picture, however, is undergoing revision in light of
emerging novel roles for RNA.
• Chemical Biology seeks to develop new tools based on small molecules that allow minimal perturbation of
biological systems while providing detailed information about their function. Further, chemical biology employs
biological systems to create non-natural hybrids between biomolecules and synthetic devices (for example
emptied viral capsids that can deliver gene therapy or drug molecules).
Biochemistry 9

Notes
a.   It should be noted that fructose is not the only sugar found in fruits. Glucose and sucrose are also found in
varying quantities in various fruits, and indeed sometimes exceed the fructose present. For example, 32 % of the
edible portion of date is glucose, compared with 23.70 % fructose and 8.20 % sucrose. However, peaches contain
more sucrose (6.66 %) than they do fructose (0.93 %) or glucose (1.47 %).[6]

References
[1] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[2] Wöhler, F. (1828). "Ueber künstliche Bildung des Harnstoffs". Ann. Phys. Chem. 12: 253–256.
[3] Kauffman, G. B. and Chooljian, S.H. (2001). "Friedrich Wöhler (1800–1882), on the Bicentennial of His Birth". The Chemical Educator 6
(2): 121–133. doi:10.1007/s00897010444a.
[4] Ultratrace minerals. Authors: Nielsen, Forrest H. USDA, ARS Source: Modern nutrition in health and disease / editors, Maurice E. Shils ... et
al.. Baltimore : Williams & Wilkins, c1999., p. 283-303. Issue Date: 1999 URI: (http:/ / hdl. handle. net/ 10113/ 46493)
[5] Whiting, G.C (1970). "Sugars". In A.C. Hulme. The Biochemistry of Fruits and their Products. Volume 1. London & New York: Academic
Press. pp. 1=31
[6] Whiting, G.C. (1970), p.5

Further reading
• Hunter, Graeme K. (2000). Vital Forces: The Discovery of the Molecular Basis of Life. San Diego: Academic
Press. ISBN 0-12-361810-X. OCLC 162129355 191848148 44187710.

External links
• The Virtual Library of Biochemistry and Cell Biology (http://www.biochemweb.org/)
• Biochemistry, 5th ed. (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=stryer.
TOC&depth=2) Full text of Berg, Tymoczko, and Stryer, courtesy of NCBI.
• Biochemistry, 2nd ed. (http://www.web.virginia.edu/Heidi/home.htm) Full text of Garrett and Grisham.
• Biochemistry Animation (http://www.1lec.com/Biochemistry/) (Narrated Flash animations.)
• SystemsX.ch - The Swiss Initiative in Systems Biology (http://www.systemsX.ch/)
• Biochemistry Online Resources (http://www.icademic.org/97445/Biochemistry/) – Lists of Biochemistry
departments, websites, journals, books and reviews, employment opportunities and events.
biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i
Cells 10

Cells
The cell is the basic structural and
functional unit of all known living
organisms. It is the smallest unit of life
that is classified as a living thing, and
is often called the building block of
life.[1] Organisms can be classified as
unicellular (consisting of a single cell;
including most bacteria) or
multicellular (including plants and
animals). Humans contain about 100
trillion cells; a typical cell size is
10 µm and a typical cell mass is
1 nanogram. The human cell extrema
are: largest - anterior horn in the spinal
cord (135 μ vs. 120 μ for the ovum), Allium cells in different phases of the cell cycle
longest - pseudounipolar cells which
reach from extremities, including the
toes to the lower brain stem, and
smallest - granule cells in the
cerebellum, at 4 µ.[2] The largest
known cells are unfertilised ostrich egg
cells, which weigh 3.3 pounds.[3] [4]

The cell was discovered by Robert

Hooke in 1665. In 1835, before the
final cell theory was developed, Jan
Evangelista Purkyně observed small
"granules" while looking at the plant
tissue through a microscope. The cell Cells in culture, stained for keratin (red) and
theory, first developed in 1839 by DNA (green)
Matthias Jakob Schleiden and Theodor
Schwann, states that all organisms are composed of one or more cells, that all cells come from preexisting cells, that
vital functions of an organism occur within cells, and that all cells contain the hereditary information necessary for
regulating cell functions and for transmitting information to the next generation of cells.[5]

The word cell comes from the Latin cellula, meaning "a small room". The
Cells 11

descriptive term for the smallest living biological structure was coined
by Robert Hooke in a book he published in 1665 when he compared
the cork cells he saw through his microscope to the small rooms monks
lived in.[6]

Drawing of the structure of cork as it appeared

under the microscope to Robert Hooke from
Micrographia, which is the origin of the word
"cell" being used to describe the smallest unit of a
living organism

Anatomy
There are two types of cells: eukaryotic and
prokaryotic. Prokaryotic cells are usually
independent, while eukaryotic cells are often
found in multicellular organisms.

The cells of eukaryotes (left) and prokaryotes (right)

Table 1: Comparison of features of prokaryotic and eukaryotic cells

Prokaryotes Eukaryotes

Typical organisms bacteria, archaea protists, fungi, plants, animals

Typical size ~ 1–10 µm ~ 10–100 µm (sperm cells, apart from the tail, are smaller)

Type of nucleus nucleoid region; no real nucleus real nucleus with double membrane

DNA circular (usually) linear molecules (chromosomes) with histone proteins

RNA-/protein-synthesis coupled in cytoplasm RNA-synthesis inside the nucleus

protein synthesis in cytoplasm

Ribosomes 50S+30S 60S+40S

Cells 12

Cytoplasmatic structure very few structures highly structured by endomembranes and a cytoskeleton

Cell movement flagella made of flagellin flagella and cilia containing microtubules; lamellipodia and filopodia containing actin

Mitochondria none one to several thousand (though some lack mitochondria)

Chloroplasts none in algae and plants

Organization usually single cells single cells, colonies, higher multicellular organisms with specialized cells

Cell division Binary fission (simple division) Mitosis (fission or budding)

Meiosis

Prokaryotic cells
The prokaryote cell is simpler, and
therefore smaller, than a eukaryote
cell, lacking a nucleus and most of the
other organelles of eukaryotes. There
are two kinds of prokaryotes: bacteria
and archaea; these share a similar
structure.

Nuclear material of prokaryotic cell

consist of a single chromosome that is
in direct contact with cytoplasm. Here,
the undefined nuclear region in the
cytoplasm is called nucleoid.
A prokaryotic cell has three
architectural regions:
• On the outside, flagella and pili
project from the cell's surface.
Diagram of a typical prokaryotic cell
These are structures (not present in
all prokaryotes) made of proteins
that facilitate movement and communication between cells;
• Enclosing the cell is the cell envelope – generally consisting of a cell wall covering a plasma membrane though
some bacteria also have a further covering layer called a capsule. The envelope gives rigidity to the cell and
separates the interior of the cell from its environment, serving as a protective filter. Though most prokaryotes
have a cell wall, there are exceptions such as Mycoplasma (bacteria) and Thermoplasma (archaea). The cell wall
consists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents the
cell from expanding and finally bursting (cytolysis) from osmotic pressure against a hypotonic environment.
Some eukaryote cells (plant cells and fungi cells) also have a cell wall;
• Inside the cell is the cytoplasmic region that contains the cell genome (DNA) and ribosomes and various sorts of
inclusions. A prokaryotic chromosome is usually a circular molecule (an exception is that of the bacterium
Borrelia burgdorferi, which causes Lyme disease). Though not forming a nucleus, the DNA is condensed in a
nucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular.
Plasmids enable additional functions, such as antibiotic resistance.
Cells 13

Eukaryotic cells
Plants, animals, fungi, slime moulds, protozoa, & algae are all Eukaryotic. These cells are about 15 times wider than
a typical prokaryote and can be as much as 1000 times greater in volume. The major difference between prokaryotes
and eukaryotes is that eukaryotic cells contain membrane-bound compartments in which specific metabolic activities
take place. Most important among these is a cell nucleus, a membrane-delineated compartment that houses the
eukaryotic cell's DNA. This nucleus gives the eukaryote its name, which means "true nucleus." Other differences
include:
• The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls
may or may not be present.
• The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated
with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by a
membrane. Some eukaryotic organelles such as mitochondria also contain some DNA.
• Many eukaryotic cells are ciliated with primary cilia. Primary cilia play important roles in chemosensation,
mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory cellular antennae that coordinate a
large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively
to cell division and differentiation."[7]
• Eukaryotes can move using motile cilia or flagella. The flagella are more complex than those of prokaryotes.

Structure of a typical animal cell Structure of a typical plant cell

Table 2: Comparison of structures between animal and plant cells

Typical animal cell Typical plant cell

Organelles • Nucleus • Nucleus

• Nucleolus (within nucleus) • Nucleolus (within nucleus)
• Rough endoplasmic reticulum (ER) • Rough ER
• Smooth ER • Smooth ER
• Ribosomes • Ribosomes
• Cytoskeleton • Cytoskeleton
• Golgi apparatus • Golgi apparatus (dictiosomes)
• Cytoplasm • Cytoplasm
• Mitochondria • Mitochondria
• Vesicles • Plastids and its derivatives
• Lysosomes • Vacuole(s)
• Centrosome • Cell wall
• Centrioles
Cells 14

Subcellular components
All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates its interior from its
environment, regulates what moves in and out (selectively permeable), and maintains the electric potential of the
cell. Inside the membrane, a salty cytoplasm takes up most of the cell volume. All cells possess DNA, the hereditary
material of genes, and RNA, containing the information necessary to build various proteins such as enzymes, the
cell's primary machinery. There are also other kinds of biomolecules in cells. This article lists these primary
components of the cell, then briefly describe their function.

Membrane
The cytoplasm of a cell is surrounded by a cell membrane or plasma membrane. The plasma membrane in plants and
prokaryotes is usually covered by a cell wall. This membrane serves to separate and protect a cell from its
surrounding environment and is made mostly from a double layer of lipids (hydrophobic fat-like molecules) and
hydrophilic phosphorus molecules. Hence, the layer is called a phospholipid bilayer. It may also be called a fluid
mosaic membrane. Embedded within this membrane is a variety of protein molecules that act as channels and pumps
that move different molecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can
either let a substance (molecule or ion) pass through freely, pass through to a limited extent or not pass through at all.
Cell surface membranes also contain receptor proteins that allow cells to detect external signaling molecules such as
hormones.

Cytoskeleton
The cytoskeleton acts to organize and maintain the
cell's shape; anchors organelles in place; helps during
endocytosis, the uptake of external materials by a cell,
and cytokinesis, the separation of daughter cells after
cell division; and moves parts of the cell in processes of
growth and mobility. The eukaryotic cytoskeleton is
composed of microfilaments, intermediate filaments
and microtubules. There is a great number of proteins
associated with them, each controlling a cell's structure
by directing, bundling, and aligning filaments. The
prokaryotic cytoskeleton is less well-studied but is
involved in the maintenance of cell shape, polarity and
cytokinesis.[8] Bovine Pulmonary Artery Endothelial cell: nuclei stained blue,
mitochondria stained red, and F-actin, an important component in
microfilaments, stained green. Cell imaged on a fluorescent
Genetic material microscope.

Two different kinds of genetic material exist:

deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Most organisms use DNA for their long-term information
storage, but some viruses (e.g., retroviruses) have RNA as their genetic material. The biological information
contained in an organism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g.,
mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic code itself.
Transfer RNA (tRNA) molecules are used to add amino acids during protein translation.

Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial chromosome) in the
nucleoid region of the cytoplasm. Eukaryotic genetic material is divided into different, linear molecules called
chromosomes inside a discrete nucleus, usually with additional genetic material in some organelles like mitochondria
and chloroplasts (see endosymbiotic theory).
Cells 15

A human cell has genetic material contained in the cell nucleus (the nuclear genome) and in the mitochondria (the
mitochondrial genome). In humans the nuclear genome is divided into 23 pairs of linear DNA molecules called
chromosomes. The mitochondrial genome is a circular DNA molecule distinct from the nuclear DNA. Although the
mitochondrial DNA is very small compared to nuclear chromosomes, it codes for 13 proteins involved in
mitochondrial energy production and specific tRNAs.
Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a process called
transfection. This can be transient, if the DNA is not inserted into the cell's genome, or stable, if it is. Certain viruses
also insert their genetic material into the genome.

Organelles
The human body contains many different organs, such as the heart, lung, and kidney, with each organ performing a
different function. Cells also have a set of "little organs," called organelles, that are adapted and/or specialized for
carrying out one or more vital functions. Both eukaryotic and prokaryotic cells have organelles but organelles in
eukaryotes are generally more complex and may be membrane bound.
There are several types of organelles in a cell. Some (such as the nucleus and golgi apparatus) are typically solitary,
while others (such as mitochondria, peroxisomes and lysosomes) can be numerous (hundreds to thousands). The
cytosol is the gelatinous fluid that fills the cell and surrounds the organelles.

Cell nucleus – eukaryotes only - a cell's information center

The cell nucleus is the most conspicuous organelle found in a eukaryotic cell. It
houses the cell's chromosomes, and is the place where almost all DNA
replication and RNA synthesis (transcription) occur. The nucleus is spherical and
separated from the cytoplasm by a double membrane called the nuclear envelope.
The nuclear envelope isolates and protects a cell's DNA from various molecules
that could accidentally damage its structure or interfere with its processing.
During processing, DNA is transcribed, or copied into a special RNA, called
messenger RNA (mRNA). This mRNA is then transported out of the nucleus,
where it is translated into a specific protein molecule. The nucleolus is a
specialized region within the nucleus where ribosome subunits are assembled. In
prokaryotes, DNA processing takes place in the cytoplasm.

Diagram of a cell nucleus

Mitochondria and Chloroplasts – eukaryotes only - the power generators

Mitochondria are self-replicating organelles that occur in various numbers,
shapes, and sizes in the cytoplasm of all eukaryotic cells. Mitochondria play a
critical role in generating energy in the eukaryotic cell. Mitochondria generate
the cell's energy by oxidative phosphorylation, using oxygen to release energy
stored in cellular nutrients (typically pertaining to glucose) to generate ATP.
Mitochondria multiply by splitting in two. Respiration occurs in the cell
mitochondria.

Endoplasmic reticulum – eukaryotes only

The endoplasmic reticulum (ER) is the transport network for molecules targeted
for certain modifications and specific destinations, as compared to molecules that
float freely in the cytoplasm. The ER has two forms: the rough ER, which has
ribosomes on its surface and secretes proteins into the cytoplasm, and the smooth
ER, which lacks them. Smooth ER plays a role in calcium sequestration and
release.
Cells 16

Golgi apparatus – eukaryotes only

The primary function of the Golgi apparatus is to process and package the
macromolecules such as proteins and lipids that are synthesized by the cell.

Diagram of an endomembrane system

Ribosomes
The ribosome is a large complex of RNA and protein molecules. They each
consist of two subunits, and act as an assembly line where RNA from the nucleus
is used to synthesise proteins from amino acids. Ribosomes can be found either
floating freely or bound to a membrane (the rough endoplasmatic reticulum in
[9]
eukaryotes, or the cell membrane in prokaryotes).

Lysosomes and Peroxisomes – eukaryotes only

Lysosomes contain digestive enzymes (acid hydrolases). They digest excess or worn-out organelles, food particles, and engulfed viruses or
bacteria. Peroxisomes have enzymes that rid the cell of toxic peroxides. The cell could not house these destructive enzymes if they were not
contained in a membrane-bound system.

Centrosome – the cytoskeleton organiser

The centrosome produces the microtubules of a cell – a key component of the cytoskeleton. It directs the transport through the ER and the
Golgi apparatus. Centrosomes are composed of two centrioles, which separate during cell division and help in the formation of the mitotic
spindle. A single centrosome is present in the animal cells. They are also found in some fungi and algae cells.

Vacuoles
Vacuoles store food and waste. Some vacuoles store extra water. They are often described as liquid filled space and are surrounded by a
membrane. Some cells, most notably Amoeba, have contractile vacuoles, which can pump water out of the cell if there is too much water.
The vacuoles of eukaryotic cells are usually larger in those of plants than animals.

Structures outside the cell wall

Capsule
A gelatinous capsule is present in some bacteria outside the cell wall. The capsule may be polysaccharide as in
pneumococci, meningococci or polypeptide as Bacillus anthracis or hyaluronic acid as in streptococci. Capsules are
not marked by ordinary stain and can be detected by special stain.

Flagella
Flagella are the organelles of cellular mobility. They arise from cytoplasm and extrude through the cell wall. They
are long and thick thread-like appendages, protein in nature. Are most commonly found in bacteria cells but are
found in animal cells as well.
Cells 17

Fimbriae (pili)
They are short and thin hair like filaments, formed of protein called pilin (antigenic). Fimbriae are responsible for
attachment of bacteria to specific receptors of human cell (adherence). There are special types of pili called (sex pili)
involved in conjunction.

Functions

Growth and metabolism

Between successive cell divisions, cells grow through the functioning of cellular metabolism. Cell metabolism is the
process by which individual cells process nutrient molecules. Metabolism has two distinct divisions: catabolism, in
which the cell breaks down complex molecules to produce energy and reducing power, and anabolism, in which the
cell uses energy and reducing power to construct complex molecules and perform other biological functions.
Complex sugars consumed by the organism can be broken down into a less chemically complex sugar molecule
called glucose. Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of
energy, through two different pathways.
The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each reaction is
designed to produce some hydrogen ions that can then be used to make energy packets (ATP). In prokaryotes,
glycolysis is the only method used for converting energy.
The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and can generate
enough ATP to run all the cell functions.
Cells 18

Creation
Cell division involves a single cell (called a mother cell) dividing into two daughter
cells. This leads to growth in multicellular organisms (the growth of tissue) and to
procreation (vegetative reproduction) in unicellular organisms.
Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of
nuclear division, called mitosis, followed by division of the cell, called cytokinesis. A
diploid cell may also undergo meiosis to produce haploid cells, usually four. Haploid
cells serve as gametes in multicellular organisms, fusing to form new diploid cells.
DNA replication, or the process of duplicating a cell's genome, is required every time a
cell divides. Replication, like all cellular activities, requires specialized proteins for An overview of protein
carrying out the job. synthesis.Within the
nucleus of the cell (light
blue), genes (DNA, dark
Protein synthesis blue) are transcribed into
RNA. This RNA is then
Cells are capable of synthesizing new proteins, which are essential for the modulation
subject to
and maintenance of cellular activities. This process involves the formation of new post-transcriptional
protein molecules from amino acid building blocks based on information encoded in modification and control,
DNA/RNA. Protein synthesis generally consists of two major steps: transcription and resulting in a mature
mRNA (red) that is then
translation.
transported out of the
Transcription is the process where genetic information in DNA is used to produce a nucleus and into the
complementary RNA strand. This RNA strand is then processed to give messenger RNA cytoplasm (peach), where
it undergoes translation
(mRNA), which is free to migrate through the cell. mRNA molecules bind to
into a protein. mRNA is
protein-RNA complexes called ribosomes located in the cytosol, where they are translated by ribosomes
translated into polypeptide sequences. The ribosome mediates the formation of a (purple) that match the
polypeptide sequence based on the mRNA sequence. The mRNA sequence directly three-base codons of the
mRNA to the three-base
relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter
anti-codons of the
molecules in binding pockets within the ribosome. The new polypeptide then folds into a appropriate tRNA. Newly
functional three-dimensional protein molecule. synthesized proteins
(black) are often further
modified, such as by
Movement or motility binding to an effector
molecule (orange), to
Cells can move during many processes: such as wound healing, the immune response become fully active.
and cancer metastasis. For wound healing to occur, white blood cells and cells that ingest
bacteria move to the wound site to kill the microorganisms that cause infection.
At the same time fibroblasts (connective tissue cells) move there to remodel damaged structures. In the case of tumor
development, cells from a primary tumor move away and spread to other parts of the body. Cell motility involves
many receptors, crosslinking, bundling, binding, adhesion, motor and other proteins.[10] The process is divided into
three steps – protrusion of the leading edge of the cell, adhesion of the leading edge and de-adhesion at the cell body
and rear, and cytoskeletal contraction to pull the cell forward. Each step is driven by physical forces generated by
unique segments of the cytoskeleton.[11] [12]
Cells 19

Evolution
The origin of cells has to do with the origin of life, which began the history of life on Earth.

Origin of the first cell

Further information: Abiogenesis
There are several theories about the origin of small molecules that could lead to life in an early Earth. One is that
they came from meteorites (see Murchison meteorite). Another is that they were created at deep-sea vents. A third is
that they were synthesized by lightning in a reducing atmosphere (see Miller–Urey experiment); although it is not
clear if Earth had such an atmosphere. There are essentially no experimental data defining what the first
self-replicating forms were. RNA is generally assumed the earliest self-replicating molecule, as it is capable of both
storing genetic information and catalyzing chemical reactions (see RNA world hypothesis). But some other entity
with the potential to self-replicate could have preceded RNA, like clay or peptide nucleic acid.[13]
Cells emerged at least 4.0–4.3 billion years ago. The current belief is that these cells were heterotrophs. An
important characteristic of cells is the cell membrane, composed of a bilayer of lipids. The early cell membranes
were probably more simple and permeable than modern ones, with only a single fatty acid chain per lipid. Lipids are
known to spontaneously form bilayered vesicles in water, and could have preceded RNA, but the first cell
membranes could also have been produced by catalytic RNA, or even have required structural proteins before they
could form.[14]

Origin of eukaryotic cells

The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearing
organelles like the mitochondria and the chloroplasts are almost certainly what remains of ancient symbiotic
oxygen-breathing proteobacteria and cyanobacteria, respectively, where the rest of the cell appears derived from an
ancestral archaean prokaryote cell—an idea called the endosymbiotic theory.
There is still considerable debate about whether organelles like the hydrogenosome predated the origin of
mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.
Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant eukaryotes, may have
played a role in the transition from prokaryotes to eukaryotes. An 'origin of sex as vaccination' theory suggests that
the eukaryote genome accreted from prokaryan parasite genomes in numerous rounds of lateral gene transfer.
Sex-as-syngamy (fusion sex) arose when infected hosts began swapping nuclearized genomes containing co-evolved,
vertically transmitted symbionts that conveyed protection against horizontal infection by more virulent
symbionts.[15]

History
• 1632–1723: Antonie van Leeuwenhoek teaches himself to grind lenses, builds a microscope and draws protozoa,
such as Vorticella from rain water, and bacteria from his own mouth.
• 1665: Robert Hooke discovers cells in cork, then in living plant tissue using an early microscope.[6]
• 1839: Theodor Schwann and Matthias Jakob Schleiden elucidate the principle that plants and animals are made of
cells, concluding that cells are a common unit of structure and development, and thus founding the cell theory.
• The belief that life forms can occur spontaneously (generatio spontanea) is contradicted by Louis Pasteur
(1822–1895) (although Francesco Redi had performed an experiment in 1668 that suggested the same
conclusion).
• 1855: Rudolf Virchow states that cells always emerge from cell divisions (omnis cellula ex cellula).
• 1931: Ernst Ruska builds first transmission electron microscope (TEM) at the University of Berlin. By 1935, he
has built an EM with twice the resolution of a light microscope, revealing previously unresolvable organelles.
Cells 20

• 1953: Watson and Crick made their first announcement on the double-helix structure for DNA on February 28.
• 1981: Lynn Margulis published Symbiosis in Cell Evolution detailing the endosymbiotic theory.

References
[1] Cell Movements and the Shaping of the Vertebrate Body (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search& db=books&
doptcmdl=GenBookHL& term=Cell+ Movements+ and+ the+ Shaping+ of+ the+ Vertebrate+ Body+ AND+ mboc4[book]+ AND+
374635[uid]& rid=mboc4. section. 3919) in Chapter 21 of Molecular Biology of the Cell (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query.
fcgi?cmd=Search& db=books& doptcmdl=GenBookHL& term=cell+ biology+ AND+ mboc4[book]+ AND+ 373693[uid]& rid=mboc4)
fourth edition, edited by Bruce Alberts (2002) published by Garland Science.
The Alberts text discusses how the "cellular building blocks" move to shape developing embryos. It is also common to describe small
molecules such as amino acids as " molecular building blocks (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search&
db=books& doptcmdl=GenBookHL& term="all+ cells"+ AND+ mboc4[book]+ AND+ 372023[uid]& rid=mboc4. section. 4#23)".
[2] Integrative Biology 131 - Lecture 03: Skeletal System (https:/ / www. youtube. com/ watch?v=EvrWHa1PLUQ) on YouTube first 12 minutes
of the lecture covers cells (by Marian Diamond).
[3] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[4] Mitzi Perdue. "Facts about Birds and Eggs" (http:/ / www. eggscape. com/ birds. htm). . Retrieved 2010-04-15.
[5] Maton, Anthea; Hopkins, Jean Johnson, Susan LaHart, David Quon Warner, Maryanna Wright, Jill D (1997). Cells Building Blocks of Life.
New Jersey: Prentice Hall. ISBN 0-13-423476-6.
[6] "... I could exceedingly plainly perceive it to be all perforated and porous, much like a Honey-comb, but that the pores of it were not regular
[..] these pores, or cells, [..] were indeed the first microscopical pores I ever saw, and perhaps, that were ever seen, for I had not met with any
Writer or Person, that had made any mention of them before this. . ." – Hooke describing his observations on a thin slice of cork. Robert
Hooke (http:/ / www. ucmp. berkeley. edu/ history/ hooke. html)
[7] Satir, P; Christensen, ST; Søren T. Christensen (2008-03-26). "Structure and function of mammalian cilia" (http:/ / www. springerlink. com/
content/ x5051hq648t3152q/ ). Histochemistry and Cell Biology (Springer Berlin / Heidelberg) 129 (6): 687–693.
doi:10.1007/s00418-008-0416-9. PMC 2386530. PMID 18365235. 1432-119X. . Retrieved 2009-09-12.
[8] Michie K, Löwe J (2006). "Dynamic filaments of the bacterial cytoskeleton". Annu Rev Biochem 75: 467–92.
doi:10.1146/annurev.biochem.75.103004.142452. PMID 16756499.
[9] Ménétret JF, Schaletzky J, Clemons WM, et al., CW; Akey (December 2007). "Ribosome binding of a single copy of the SecY complex:
implications for protein translocation". Mol. Cell 28 (6): 1083–92. doi:10.1016/j.molcel.2007.10.034. PMID 18158904.
[10] Revathi Ananthakrishnan1 *, Allen Ehrlicher2 ✉. "The Forces Behind Cell Movement" (http:/ / www. biolsci. org/ v03p0303. htm).
Biolsci.org. . Retrieved 2009-04-17.
[11] Alberts B, Johnson A, Lewis J. et al. Molecular Biology of the Cell, 4e. Garland Science. 2002
[12] Ananthakrishnan R, Ehrlicher A. The Forces Behind Cell Movement. Int J Biol Sci 2007; 3:303–317. http:/ / www. biolsci. org/ v03p0303.
htm
[13] Orgel LE (1998). "The origin of life--a review of facts and speculations". Trends Biochem Sci 23 (12): 491–5.
doi:10.1016/S0968-0004(98)01300-0. PMID 9868373.
[14] Griffiths G (December 2007). "Cell evolution and the problem of membrane topology". Nature reviews. Molecular cell biology 8 (12):
1018–24. doi:10.1038/nrm2287. PMID 17971839.
[15] Sterrer W (2002). "On the origin of sex as vaccination". Journal of Theoretical Biology 216: 387–396. doi:10.1006/jtbi.2002.3008.
PMID 12151256.

•  This article incorporates public domain material from the NCBI document "Science Primer" (http://www.
ncbi.nlm.nih.gov/About/primer/index.html).

External links
• Inside the Cell (http://publications.nigms.nih.gov/insidethecell/)
• Virtual Cell's Educational Animations (http://vcell.ndsu.nodak.edu/animations/)
• The Inner Life of A Cell (http://www.studiodaily.com/main/searchlist/6850.html), a flash video showing
what happens inside of a cell. Daniel Reda of Singularity University narrates (beginning at 22:24) (http://www.
youtube.com/watch?v=It83JKAxejM)
• The Virtual Cell (http://www.ibiblio.org/virtualcell/tour/cell/cell.htm)
• Cells Alive! (http://www.cellsalive.com/)
• Journal of Cell Biology (http://www.jcb.org/)
Cells 21

• The Biology Project > Cell Biology (http://www.biology.arizona.edu/cell_bio/cell_bio.html)

• Centre of the Cell online (http://www.centreofthecell.org/)
• The Image & Video Library of The American Society for Cell Biology (http://cellimages.ascb.org/), a
collection of peer-reviewed still images, video clips and digital books that illustrate the structure, function and
biology of the cell.
• HighMag Blog (http://highmagblog.blogspot.com/), still images of cells from recent research articles.
• New Microscope Produces Dazzling 3D Movies of Live Cells (http://www.hhmi.org/news/betzig20110304.
html), March 4, 2011 - Howard Hughes Medical Institute.
• WormWeb.org: Interactive Visualization of the C. elegans Cell lineage (http://wormweb.org/celllineage) -
Visualize the entire cell lineage tree of the nematode C. elegans

Textbooks
• Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell (http://www.
ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.TOC&depth=2) (4th ed.). Garland. ISBN 0815332181.
• Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipurksy SL, Darnell J (2004). Molecular
Cell Biology (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.TOC) (5th ed.). WH Freeman: New
York, NY. ISBN 978-0716743668.
• Cooper GM (2000). The cell: a molecular approach (http://www.ncbi.nlm.nih.gov/books/bv.
fcgi?rid=cooper.TOC&depth=2) (2nd ed.). Washington, D.C: ASM Press. ISBN 0-87893-102-3.

Water
Water is a chemical substance with the
chemical formula H2O. A water molecule
contains one oxygen and two hydrogen
atoms connected by covalent bonds. Water
is a liquid at ambient conditions, but it often
co-exists on Earth with its solid state, ice,
and gaseous state (water vapor or steam).
Water also exists in a liquid crystal state
near hydrophilic surfaces.[1] [2] Under
nomenclature used to name chemical
compounds, Dihydrogen monoxide is the
scientific name for water, though it is almost Water in three states: liquid, solid (ice), and (invisible) water vapor in the air.
Clouds are accumulations of water droplets, condensed from vapor-saturated air.
never used.[3]

Water covers 70.9% of the Earth's surface,[4] and is vital for all known forms of life.[5] On Earth, 96.5% of the
planet's water is found mostly in oceans; 1.7% in groundwater; 1.7% in glaciers and the ice caps of Antarctica and
Greenland; a small fraction in other large water bodies, and 0.001% in the air as vapor, clouds (formed of solid and
liquid water particles suspended in air), and precipitation.[6] [7] Only 2.5% of the Earth's water is freshwater, and
98.8% of that water is in ice and groundwater. Less than 0.3% of all freshwater is in rivers, lakes, and the
atmosphere, and an even smaller amount of the Earth's freshwater (0.003%) is contained within biological bodies
and manufactured products.[6]

Water on Earth moves continually through the hydrological cycle of evaporation and transpiration
(evapotranspiration), condensation, precipitation, and runoff, usually reaching the sea. Evaporation and transpiration
contribute to the precipitation over land.
Water 22

Safe drinking water is essential to humans and other lifeforms. Access to safe drinking water has improved over the
last decades in almost every part of the world, but approximately one billion people still lack access to safe water and
over 2.5 billion lack access to adequate sanitation.[8] There is a clear correlation between access to safe water and
GDP per capita.[9] However, some observers have estimated that by 2025 more than half of the world population will
be facing water-based vulnerability.[10] A recent report (November 2009) suggests that by 2030, in some developing
regions of the world, water demand will exceed supply by 50%.[11] Water plays an important role in the world
economy, as it functions as a solvent for a wide variety of chemical substances and facilitates industrial cooling and
transportation. Approximately 70% of the fresh water used by humans goes to agriculture.[12]

Chemical and physical properties

Water is the chemical substance with chemical formula H2O: one
molecule of water has two hydrogen atoms covalently bonded to a
single oxygen atom.
Water appears in nature in all three common states of matter and may
take many different forms on Earth: water vapor and clouds in the sky;
seawater and icebergs in the polar oceans; glaciers and rivers in the
mountains; and the liquid in aquifers in the ground.
At high temperatures and pressures, such as in the interior of giant
planets, it is argued that water exists as ionic water in which the
molecules break down into a soup of hydrogen and oxygen ions, and at
even higher pressures as superionic water in which the oxygen
Model of hydrogen bonds (1) between molecules
crystallises but the hydrogen ions float around freely within the oxygen
of water
lattice.[13]

The major chemical and physical properties of water are:

• Water is a liquid at standard temperature and pressure. It is tasteless
and odorless. The intrinsic colour of water and ice is a very slight
blue hue, although both appear colorless in small quantities. Water
vapour is essentially invisible as a gas.[14]
• Water is transparent in the visible electromagnetic spectrum. Thus
aquatic plants can live in water because sunlight can reach them.
Infrared light is strongly absorbed by the hydrogen-oxygen or OH
Impact from a water drop causes an upward bonds.
"rebound" jet surrounded by circular capillary
• Since the water molecule is not linear and the oxygen atom has a
waves.
higher electronegativity than hydrogen atoms, it carries a slight
negative charge, whereas the hydrogen atoms are slightly positive. As a result, water is a polar molecule with an
electrical dipole moment. Water also can form an unusually large number of intermolecular hydrogen bonds
(four) for a molecule of its size. These factors lead to strong attractive forces between molecules of water, giving
rise to water's high surface tension[15] and capillary forces. The capillary action refers to the tendency of water to
move up a narrow tube against the force of gravity. This property is relied upon by all vascular plants, such as
trees.[16]
Water 23

• Water is a good solvent and is often referred to as the universal

solvent. Substances that dissolve in water, e.g., salts, sugars, acids,
alkalis, and some gases – especially oxygen, carbon dioxide
(carbonation) are known as hydrophilic (water-loving) substances,
while those that do not mix well with water (e.g., fats and oils), are
known as hydrophobic (water-fearing) substances.
• All the major components in cells (proteins, DNA and
polysaccharides) are also dissolved in water.
• Pure water has a low electrical conductivity, but this increases
significantly with the dissolution of a small amount of ionic material
such as sodium chloride.
• The boiling point of water (and all other liquids) is dependent on the
barometric pressure. For example, on the top of Mt. Everest water
boils at 68 °C (154 °F), compared to 100 °C (212 °F) at sea level.
Conversely, water deep in the ocean near geothermal vents can Snowflakes by Wilson Bentley, 1902
reach temperatures of hundreds of degrees and remain liquid.
• At 4181.3 J/(kg·K), water has the second highest specific heat
capacity of any known substance (after ammonia), as well as a high
heat of vaporization (40.65 kJ·mol−1), both of which are a result of
the extensive hydrogen bonding between its molecules. These two
unusual properties allow water to moderate Earth's climate by
buffering large fluctuations in temperature.
• The maximum density of water occurs at 3.98 °C (39.16 °F).[17] It
has the anomalous property of becoming less dense, not more, when
it is cooled down to its solid form, ice. It expands to occupy 9%
greater volume in this solid state, which accounts for the fact of ice Dew drops adhering to a spider web

floating on liquid water, as in icebergs.

• Its density is 1,000 kg/m3 liquid (4 °C), weighs 62.4 lb/ft.3
(917 kg/m3, solid). It weighs 8.3454 lb/gal. (US, liquid).[18]

Capillary action of water compared to mercury

Water 24

• Water is miscible with many liquids, such as ethanol, in all

proportions, forming a single homogeneous liquid. On the other
hand, water and most oils are immiscible, usually forming layers
according to increasing density from the top. As a gas, water vapor
is completely miscible with air.
• Water forms an azeotrope with many other solvents.
• Water can be split by electrolysis into hydrogen and oxygen.
• As an oxide of hydrogen, water is formed when hydrogen or
hydrogen-containing compounds burn or react with oxygen or
oxygen-containing compounds. Water is not a fuel, it is an
end-product of the combustion of hydrogen. The energy required to
split water into hydrogen and oxygen by electrolysis or any other ADR label for transporting goods dangerously
means is greater than the energy that can be collected when the reactive with water
hydrogen and oxygen recombine.[19]
• Elements which are more electropositive than hydrogen such as lithium, sodium, calcium, potassium and caesium
displace hydrogen from water, forming hydroxides. Being a flammable gas, the hydrogen given off is dangerous
and the reaction of water with the more electropositive of these elements may be violently explosive.

Taste and odor

Water can dissolve many different substances, giving it varying tastes and odors. Humans and other animals have
developed senses that enable them to evaluate the potability of water by avoiding water that is too salty or putrid.
The taste of spring water and mineral water, often advertised in marketing of consumer products, derives from the
minerals dissolved in it. However, pure H2O is tasteless and odorless. The advertised purity of spring and mineral
water refers to absence of toxins, pollutants and microbes, not the absence of naturally occurring minerals.

Distribution in nature

In the universe
Much of the universe's water is produced as a byproduct of star formation. When stars are born, their birth is
accompanied by a strong outward wind of gas and dust. When this outflow of material eventually impacts the
surrounding gas, the shock waves that are created compress and heat the gas. The water observed is quickly
produced in this warm dense gas.[20]
On 22 July 2011, a report described the discovery of a gigantic cloud of water vapor, containing "140 trillion times
more water than all of Earth's oceans combined," around a quasar located 12 billion light years from Earth.
According to the researchers, the "discovery shows that water has been prevalent in the universe for nearly its entire
existence."[21] [22]
Water has been detected in interstellar clouds within our galaxy, the Milky Way. Water probably exists in abundance
in other galaxies, too, because its components, hydrogen and oxygen, are among the most abundant elements in the
universe. Interstellar clouds eventually condense into solar nebulae and solar systems such as ours.
Water vapor is present in
• Atmosphere of Mercury: 3.4%, and large amounts of water in Mercury's exosphere[23]
• Atmosphere of Venus: 0.002%
• Earth's atmosphere: ~0.40% over full atmosphere, typically 1–4% at surface
• Atmosphere of Mars: 0.03%
• Atmosphere of Jupiter: 0.0004%
Water 25

• Atmosphere of Saturn – in ices only

• Enceladus (moon of Saturn): 91%
• exoplanets known as HD 189733 b[24] and HD 209458 b.[25]
Liquid water is present on
• Earth: 71% of surface
• Europa: 100 km deep subsurface ocean
Strong evidence suggests that liquid water is present just under the surface of Saturn's moon Enceladus.
Water ice is present on
• Earth – mainly as ice sheets
• polar ice caps on Mars
• Moon
• Titan
• Europa
• Saturn's rings[26]
• Enceladus
• Pluto and Charon[26]
• Comets and comet source populations (Kuiper belt and Oort cloud objects).
Water ice may be present on Ceres and Tethys. Water and other volatiles probably comprise much of the internal
structures of Uranus and Neptune and the water in the deeper layers may be in the form of ionic water in which the
molecules break down into a soup of hydrogen and oxygen ions, and deeper down as superionic water in which the
oxygen crystallises but the hydrogen ions float around freely within the oxygen lattice.[13]
Some of the Moon's minerals contain water molecules. For instance, in 2008 a laboratory device which ejects and
identifies particles found small amounts of the compound in the inside of volcanic rock brought from Moon to Earth
by the Apollo 15 crew in 1971.[27] NASA reported the detection of water molecules by NASA's Moon Mineralogy
Mapper aboard the Indian Space Research Organization's Chandrayaan-1 spacecraft in September 2009.[28]

Water and habitable zone

The existence of liquid water, and to a lesser extent its gaseous and solid forms, on Earth are vital to the existence of
life on Earth as we know it. The Earth is located in the habitable zone of the solar system; if it were slightly closer to
or farther from the Sun (about 5%, or about 8 million kilometers), the conditions which allow the three forms to be
present simultaneously would be far less likely to exist.[29] [30]
Earth's gravity allows it to hold an atmosphere. Water vapor and carbon dioxide in the atmosphere provide a
temperature buffer (greenhouse effect) which helps maintain a relatively steady surface temperature. If Earth were
smaller, a thinner atmosphere would allow temperature extremes, thus preventing the accumulation of water except
in polar ice caps (as on Mars).
The surface temperature of Earth has been relatively constant through geologic time despite varying levels of
incoming solar radiation (insolation), indicating that a dynamic process governs Earth's temperature via a
combination of greenhouse gases and surface or atmospheric albedo. This proposal is known as the Gaia hypothesis.
The state of water on a planet depends on ambient pressure, which is determined by the planet's gravity. If a planet is
sufficiently massive, the water on it may be solid even at high temperatures, because of the high pressure caused by
gravity, as it was observed on exoplanets Gliese 436 b[31] and GJ 1214 b.[32]
There are various theories about origin of water on Earth.
Water 26

On Earth
Hydrology is the study of the
movement, distribution, and quality of
water throughout the Earth. The study
of the distribution of water is
hydrography. The study of the
distribution and movement of
groundwater is hydrogeology, of
glaciers is glaciology, of inland waters
is limnology and distribution of oceans
is oceanography. Ecological processes
with hydrology are in focus of
ecohydrology.

The collective mass of water found on,

under, and over the surface of a planet
A graphical distribution of the locations of water on Earth.
is called the hydrosphere. Earth's
approximate water volume (the total
water supply of the world) is
1,338,000,000 km3
(321,000,000 mi3).[6]

Liquid water is found in bodies of

water, such as an ocean, sea, lake,
river, stream, canal, pond, or puddle.
The majority of water on Earth is sea
water. Water is also present in the
atmosphere in solid, liquid, and vapor
states. It also exists as groundwater in
aquifers.
Water covers 71% of the Earth's surface; the
Water is important in many geological oceans contain 96.5% of the Earth's water. The
processes. Groundwater is present in Antarctic ice sheet, which contains 61% of all
most rocks, and the pressure of this fresh water on Earth, is visible at the bottom.
Condensed atmospheric water can be seen as
groundwater affects patterns of
clouds, contributing to the Earth's albedo.
faulting. Water in the mantle is
responsible for the melt that produces
volcanoes at subduction zones. On the surface of the Earth, water is important in both chemical and physical
weathering processes. Water and, to a lesser but still significant extent, ice, are also responsible for a large amount of
sediment transport that occurs on the surface of the earth. Deposition of transported sediment forms many types of
sedimentary rocks, which make up the geologic record of Earth history.
Water 27

Water cycle
The water cycle (known scientifically
as the hydrologic cycle) refers to the
continuous exchange of water within
the hydrosphere, between the
atmosphere, soil water, surface water,
groundwater, and plants.

Water moves perpetually through each

of these regions in the water cycle
consisting of following transfer
processes:
• evaporation from oceans and other
water bodies into the air and
transpiration from land plants and
animals into air. Water cycle
• precipitation, from water vapor
condensing from the air and falling to earth or ocean.
• runoff from the land usually reaching the sea.
Most water vapor over the oceans returns to the oceans, but winds carry water vapor over land at the same rate as
runoff into the sea, about 47 Tt per year. Over land, evaporation and transpiration contribute another 72 Tt per year.
Precipitation, at a rate of 119 Tt per year over land, has several forms: most commonly rain, snow, and hail, with
some contribution from fog and dew.[33] Condensed water in the air may also refract sunlight to produce rainbows.
Water runoff often collects over watersheds flowing into rivers. A mathematical model used to simulate river or
stream flow and calculate water quality parameters is hydrological transport model. Some of water is diverted to
irrigation for agriculture. Rivers and seas offer opportunity for travel and commerce. Through erosion, runoff shapes
the environment creating river valleys and deltas which provide rich soil and level ground for the establishment of
population centers. A flood occurs when an area of land, usually low-lying, is covered with water. It is when a river
overflows its banks or flood from the sea. A drought is an extended period of months or years when a region notes a
deficiency in its water supply. This occurs when a region receives consistently below average precipitation.

Fresh water storage

The Bay of Fundy at high tide (left) and low tide (right)
Water 28

Some runoff water is trapped for periods of time, for example in lakes. At high altitude, during winter, and in the far
north and south, snow collects in ice caps, snow pack and glaciers. Water also infiltrates the ground and goes into
aquifers. This groundwater later flows back to the surface in springs, or more spectacularly in hot springs and
geysers. Groundwater is also extracted artificially in wells. This water storage is important, since clean, fresh water
is essential to human and other land-based life. In many parts of the world, it is in short supply.

Sea water
Sea water contains about 3.5% salt on average, plus smaller amounts of other substances. The physical properties of
sea water differ from fresh water in some important respects. It freezes at a lower temperature (about −1.9 °C) and its
density increases with decreasing temperature to the freezing point, instead of reaching maximum density at a
temperature above freezing. The salinity of water in major seas varies from about 0.7% in the Baltic Sea to 4.0% in
the Red Sea.

Tides
Tides are the cyclic rising and falling of local sea levels caused by the tidal forces of the Moon and the Sun acting on
the oceans. Tides cause changes in the depth of the marine and estuarine water bodies and produce oscillating
currents known as tidal streams. The changing tide produced at a given location is the result of the changing
positions of the Moon and Sun relative to the Earth coupled with the effects of Earth rotation and the local
bathymetry. The strip of seashore that is submerged at high tide and exposed at low tide, the intertidal zone, is an
important ecological product of ocean tides.

Effects on life
From a biological standpoint, water has many distinct properties that
are critical for the proliferation of life that set it apart from other
substances. It carries out this role by allowing organic compounds to
react in ways that ultimately allow replication. All known forms of life
depend on water. Water is vital both as a solvent in which many of the
body's solutes dissolve and as an essential part of many metabolic
processes within the body. Metabolism is the sum total of anabolism
and catabolism. In anabolism, water is removed from molecules
(through energy requiring enzymatic chemical reactions) in order to
An oasis is an isolated water source with
grow larger molecules (e.g. starches, triglycerides and proteins for
vegetation in a desert
storage of fuels and information). In catabolism, water is used to break
bonds in order to generate smaller molecules (e.g. glucose, fatty acids
and amino acids to be used for fuels for energy use or other purposes). Without water, these particular metabolic
processes could not exist.

Water is fundamental to photosynthesis and respiration. Photosynthetic cells use the sun's energy to split off water's
hydrogen from oxygen. Hydrogen is combined with CO2 (absorbed from air or water) to form glucose and release
oxygen. All living cells use such fuels and oxidize the hydrogen and carbon to capture the sun's energy and reform
water and CO2 in the process (cellular respiration).
Water 29

Water is also central to acid-base neutrality and enzyme function. An

acid, a hydrogen ion (H+, that is, a proton) donor, can be neutralized by
a base, a proton acceptor such as hydroxide ion (OH−) to form water.
Water is considered to be neutral, with a pH (the negative log of the
hydrogen ion concentration) of 7. Acids have pH values less than 7
while bases have values greater than 7.

Overview of photosynthesis and respiration.

Water (at right), together with carbon dioxide
(CO2), form oxygen and organic compounds (at
left), which can be respired to water and (CO2).

Some of the biodiversity of a coral reef

Water 30

Aquatic life forms

Earth surface waters are filled with life. The earliest life forms
appeared in water; nearly all fish live exclusively in water, and there
are many types of marine mammals, such as dolphins and whales.
Some kinds of animals, such as amphibians, spend portions of their
lives in water and portions on land. Plants such as kelp and algae grow
in the water and are the basis for some underwater ecosystems.
Plankton is generally the foundation of the ocean food chain.

Some marine diatoms – a key phytoplankton Aquatic vertebrates must obtain oxygen to survive, and they do so in
group various ways. Fish have gills instead of lungs, although some species
of fish, such as the lungfish, have both. Marine mammals, such as
dolphins, whales, otters, and seals need to surface periodically to breathe air. Some amphibians are able to absorb
oxygen through their skin. Invertebrates exhibit a wide range of modifications to survive in poorly oxygenated
waters including breathing tubes (see insect and mollusc siphons) and gills (Carcinus). However as invertebrate life
evolved in an aquatic habitat most have little or no specialisation for respiration in water.

Effects on human civilization

Civilization has historically flourished around rivers and major
waterways; Mesopotamia, the so-called cradle of civilization, was
situated between the major rivers Tigris and Euphrates; the ancient
society of the Egyptians depended entirely upon the Nile. Large
metropolises like Rotterdam, London, Montreal, Paris, New York City,
Buenos Aires, Shanghai, Tokyo, Chicago, and Hong Kong owe their
success in part to their easy accessibility via water and the resultant
expansion of trade. Islands with safe water ports, like Singapore, have
flourished for the same reason. In places such as North Africa and the
Water fountain
Middle East, where water is more scarce, access to clean drinking
water was and is a major factor in human development.

Health and pollution

Environmental Science Program, Iowa State
University student sampling water.
bathing may be maintained in satisfactory microbiological condition using chemical disinfectants such as chlorine or
ozone or by the use of ultraviolet light.
Water fit for human consumption is called drinking water or potable
water. Water that is not potable may be made potable by filtration or
distillation, or by a range of other methods.
Water that is not fit for drinking but is not harmful for humans when
used for swimming or bathing is called by various names other than
potable or drinking water, and is sometimes called safe water, or "safe
for bathing". Chlorine is a skin and mucous membrane irritant that is
used to make water safe for bathing or drinking. Its use is highly
technical and is usually monitored by government regulations
(typically 1 part per million (ppm) for drinking water, and 1–2 ppm of
chlorine not yet reacted with impurities for bathing water). Water for
Water 31

In the USA, non-potable forms of wastewater generated by humans may be referred to as greywater, which is
treatable and thus easily able to be made potable again, and blackwater, which generally contains sewage and other
forms of waste which require further treatment in order to be made reusable. Greywater composes 50–80% of
residential wastewater generated by a household's sanitation equipment (sinks, showers and kitchen runoff, but not
toilets, which generate blackwater.) These terms may have different meanings in other countries and cultures.
This natural resource is becoming scarcer in certain places, and its availability is a major social and economic
concern. Currently, about a billion people around the world routinely drink unhealthy water. Most countries accepted
the goal of halving by 2015 the number of people worldwide who do not have access to safe water and sanitation
during the 2003 G8 Evian summit.[34] Even if this difficult goal is met, it will still leave more than an estimated half
a billion people without access to safe drinking water and over a billion without access to adequate sanitation. Poor
water quality and bad sanitation are deadly; some five million deaths a year are caused by polluted drinking water.
The World Health Organization estimates that safe water could prevent 1.4 million child deaths from diarrhea each
year.[35] Water, however, is not a finite resource, but rather re-circulated as potable water in precipitation in
quantities many degrees of magnitude higher than human consumption. Therefore, it is the relatively small quantity
of water in reserve in the earth (about 1% of our drinking water supply, which is replenished in aquifers around
every 1 to 10 years), that is a non-renewable resource, and it is, rather, the distribution of potable and irrigation water
which is scarce, rather than the actual amount of it that exists on the earth. Water-poor countries use importation of
goods as the primary method of importing water (to leave enough for local human consumption), since the
manufacturing process uses around 10 to 100 times products' masses in water.
In the developing world, 90% of all wastewater still goes untreated into local rivers and streams.[36] Some 50
countries, with roughly a third of the world’s population, also suffer from medium or high water stress, and 17 of
these extract more water annually than is recharged through their natural water cycles.[37] The strain not only affects
surface freshwater bodies like rivers and lakes, but it also degrades groundwater resources.

Human uses
Further information: Water supply

Agriculture

The most important use of water in agriculture is for irrigation, which

is a key component to produce enough food. Irrigation takes up to 90%
of water withdrawn in some developing countries[38] and significant
proportions in more economically developed countries (United States,
30% of freshwater usage is for irrigation).[39] It takes around 3,000
litres of water, converted from liquid to vapour, to produce enough
food to satisfy one person's daily dietary need. This is a considerable
amount, when compared to that required for drinking, which is
between two and five litres. To produce food for the 6.5 billion or so Irrigation of field crops
people who inhabit the planet today requires the water that would fill a
canal ten metres deep, 100 metres wide and 7.1 million kilometres long – that's enough to circle the globe 180 times.

Fifty years ago, the common perception was that water was an infinite resource. At this time, there were fewer than
half the current number of people on the planet. People were not as wealthy as today, consumed fewer calories and
ate less meat, so less water was needed to produce their food. They required a third of the volume of water we
presently take from rivers. Today, the competition for the fixed amount of water resources is much more intense,
giving rise to the concept of peak water.[40] This is because there are now nearly seven billion people on the planet,
their consumption of water-thirsty meat and vegetables is rising, and there is increasing competition for water from
industry, urbanisation and biofuel crops. In future, even more water will be needed to produce food because the
Water 32

Earth's population is forecast to rise to 9 billion by 2050.[41] An additional 2.5 or 3 billion people, choosing to eat
fewer cereals and more meat and vegetables could add an additional five million kilometres to the virtual canal
mentioned above.
An assessment of water management in agriculture was conducted in 2007 by the International Water Management
Institute in Sri Lanka to see if the world had sufficient water to provide food for its growing population.[42] It
assessed the current availability of water for agriculture on a global scale and mapped out locations suffering from
water scarcity. It found that a fifth of the world's people, more than 1.2 billion, live in areas of physical water
scarcity, where there is not enough water to meet all demands. A further 1.6 billion people live in areas experiencing
economic water scarcity, where the lack of investment in water or insufficient human capacity make it impossible for
authorities to satisfy the demand for water. The report found that it would be possible to produce the food required in
future, but that continuation of today's food production and environmental trends would lead to crises in many parts
of the world. To avoid a global water crisis, farmers will have to strive to increase productivity to meet growing
demands for food, while industry and cities find ways to use water more efficiently.[43]

As a scientific standard
On 7 April 1795, the gram was defined in France to be equal to "the absolute weight of a volume of pure water equal
to a cube of one hundredth of a meter, and to the temperature of the melting ice."[44] For practical purposes though, a
metallic reference standard was required, one thousand times more massive, the kilogram. Work was therefore
commissioned to determine precisely the mass of one liter of water. In spite of the fact that the decreed definition of
the gram specified water at 0 °C — a highly reproducible temperature — the scientists chose to redefine the standard
and to perform their measurements at the temperature of highest water density, which was measured at the time as 4
°C (39 °F).[45]
The Kelvin temperature scale of the SI system is based on the triple point of water, defined as exactly 273.16 K or
0.01 °C. The scale is an absolute temperature scale with the same increment as the Celsius temperature scale, which
was originally defined according the boiling point (set to 100 °C) and melting point (set to 0 °C) of water.
Natural water consists mainly of the isotopes hydrogen-1 and oxygen-16, but there is also small quantity of heavier
isotopes such as hydrogen-2 (deuterium). The amount of deuterium oxides or heavy water is very small, but it still
affects the properties of water. Water from rivers and lakes tends to contain less deuterium than seawater. Therefore,
standard water is defined in the Vienna Standard Mean Ocean Water specification.

For drinking

The human body contains from 55% to 78% water, depending on body
size.[46] To function properly, the body requires between one and
seven liters of water per day to avoid dehydration; the precise amount
depends on the level of activity, temperature, humidity, and other
factors. Most of this is ingested through foods or beverages other than
drinking straight water. It is not clear how much water intake is needed
by healthy people, though most advocates agree that approximately 2
liters (6 to 7 glasses) of water daily is the minimum to maintain proper
hydration.[47] Medical literature favors a lower consumption, typically
A young girl drinking bottled water
1 liter of water for an average male, excluding extra requirements due
to fluid loss from exercise or warm weather.[48] For those who have
healthy kidneys, it is rather difficult to drink too much water, but (especially in warm humid weather and while
exercising) it is
Water 33

dangerous to drink too little. People can drink far more water than
necessary while exercising, however, putting them at risk of water
intoxication (hyperhydration), which can be fatal.[49] [50] The popular
claim that "a person should consume eight glasses of water per day"
seems to have no real basis in science.[51] Similar misconceptions
concerning the effect of water on weight loss and constipation have
also been dispelled.[52] Water quality: fraction of population using
improved water sources by country

An original recommendation for water intake in 1945 by the Food and

Nutrition Board of the United States National Research Council read:
"An ordinary standard for diverse persons is 1 milliliter for each calorie
of food. Most of this quantity is contained in prepared foods."[53] The
latest dietary reference intake report by the United States National
Research Council in general recommended (including food sources):
3.7 liters for men and 2.7 liters of water total for women.[54]
Specifically, pregnant and breastfeeding women need additional fluids
to stay hydrated. The Institute of Medicine (U.S.) recommends that, on
average, men consume 3.0 liters and women 2.2 liters; pregnant
women should increase intake to 2.4 liters (10 cups) and breastfeeding
women should get 3 liters (12 cups), since an especially large amount Hazard symbol for non-potable water
of fluid is lost during nursing.[55] Also noted is that normally, about
20% of water intake comes from food, while the rest comes from drinking water and beverages (caffeinated
included). Water is excreted from the body in multiple forms; through urine and feces, through sweating, and by
exhalation of water vapor in the breath. With physical exertion and heat exposure, water loss will increase and daily
fluid needs may increase as well.

Humans require water with few impurities. Common impurities include metal salts and oxides, including copper,
iron, calcium and lead,[56] and/or harmful bacteria, such as Vibrio. Some solutes are acceptable and even desirable
for taste enhancement and to provide needed electrolytes.[57]
The single largest (by volume) freshwater resource suitable for drinking is Lake Baikal in Siberia.[58]

Washing
The propensity of water to form solutions and emulsions is useful in various washing processes. Many industrial
processes rely on reactions using chemicals dissolved in water, suspension of solids in water slurries or using water
to dissolve and extract substances. Washing is also an important component of several aspects of personal body
hygiene.

Transportation
The use of water for transportation of materials through rivers and canals as well as the international shipping lanes
is an important part of the world economy.
Water 34

Chemical uses
Water is widely used in chemical reactions as a solvent or reactant and less commonly as a solute or catalyst. In
inorganic reactions, water is a common solvent, dissolving many ionic compounds. In organic reactions, it is not
usually used as a reaction solvent, because it does not dissolve the reactants well and is amphoteric (acidic and basic)
and nucleophilic. Nevertheless, these properties are sometimes desirable. Also, acceleration of Diels-Alder reactions
by water has been observed. Supercritical water has recently been a topic of research. Oxygen-saturated supercritical
water combusts organic pollutants efficiently.

Heat exchange
Water and steam are used as heat transfer fluids in diverse heat exchange systems, due to its availability and high
heat capacity, both as a coolant and for heating. Cool water may even be naturally available from a lake or the sea.
Condensing steam is a particularly efficient heating fluid because of the large heat of vaporization. A disadvantage is
that water and steam are somewhat corrosive. In almost all electric power stations, water is the coolant, which
vaporizes and drives steam turbines to drive generators. In the U.S., cooling power plants is the largest use of
water.[39]
In the nuclear power industry, water can also be used as a neutron moderator. In most nuclear reactors, water is both
a coolant and a moderator. This provides something of a passive safety measure, as removing the water from the
reactor also slows the nuclear reaction down – however other methods are favored for stopping a reaction and it is
preferred to keep the nuclear core covered with water so as to ensure adequate cooling.

Fire extinction

Water has a high heat of vaporization and is relatively inert, which

makes it a good fire extinguishing fluid. The evaporation of water
carries heat away from the fire. It is dangerous to use water on fires
involving oils and organic solvents, because many organic materials
float on water and the water tends to spread the burning liquid.
Use of water in fire fighting should also take into account the hazards
of a steam explosion, which may occur when water is used on very hot
fires in confined spaces, and of a hydrogen explosion, when substances
which react with water, such as certain metals or hot carbon such as Water is used for fighting wildfires.

coal, charcoal, coke graphite, decompose the water, producing water

gas.

The power of such explosions was seen in the Chernobyl disaster, although the water involved did not come from
fire-fighting at that time but the reactor's own water cooling system. A steam explosion occurred when the extreme
overheating of the core caused water to flash into steam. A hydrogen explosion may have occurred as a result of
reaction between steam and hot zirconium.
Water 35

Recreation

Humans use water for many recreational purposes, as well as for

exercising and for sports. Some of these include swimming,
waterskiing, boating, surfing and diving. In addition, some sports, like
ice hockey and ice skating, are played on ice. Lakesides, beaches and
waterparks are popular places for people to go to relax and enjoy
recreation. Many find the sound and appearance of flowing water to be
calming, and fountains and other water features are popular
decorations. Some keep fish and other life in aquariums or ponds for
show, fun, and companionship. Humans also use water for snow sports Grand Anse Beach, St. George's, Grenada, West
Indies, often reported as one of the top 10
i.e. skiing, sledding, snowmobiling or snowboarding, which requires
beaches in the world.
the water to be frozen.

Water industry

The water industry provides drinking water and wastewater services

(including sewage treatment) to households and industry. Water supply
facilities include water wells cisterns for rainwater harvesting, water
supply network, water purification facilities, water tanks, water towers,
water pipes including old aqueducts. Atmospheric water generators are
in development.

Drinking water is often collected at springs, extracted from artificial

borings (wells) in the ground, or pumped from lakes and rivers.
Building more wells in adequate places is thus a possible way to
produce more water, assuming the aquifers can supply an adequate
flow. Other water sources include rainwater collection. Water may
require purification for human consumption. This may involve removal
of undissolved substances, dissolved substances and harmful microbes.
Popular methods are filtering with sand which only removes
undissolved material, while chlorination and boiling kill harmful
microbes. Distillation does all three functions. More advanced A water-carrier in India, 1882. In many places
techniques exist, such as reverse osmosis. Desalination of abundant where running water is not available, water has to
seawater is a more expensive solution used in coastal arid climates. be transported by people.

The distribution of drinking water is done through municipal water

systems, tanker delivery or as bottled water. Governments in many
countries have programs to distribute water to the needy at no charge.
Reducing usage by using drinking (potable) water only for human
consumption is another option. In some cities such as Hong Kong, sea
water is extensively used for flushing toilets citywide in order to
conserve fresh water resources.
Polluting water may be the biggest single misuse of water; to the extent
that a pollutant limits other uses of the water, it becomes a waste of the
resource, regardless of benefits to the polluter. Like other types of A manual water pump in China
Water 36

pollution, this does not enter standard accounting of market costs,

being conceived as externalities for which the market cannot account.
Thus other people pay the price of water pollution, while the private
firms' profits are not redistributed to the local population victim of this
pollution. Pharmaceuticals consumed by humans often end up in the
waterways and can have detrimental effects on aquatic life if they
bioaccumulate and if they are not biodegradable.

Wastewater facilities are storm sewers and wastewater treatment

Water purification facility
plants. Another way to remove pollution from surface runoff water is
bioswale.

Industrial applications

Water is used in power generation. Hydroelectricity is electricity obtained from hydropower. Hydroelectric power
comes from water driving a water turbine connected to a generator. Hydroelectricity is a low-cost, non-polluting,
renewable energy source. The energy is supplied by the motion of water. Typically a dam is constructed on a river,
creating an artificial lake behind it. Water flowing out of the lake is forced through turbines that turn generators.

Three Gorges Dam is the largest hydro-electric power station.

Pressurized water is used in water blasting and water jet cutters. Also, very high pressure water guns are used for
precise cutting. It works very well, is relatively safe, and is not harmful to the environment. It is also used in the
cooling of machinery to prevent overheating, or prevent saw blades from overheating.
Water is also used in many industrial processes and machines, such as the steam turbine and heat exchanger, in
addition to its use as a chemical solvent. Discharge of untreated water from industrial uses is pollution. Pollution
includes discharged solutes (chemical pollution) and discharged coolant water (thermal pollution). Industry requires
pure water for many applications and utilizes a variety of purification techniques both in water supply and discharge.
Water 37

Food processing

Water plays many critical roles within the field of food science. It is
important for a food scientist to understand the roles that water plays
within food processing to ensure the success of their products.
Solutes such as salts and sugars found in water affect the physical
properties of water. The boiling and freezing points of water are
affected by solutes, as well as air pressure, which is in turn affected by
altitude. Water boils at lower temperatures with the lower air pressure
which occurs at higher elevations. One mole of sucrose (sugar) per
kilogram of water raises the boiling point of water by 0.51 °C, and one
Water can be used to cook foods such as noodles.
mole of salt per kg raises the boiling point by 1.02 °C; similarly,
increasing the number of dissolved particles lowers water's freezing
[59]
point. Solutes in water also affect water activity which affects many chemical reactions and the growth of
microbes in food.[60] Water activity can be described as a ratio of the vapor pressure of water in a solution to the
vapor pressure of pure water.[59] Solutes in water lower water activity. This is important to know because most
bacterial growth ceases at low levels of water activity.[60] Not only does microbial growth affect the safety of food
but also the preservation and shelf life of food.

Water hardness is also a critical factor in food processing. It can dramatically affect the quality of a product as well
as playing a role in sanitation. Water hardness is classified based on the amounts of removable calcium carbonate
salt it contains per gallon. Water hardness is measured in grains; 0.064 g calcium carbonate is equivalent to one grain
of hardness.[59] Water is classified as soft if it contains 1 to 4 grains, medium if it contains 5 to 10 grains and hard if
it contains 11 to 20 grains. [59] The hardness of water may be altered or treated by using a chemical ion exchange
system. The hardness of water also affects its pH balance which plays a critical role in food processing. For example,
hard water prevents successful production of clear beverages. Water hardness also affects sanitation; with increasing
hardness, there is a loss of effectiveness for its use as a sanitizer.[59]
Boiling, steaming, and simmering are popular cooking methods that often require immersing food in water or its
gaseous state, steam. Water is also used for dishwashing.
Water 38

Water law, water politics and water crisis

Water politics is politics affected by water
and water resources. For this reason,
water is a strategic resource in the globe
and an important element in many
political conflicts. It causes health impacts
and damage to biodiversity.

1.6 billion people have gained access to a

safe water source since 1990.[61] The
proportion of people in developing
countries with access to safe water is
calculated to have improved from 30% in
1970[62] to 71% in 1990, 79% in 2000 and
84% in 2004. This trend is projected to
continue.[8] To halve, by 2015, the
proportion of people without sustainable An estimate of the share of people in developing countries with access to potable
access to safe drinking water is one of the water 1970–2000

Millennium Development Goals. This

goal is projected to be reached.

A 2006 United Nations report stated that "there is enough water for everyone", but that access to it is hampered by
mismanagement and corruption.[63] In addition, global initiatives to improve the efficiency of aid delivery, such as
the Paris Declaration on Aid Effectiveness, have not been taken up by water sector donors as effectively as they have
in education and health, potentially leaving multiple donors working on overlapping projects and recipient
governments without empowerment to act.[64]
The authors of the 2007 Comprehensive Assessment of Water Management in Agriculture cited poor governance as
one reason for some forms of water scarcity. Water governance is the set of formal and informal processes through
which decisions related to water management are made. Good water governance is primarily about knowing what
processes work best in a particular physical and socioeconomic context. Mistakes have sometimes been made by
trying to apply 'blueprints' that work in the developed world to developing world locations and contexts. The
Mekong river is one example; a review by the International Water Management Institute of policies in six countries
that rely on the Mekong river for water found that thorough and transparent cost-benefit analyses and environmental
impact assessments were rarely undertaken. They also discovered that Cambodia's draft water law was much more
complex than it needed to be.[65]
The UN World Water Development Report (WWDR, 2003) from the World Water Assessment Program indicates
that, in the next 20 years, the quantity of water available to everyone is predicted to decrease by 30%. 40% of the
world's inhabitants currently have insufficient fresh water for minimal hygiene. More than 2.2 million people died in
2000 from waterborne diseases (related to the consumption of contaminated water) or drought. In 2004, the UK
charity WaterAid reported that a child dies every 15 seconds from easily preventable water-related diseases; often
this means lack of sewage disposal; see toilet.
Organizations concerned with water protection include International Water Association (IWA), WaterAid, Water 1st,
American Water Resources Association [66]. The International Water Management Institute undertakes projects with
the aim of using effective water management to reduce poverty. Water related conventions are United Nations
Convention to Combat Desertification (UNCCD), International Convention for the Prevention of Pollution from
Ships, United Nations Convention on the Law of the Sea and Ramsar Convention. World Day for Water takes place
on 22 March and World Ocean Day on 8 June.
Water 39

Water used in the production of a good or service is virtual water.

In culture

Religion
Water is considered a purifier in most religions. Major faiths that incorporate ritual washing (ablution) include
Christianity, Islam, Hinduism, Rastafari movement, Shinto, Taoism, Judaism, and Wicca. Immersion (or aspersion or
affusion) of a person in water is a central sacrament of Christianity (where it is called baptism); it is also a part of the
practice of other religions, including Judaism (mikvah) and Sikhism (Amrit Sanskar). In addition, a ritual bath in
pure water is performed for the dead in many religions including Judaism and Islam. In Islam, the five daily prayers
can be done in most cases (see Tayammum) after completing washing certain parts of the body using clean water
(wudu). In Shinto, water is used in almost all rituals to cleanse a person or an area (e.g., in the ritual of misogi).
Water is mentioned numerous times in the Bible, for example: "The earth was formed out of water and by water"
(NIV). In the Qur'an it is stated that "Living things are made of water" and it is often used to describe paradise.

Philosophy
The Ancient Greek philosopher Empedocles held that water is one of the four classical elements along with fire,
earth and air, and was regarded as the ylem, or basic substance of the universe. Water was considered cold and moist.
In the theory of the four bodily humors, water was associated with phlegm. The classical element of Water was also
one of the five elements in traditional Chinese philosophy, along with earth, fire, wood, and metal.
Water is also taken as a role model in some parts of traditional and popular Asian philosophy. James Legge's 1891
translation of the Dao De Jing states "The highest excellence is like (that of) water. The excellence of water appears
in its benefiting all things, and in its occupying, without striving (to the contrary), the low place which all men
dislike. Hence (its way) is near to (that of) the Tao" and "There is nothing in the world more soft and weak than
water, and yet for attacking things that are firm and strong there is nothing that can take precedence of it—for there
is nothing (so effectual) for which it can be changed."[67]

Literature
Water is used in literature as a symbol of purification. Examples include the critical importance of a river in As I Lay
Dying by William Faulkner and the drowning of Ophelia in Hamlet.
Sherlock Holmes held that "From a drop of water, a logician could infer the possibility of an Atlantic or a Niagara
without having seen or heard of one or the other."[68]

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Water 42

Further reading
• Jones, OA., JN Lester and N Voulvoulis, Pharmaceuticals: a threat to drinking water? TRENDS in Biotechnology
23(4): 163, 2005
• Franks, F (Ed), Water, A comprehensive treatise, Plenum Press, New York, 1972–1982
Water in Crisis (http:/ / www. oup. com/ us/ catalog/ general/ subject/ EarthSciences/ Oceanography/ ?view=usa&
ci=9780195076288)
• Gleick,PH., (editor), The World's Water: The Biennial Report on Freshwater Resources. Island Press,
Washington, D.C. (published every two years, beginning in 1998.) The World's Water, Island Press (http://www.
worldwater.org)
• Postel,S., Last Oasis: Facing Water Scarcity. W.W. Norton and Company, New York. 1992
• Reisner,M., Cadillac Desert: The American West and Its Disappearing Water. Penguin Books, New York. 1986.
• Debenedetti,PG., and HE Stanley, "Supercooled and Glassy Water", Physics Today 56 (6), p. 40–46 (2003).
Downloadable PDF (1.9 MB) (http://polymer.bu.edu/hes/articles/ds03.pdf)
• Journal of Contemporary Water Resources and Education (http://ucowr.org/updates/index.html)
• United Nations World Water Development Report. Produced every three years. UN World Water Development
Report (http://www.unesco.org/water/wwap/wwdr/)

External links
• OECD Water statistics (http://stats.oecd.org/wbos/Index.aspx?DataSetCode=ENV_WAT)
• The World's Water Data Page (http://www.worldwater.org)
• FAO Comprehensive Water Database, AQUASTAT (http://www.fao.org/nr/water/aquastat/main/index.stm)
• The Water Conflict Chronology: Water Conflict Database (http://worldwater.org/conflict.html)
• US Geological Survey Water for Schools information (http://ga.water.usgs.gov/edu/)
• Portal to The World Bank's strategy, work and associated publications on water resources (http://water.
worldbank.org/water/)
 43

Structural Biochemistry
 44

Nucleic acids

Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA (deoxyribonucleic acid) and RNA
(ribonucleic acid). Together with proteins, nucleic acids make up the most important macromolecules; each is found
in abundance in all living things, where they function in encoding, transmitting and expressing genetic information.
Nucleic acids were first discovered by Friedrich Miescher in 1871.[1] Experimental studies of nucleic acids constitute
a major part of modern biological and medical research, and form a foundation for genome and forensic science, as
well as the biotechnology and pharmaceutical industries.[2] [3] [4]

Occurrence and nomenclature[5]

The term nucleic acid is the overall name for DNA and RNA, members of a family of biopolymers,[6] and is
synonymous with polynucleotide. Nucleic acids were named for their initial discovery within the nucleus, and for the
presence of phosphate groups (related to phosphoric acid). Although first discovered within the nucleus of
eukaryotic cells, nucleic acids are now known to be found in all life forms, including within bacteria, archaea,
mitochondria, chloroplasts, viruses and viroids. All living cells and organelles contain both DNA and RNA, while
viruses contain either DNA or RNA, but usually not both.[7] The basic component of biological nucleic acids is the
nucleotide, each of which contains a pentose sugar (ribose or deoxyribose), a phosphate group, and a nucleobase.
Nucleic acids are also generated within the laboratory, through the use of enzymes[8] (DNA and RNA polymerases)
and by solid-phase chemical synthesis. The chemical methods also enable the generation of altered nucleic acids that
are not found in nature,[9] for example peptide nucleic acids.

Molecular composition and size[10]

Nucleic acids can vary in size, but are generally very large molecules. Indeed, DNA molecules are probably the
largest individual molecules known. Well-studied biological nucleic acid molecules range in size from 21
nucleotides (small interfering RNA) to large chromosomes (human chromosome 1 is a single molecule that contains
247 million base pairs[11] ).
In most cases, naturally occurring DNA molecules are double-stranded and RNA molecules are single-stranded.
There are numerous exceptions, however—some viruses have genomes made of double-stranded RNA and other
viruses have single-stranded DNA genomes, and, in some circumstances, nucleic acid structures with three or four
strands can form.
Nucleic acids are linear polymers (chains) of nucleotides. Each nucleotide consists of three components: a purine or
pyrimidine nucleobase (sometimes termed nitrogenous base or simply base), a pentose sugar, and a phosphate
group. The substructure consisting of a nucleobase plus sugar is termed a nucleoside. Nucleic acid types differ in the
structure of the sugar in their nucleotides - DNA contains 2'-deoxyribose while RNA contains ribose (where the only
difference is the presence of a hydroxyl group). Also, the nucleobases found in the two nucleic acid types are
different: adenine, cytosine, and guanine are found in both RNA and DNA, while thymine occurs in DNA and uracil
occurs in RNA.
The sugars and phosphates in nucleic acids are connected to each other in an alternating chain (sugar-phosphate
backbone) through phosphodiester linkages.[10] In conventional nomenclature, the carbons to which the phosphate
groups attach are the 3'-end and the 5'-end carbons of the sugar. This gives nucleic acids directionality, and the ends
Nucleic acid 45

of nucleic acid molecules are referred to as 5'-end and 3'-end. The nucleobases are joined to the sugars via an
N-glycosidic linkage involving a nucleobase ring nitrogen (N-1 for pyrimidines and N-9 for purines) and the 1'
carbon of the pentose sugar ring.
Non-standard nucleosides are also found in both RNA and DNA and usually arise from modification of the standard
nucleosides within the DNA molecule or the primary (initial) RNA transcript. Transfer RNA (tRNA) molecules
contain a particularly large number of modified nucleosides.[12]

Topology
Double-stranded nucleic acids are made up of complementary sequences, in which extensive Watson-Crick base
pairing results in the a highly repeated and quite uniform double-helical three-dimensional structure.[13] In contrast,
single-stranded RNA and DNA molecules are not constrained to a regular double helix, and can adopt highly
complex three-dimensional structures that are based on short stretches of intramolecular base-paired sequences that
include both Watson-Crick and noncanonical base pairs, as well as a wide range of complex tertiary interactions.[14]
Nucleic acid molecules are usually unbranched, and may occur as linear and circular molecules. For example,
bacterial chromosomes, plasmids, mitochondrial DNA and chloroplast DNA are usually circular double-stranded
DNA molecules, while chromosomes of the eukaryotic nucleus are usually linear double-stranded DNA
molecules.[7] Most RNA molecules are linear, single-stranded molecules, but both circular and branched molecules
can result from RNA splicing reactions.[5]

Nucleic acid sequences

One DNA or RNA molecule differs from another primarily in the sequence of nucleotides. Nucleotide sequences are
of great importance in biology, since they carry the ultimate instructions that encode all biological molecules,
molecular assemblies, subcellular and cellular structures, organs and organisms, and directly enable cognition,
memory and behavior (See: Genetics). Enormous efforts have gone into the development of experimental methods to
determine the nucleotide sequence of biological DNA and RNA molecules,[15] [16] and today hundreds of millions of
nucleotides are sequenced daily at genome centers and smaller laboratories worldwide.

Types of nucleic acids

Deoxyribonucleic acid
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and
functioning of all known living organisms. The main role of DNA molecules is the long-term storage of information
and DNA is often compared to a set of blueprints, since it contains the instructions needed to construct other
components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information
are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this
genetic information.

Ribonucleic acid
Ribonucleic acid (RNA) functions in converting genetic information from genes into the amino acid sequences of
proteins. The three universal types of RNA include transfer RNA (tRNA), messenger RNA (mRNA), and ribosomal
RNA (rRNA). Messenger RNA acts to carry genetic sequence information between DNA and ribosomes, directing
protein synthesis. Ribosomal RNA is a major component of the ribosome, and catalyzes peptide bond formation.
Transfer RNA serves as the carrier molecule for amino acids to be used in protein synthesis, and is responsible for
decoding the mRNA. In addition, many other classes of RNA are now known.
Nucleic acid 46

Artificial nucleic acid analogs

Artificial nucleic acid analogs have been designed and synthesized by chemists, and include peptide nucleic acid,
morpholino- and locked nucleic acid, as well as glycol nucleic acid and threose nucleic acid. Each of these is
distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.

References
[1] Dahm, R (Jan 2008). "Discovering DNA: Friedrich Miescher and the early years of nucleic acid research". Human genetics 122 (6): 565–81.
doi:10.1007/s00439-007-0433-0. ISSN 0340-6717. PMID 17901982.
[2] International Human Genome Sequencing Consortium (2001). "Initial sequencing and analysis of the human genome." (http:/ / www. nature.
com/ nature/ journal/ v409/ n6822/ pdf/ 409860a0. pdf) (PDF). Nature 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011. .
[3] Venter, JC, et al. (2001). "The sequence of the human genome." (http:/ / www. sciencemag. org/ cgi/ reprint/ 291/ 5507/ 1304. pdf) (PDF).
Science 291 (5507): 1304–1351. doi:10.1126/science.1058040. PMID 11181995. .
[4] Budowle B, van Daal A (April 2009). "Extracting evidence from forensic DNA analyses: future molecular biology directions".
BioTechniques 46 (5): 339–40, 342–50. doi:10.2144/000113136. PMID 19480629.
[5] Alberts, Bruce (2008). Molecular biology of the cell. New York: Garland Science. ISBN 0-8153-4105-9.
[6] Elson D (1965). "Metabolism of nucleic acids (macromolecular DNA and RNA)". Annu. Rev. Biochem. 34: 449–86.
doi:10.1146/annurev.bi.34.070165.002313. PMID 14321176.
[7] Brock, Thomas D.; Madigan, Michael T. (2009). Brock biology of microorganisms. Pearson / Benjamin Cummings. ISBN 0-321-53615-0.
[8] Mullis, Kary B. The Polymerase Chain Reaction (Nobel Lecture). 1993. (retrieved December 1, 2010) http:/ / nobelprize. org/ nobel_prizes/
chemistry/ laureates/ 1993/ mullis-lecture. html
[9] Verma S, Eckstein F (1998). "Modified oligonucleotides: synthesis and strategy for users". Annu. Rev. Biochem. 67: 99–134.
doi:10.1146/annurev.biochem.67.1.99. PMID 9759484.
[10] Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2007). Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-6766-X.
[11] Gregory SG, Barlow KF, McLay KE, et al. (May 2006). "The DNA sequence and biological annotation of human chromosome 1". Nature
441 (7091): 315–21. doi:10.1038/nature04727. PMID 16710414.
[12] Rich A, RajBhandary UL (1976). "Transfer RNA: molecular structure, sequence, and properties". Annu. Rev. Biochem. 45: 805–60.
doi:10.1146/annurev.bi.45.070176.004105. PMID 60910.
[13] Watson JD, Crick FH (April 1953). "Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid". Nature 171 (4356):
737–8. Bibcode 1953Natur.171..737W. doi:10.1038/171737a0. PMID 13054692.
[14] Ferré-D'Amaré AR, Doudna JA (1999). "RNA folds: insights from recent crystal structures". Annu Rev Biophys Biomol Struct 28: 57–73.
doi:10.1146/annurev.biophys.28.1.57. PMID 10410795.
[15] Gilbert, Walter G. 1980. DNA Sequencing and Gene Structure (Nobel Lecture) http:/ / nobelprize. org/ nobel_prizes/ chemistry/ laureates/
1980/ gilbert-lecture. html
[16] Sanger, Frederick. 1980. Determination of Nucleotide Sequences in DNA (Nobel Lecture) http:/ / nobelprize. org/ nobel_prizes/ chemistry/
laureates/ 1980/ sanger-lecture. html

Further reading
• Wolfram Saenger, Principles of Nucleic Acid Structure, 1984, Springer-Verlag New York Inc.
• Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter Molecular Biology
of the Cell, 2007, ISBN 978-0-8153-4105-5. Fourth edition is available online through the NCBI Bookshelf: link
(http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4)
• Jeremy M Berg, John L Tymoczko, and Lubert Stryer, Biochemistry 5th edition, 2002, W H Freeman. Available
online through the NCBI Bookshelf: link (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=stryer)
Nucleic acid 47

External links
• Interview with Aaron Klug, Nobel Laureate for structural elucidation of biologically important nucleic-acid
protein complexes (http://www.vega.org.uk/video/programme/122) provided by the Vega Science Trust.
• Nucleic Acids Research (Journal) (http://nar.oxfordjournals.org/)

RNA
Ribonucleic acid (English pronunciation: /raɪbɵ.njuːˌkleɪ.ɨk ˈæsɪd/), or
RNA, is one of the three major macromolecules (along with DNA
and proteins) that are essential for all known forms of life.
Like DNA, RNA is made up of a long chain of components called
nucleotides. Each nucleotide consists of a nucleobase (sometimes
called a nitrogenous base), a ribose sugar, and a phosphate group.
The sequence of nucleotides allows RNA to encode genetic
information. All cellular organisms use messenger RNA (mRNA)
to carry the genetic information that directs the synthesis of
proteins. In addition, some viruses use RNA instead of DNA as
their genetic material; perhaps a reflection of the suggested key
role of RNA in the evolutionary history of life on Earth.[1] [2]

Like proteins, some RNA molecules play an active role in cells by

catalyzing biological reactions, controlling gene expression, or
sensing and communicating responses to cellular signals. One of
these active processes is protein synthesis, a universal function
whereby mRNA molecules direct the assembly of proteins on
ribosomes. This process uses transfer RNA (tRNA) molecules to
deliver amino acids to the ribosome, where ribosomal RNA
(rRNA) links amino acids together to form proteins. In 2011, it
was demonstrated that the methylation of mRNA has a critical role
in human energy homeostasis. This opens up the field of RNA
epigenetics.[3] A hairpin loop from a pre-mRNA. Highlighted are the
nucleobases (green) and the ribose-phosphate
The chemical structure of RNA is very similar to that of DNA, backbone (blue).

with two differences: (a) RNA contains the sugar ribose, while
DNA contains the slightly different sugar deoxyribose (a type of ribose that lacks one oxygen atom), and (b) RNA
has the nucleobase uracil while DNA contains thymine. Uracil and thymine have similar base-pairing properties.
Unlike DNA, most RNA molecules are single-stranded. Single-stranded RNA molecules adopt very complex
three-dimensional structures, since they are not restricted to the repetitive double-helical form of double-stranded
DNA. RNA is made within living cells by RNA polymerases, enzymes that act to copy a DNA or RNA template into
a new RNA strand through processes known as transcription or RNA replication, respectively.
RNA 48

Comparison with DNA

RNA and DNA are both nucleic acids, but differ in three main ways.
First, unlike double-stranded DNA, RNA is a single-stranded molecule
in many of its biological roles and has a much shorter chain of
nucleotides. Second, while DNA contains deoxyribose, RNA contains
ribose (in deoxyribose there is no hydroxyl group attached to the
pentose ring in the 2' position). These hydroxyl groups make RNA less
stable than DNA because it is more prone to hydrolysis. Third, the
complementary base to adenine is not thymine, as it is in DNA, but
rather uracil, which is an unmethylated form of thymine.[4]

Like DNA, most biologically active RNAs, including mRNA, tRNA,

rRNA, snRNAs, and other non-coding RNAs, contain Three-dimensional representation of the 50S
self-complementary sequences that allow parts of the RNA to fold and ribosomal subunit. RNA is in ochre, protein in
pair with itself to form double helices. Analysis of these RNAs has blue. The active site is in the middle (red).

revealed that they are highly structured. Unlike DNA, their structures
do not consist of long double helices but rather collections of short helices packed together into structures akin to
proteins. In this fashion, RNAs can achieve chemical catalysis, like enzymes.[5] For instance, determination of the
structure of the ribosome—an enzyme that catalyzes peptide bond formation—revealed that its active site is
composed entirely of RNA.[6]

Structure
Each nucleotide in RNA contains a ribose sugar, with
carbons numbered 1' through 5'. A base is attached to the 1'
position, in general, adenine (A), cytosine (C), guanine (G),
or uracil (U). Adenine and guanine are purines, cytosine,
and uracil are pyrimidines. A phosphate group is attached to
the 3' position of one ribose and the 5' position of the next.
The phosphate groups have a negative charge each at
physiological pH, making RNA a charged molecule
(polyanion). The bases may form hydrogen bonds between
cytosine and guanine, between adenine and uracil and
between guanine and uracil.[7] However, other interactions
Watson-Crick base pairs in a siRNA (hydrogen atoms are not
are possible, such as a group of adenine bases binding to shown)
each other in a bulge,[8] or the GNRA tetraloop that has a
guanine–adenine base-pair.[7]
RNA 49

An important structural feature of RNA that distinguishes it from DNA

is the presence of a hydroxyl group at the 2' position of the ribose
sugar. The presence of this functional group causes the helix to adopt
the A-form geometry rather than the B-form most commonly observed
in DNA.[9] This results in a very deep and narrow major groove and a
shallow and wide minor groove.[10] A second consequence of the
presence of the 2'-hydroxyl group is that in conformationally flexible
regions of an RNA molecule (that is, not involved in formation of a
double helix), it can chemically attack the adjacent phosphodiester
bond to cleave the backbone.[11]

Chemical structure of RNA

RNA is transcribed with only four bases (adenine, cytosine, guanine

and uracil),[12] but these bases and attached sugars can be modified in
numerous ways as the RNAs mature. Pseudouridine (Ψ), in which the
linkage between uracil and ribose is changed from a C–N bond to a
C–C bond, and ribothymidine (T) are found in various places (the most
notable ones being in the TΨC loop of tRNA).[13] Another notable
modified base is hypoxanthine, a deaminated adenine base whose
nucleoside is called inosine (I). Inosine plays a key role in the wobble
hypothesis of the genetic code.[14]
Secondary structure of a telomerase RNA.
There are nearly 100 other naturally occurring modified
nucleosides,[15] of which pseudouridine and nucleosides with 2'-O-methylribose are the most common.[16] The
specific roles of many of these modifications in RNA are not fully understood. However, it is notable that, in
ribosomal RNA, many of the post-transcriptional modifications occur in highly functional regions, such as the
peptidyl transferase center and the subunit interface, implying that they are important for normal function.[17]
The functional form of single stranded RNA molecules, just like proteins, frequently requires a specific tertiary
structure. The scaffold for this structure is provided by secondary structural elements that are hydrogen bonds within
the molecule. This leads to several recognizable "domains" of secondary structure like hairpin loops, bulges, and
internal loops.[18] Since RNA is charged, metal ions such as Mg2+ are needed to stabilise many secondary and
tertiary structures.[19]

Synthesis
Synthesis of RNA is usually catalyzed by an enzyme—RNA polymerase—using DNA as a template, a process
known as transcription. Initiation of transcription begins with the binding of the enzyme to a promoter sequence in
the DNA (usually found "upstream" of a gene). The DNA double helix is unwound by the helicase activity of the
enzyme. The enzyme then progresses along the template strand in the 3’ to 5’ direction, synthesizing a
complementary RNA molecule with elongation occurring in the 5’ to 3’ direction. The DNA sequence also dictates
where termination of RNA synthesis will occur.[20]
RNAs are often modified by enzymes after transcription. For example, a poly(A) tail and a 5' cap are added to
eukaryotic pre-mRNA and introns are removed by the spliceosome.
There are also a number of RNA-dependent RNA polymerases that use RNA as their template for synthesis of a new
strand of RNA. For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their
genetic material.[21] Also, RNA-dependent RNA polymerase is part of the RNA interference pathway in many
RNA 50

organisms.[22]

Types of RNA

Overview
Messenger RNA (mRNA) is the RNA that carries information from
DNA to the ribosome, the sites of protein synthesis (translation) in the
cell. The coding sequence of the mRNA determines the amino acid
sequence in the protein that is produced.[23] Many RNAs do not code
for protein however (about 97% of the transcriptional output is
non-protein-coding in eukaryotes [24] [25] [26] [27] ).

These so-called non-coding RNAs ("ncRNA") can be encoded by their

own genes (RNA genes), but can also derive from mRNA introns.[28]
The most prominent examples of non-coding RNAs are transfer RNA
(tRNA) and ribosomal RNA (rRNA), both of which are involved in the
process of translation.[4] There are also non-coding RNAs involved in
gene regulation, RNA processing and other roles. Certain RNAs are
able to catalyse chemical reactions such as cutting and ligating other
RNA molecules,[29] and the catalysis of peptide bond formation in the
ribosome;[6] these are known as ribozymes.

In translation
Messenger RNA (mRNA) carries information about a protein sequence
Structure of a hammerhead ribozyme, a ribozyme
to the ribosomes, the protein synthesis factories in the cell. It is coded that cuts RNA
so that every three nucleotides (a codon) correspond to one amino acid.
In eukaryotic cells, once precursor mRNA (pre-mRNA) has been transcribed from DNA, it is processed to mature
mRNA. This removes its introns—non-coding sections of the pre-mRNA. The mRNA is then exported from the
nucleus to the cytoplasm, where it is bound to ribosomes and translated into its corresponding protein form with the
help of tRNA. In prokaryotic cells, which do not have nucleus and cytoplasm compartments, mRNA can bind to
ribosomes while it is being transcribed from DNA. After a certain amount of time the message degrades into its
component nucleotides with the assistance of ribonucleases.[23]

Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing
polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment
and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain
through hydrogen bonding.[28]
Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. Eukaryotic ribosomes contain four different
rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and
one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called
a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a
single mRNA at any time.[23] Nearly all the RNA found in a typical eukaryotic cell is rRNA.
Transfer-messenger RNA (tmRNA) is found in many bacteria and plastids. It tags proteins encoded by mRNAs that
lack stop codons for degradation and prevents the ribosome from stalling.[30]
RNA 51

Regulatory RNAs
Several types of RNA can downregulate gene expression by being complementary to a part of an mRNA or a gene's
DNA. MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an
effector complex of miRNA and enzymes can cleave complementary mRNA, block the mRNA from being
translated, or accelerate its degradation.[31] [32] While small interfering RNAs (siRNA; 20-25 nt) are often produced
by breakdown of viral RNA, there are also endogenous sources of siRNAs.[33] [34]
siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes
they target to be methylated, thereby decreasing or increasing transcription of those genes.[35] [36] [37] Animals have
Piwi-interacting RNAs (piRNA; 29-30 nt) which are active in germline cells and are thought to be a defense against
transposons and play a role in gametogenesis.[38] [39]
Many prokaryotes have CRISPR RNAs, a regulatory system similar to RNA interference.[40] Antisense RNAs are
widespread; most downregulate a gene, but a few are activators of transcription.[41] One way antisense RNA can act
is by binding to an mRNA, forming double-stranded RNA that is enzymatically degraded.[42] There are many long
noncoding RNAs that regulate genes in eukaryotes,[43] one such RNA is Xist, which coats one X chromosome in
female mammals and inactivates it.[44]
An mRNA may contain regulatory elements itself, such as riboswitches, in the 5' untranslated region or 3'
untranslated region; these cis-regulatory elements regulate the activity of that mRNA.[45] The untranslated regions
can also contain elements that regulate other genes.[46]

In RNA processing
Many RNAs are involved in modifying other RNAs. Introns are
spliced out of pre-mRNA by spliceosomes, which contain several
small nuclear RNAs (snRNA),[4] or the introns can be ribozymes that
are spliced by themselves.[47] RNA can also be altered by having its
nucleotides modified to other nucleotides than A, C, G and U. In
eukaryotes, modifications of RNA nucleotides are generally directed
by small nucleolar RNAs (snoRNA; 60-300 nt),[28] found in the Uridine to pseudouridine is a common RNA
nucleolus and cajal bodies. snoRNAs associate with enzymes and modification.
guide them to a spot on an RNA by basepairing to that RNA. These
enzymes then perform the nucleotide modification. rRNAs and tRNAs are extensively modified, but snRNAs and
mRNAs can also be the target of base modification.[48] [49] RNA can also be methylated.[50] [51]

RNA genomes
Like DNA, RNA can carry genetic information. RNA viruses have genomes composed of RNA which encodes a
number of proteins. The viral genome is replicated by some of those proteins, while other proteins protect the
genome as the virus particle moves to a new host cell. Viroids are another group of pathogens, but they consist only
of RNA, do not encode any protein and are replicated by a host plant cell's polymerase.[52]

In reverse transcription
Reverse transcribing viruses replicate their genomes by reverse transcribing DNA copies from their RNA; these
DNA copies are then transcribed to new RNA. Retrotransposons also spread by copying DNA and RNA from one
another,[53] and telomerase contains an RNA that is used as template for building the ends of eukaryotic
chromosomes.[54]
RNA 52

Double-stranded RNA
Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells.
dsRNA forms the genetic material of some viruses (double-stranded RNA viruses). Double-stranded RNA such as
viral RNA or siRNA can trigger RNA interference in eukaryotes, as well as interferon response in vertebrates.[55] [56]
[57]

Key discoveries in RNA biology

Further information: History of RNA biology
Research on RNA has led to many important biological discoveries and numerous Nobel Prizes. Nucleic acids were
discovered in 1868 by Friedrich Miescher, who called the material 'nuclein' since it was found in the nucleus.[58] It
was later discovered that prokaryotic cells, which do not have a nucleus, also contain nucleic acids. The role of RNA
in protein synthesis was suspected already in 1939.[59] Severo Ochoa won the 1959 Nobel Prize in Medicine (shared
with Arthur Kornberg) after he discovered an enzyme that can synthesize RNA in the laboratory.[60] Ironically, the
enzyme discovered by Ochoa (polynucleotide phosphorylase) was later shown to be responsible for RNA
degradation, not RNA synthesis.
The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965,[61] winning Holley the
1968 Nobel Prize in Medicine (shared with Har Gobind Khorana and Marshall Nirenberg). In 1967, Carl Woese
hypothesized that RNA might be catalytic and suggested that the earliest forms of life (self-replicating molecules)
could have relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA
world.[62] [63]
During the early 1970s, retroviruses and reverse transcriptase were discovered, showing for the first time that
enzymes could copy RNA into DNA (the opposite of the usual route for transmission of genetic information). For
this work, David Baltimore, Renato Dulbecco and Howard Temin were awarded a Nobel Prize in 1975. In 1976,
Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of
bacteriophage MS2.[64]
In 1977, introns and RNA splicing were discovered in both mammalian viruses and in cellular genes, resulting in a
1993 Nobel to Philip Sharp and Richard Roberts. Catalytic RNA molecules (ribozymes) were discovered in the early
1980s, leading to a 1989 Nobel award to Thomas Cech and Sidney Altman. In 1990 it was found in petunia that
introduced genes can silence similar genes of the plant's own, now known to be a result of RNA interference.[65] [66]
At about the same time, 22 nt long RNAs, now called microRNAs, were found to have a role in the development of
C. elegans.[67] Studies on RNA interference gleaned a Nobel Prize for Andrew Fire and Craig Mello in 2006, and
another Nobel was awarded for studies on transcription of RNA to Roger Kornberg in the same year. The discovery
of gene regulatory RNAs has led to attempts to develop drugs made of RNA, such as siRNA, to silence genes.[68]

References
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RNA 53

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External links
• RNA World website (http://www.imb-jena.de/RNA.html) Link collection (structures, sequences, tools,
journals)
• Nucleic Acid Database (http://ndbserver.rutgers.edu/atlas/xray/) Images of DNA, RNA and complexes.
• EteRNA (http://eterna.cmu.edu/content/EteRNA) a game forming RNA by pairing bases.

DNA
Deoxyribonucleic acid (English
pronunciation: /diˌɒksiˌraɪbɵ.njuːˌkleɪ.ɨk
ˈæsɪd/ ( listen); DNA) is a nucleic
acid that contains the genetic
instructions used in the development
and functioning of all known living
organisms (with the exception of RNA
viruses). The DNA segments that carry
this genetic information are called
genes, but other DNA sequences have
structural purposes, or are involved in
regulating the use of this genetic
information. Along with RNA and
proteins, DNA is one of the three
major macromolecules that are
essential for all known forms of life.

DNA consists of two long polymers of

simple units called nucleotides, with
backbones made of sugars and
phosphate groups joined by ester The structure of the DNA double helix. The atoms in the structure are colour coded by
element and the detailed structure of two base pairs is shown in the bottom right.
DNA 56

bonds. These two strands run in opposite directions to each other and
are therefore anti-parallel. Attached to each sugar is one of four types
of molecules called nucleobases (informally, bases). It is the sequence
of these four nucleobases along the backbone that encodes information.
This information is read using the genetic code, which specifies the
sequence of the amino acids within proteins. The code is read by
copying stretches of DNA into the related nucleic acid RNA in a
process called transcription.

Within cells DNA is organized into long structures called

chromosomes. During cell division these chromosomes are duplicated
in the process of DNA replication, providing each cell its own
complete set of chromosomes. Eukaryotic organisms (animals, plants,
fungi, and protists) store most of their DNA inside the cell nucleus and
some of their DNA in organelles, such as mitochondria or
chloroplasts.[1] In contrast, prokaryotes (bacteria and archaea) store
their DNA only in the cytoplasm. Within the chromosomes, chromatin
proteins such as histones compact and organize DNA. These compact
structures guide the interactions between DNA and other proteins,
helping control which parts of the DNA are transcribed.
The structure of part of a DNA double helix
DNA 57

Properties
DNA is a long polymer made from
repeating units called nucleotides.[2] [3] [4]
As first discovered by James D. Watson and
Francis Crick, the structure of DNA of all
species comprises two helical chains each
coiled round the same axis, and each with a
pitch of 34 Ångströms (3.4 nanometres) and
a radius of 10 Ångströms
(1.0 nanometres).[5] According to another
study, when measured in a particular
solution, the DNA chain measured 22 to
26 Ångströms wide (2.2 to 2.6 nanometres),
and one nucleotide unit measured 3.3 Å
(0.33 nm) long.[6] Although each individual
repeating unit is very small, DNA polymers
can be very large molecules containing
millions of nucleotides. For instance, the
largest human chromosome, chromosome
number 1, is approximately 220 million base
pairs long.[7]

In living organisms DNA does not usually

Chemical structure of DNA. Hydrogen bonds shown as dotted lines.
exist as a single molecule, but instead as a
pair of molecules that are held tightly
together.[5] [8] These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeats
contain both the segment of the backbone of the molecule, which holds the chain together, and a nucleobase, which
interacts with the other DNA strand in the helix. A nucleobase linked to a sugar is called a nucleoside and a base
linked to a sugar and one or more phosphate groups is called a nucleotide. Polymers comprising multiple linked
nucleotides (as in DNA) are called a polynucleotide.[9]

The backbone of the DNA strand is made from alternating phosphate and sugar residues.[10] The sugar in DNA is
2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form
phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds
mean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite to
their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are called the 5′
(five prime) and 3′ (three prime) ends, with the 5' end having a terminal phosphate group and the 3' end a terminal
hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being
replaced by the alternative pentose sugar ribose in RNA.[8]
DNA 58

The DNA double helix is stabilized primarily by two forces: hydrogen bonds
between nucleotides and base-stacking interactions among the aromatic
nucleobases.[12] In the aqueous environment of the cell, the conjugated π bonds
of nucleotide bases align perpendicular to the axis of the DNA molecule,
minimizing their interaction with the solvation shell and therefore, the Gibbs free
energy. The four bases found in DNA are adenine (abbreviated A), cytosine (C),
guanine (G) and thymine (T). These four bases are attached to the
sugar/phosphate to form the complete nucleotide, as shown for adenosine
monophosphate.

The nucleobases are classified into two types: the purines, A and G, being fused
five- and six-membered heterocyclic compounds, and the pyrimidines, the
six-membered rings C and T.[8] A fifth pyrimidine nucleobase, uracil (U), usually
takes the place of thymine in RNA and differs from thymine by lacking a methyl
group on its ring. Uracil is not usually found in DNA, occurring only as a
breakdown product of cytosine. In addition to RNA and DNA a large number of
artificial nucleic acid analogues have also been created to study the proprieties of A section of DNA. The bases lie
nucleic acids, or for use in biotechnology.[13] horizontally between the two
[11]
spiraling strands. Animated
version at File:DNA orbit
animated.gif.

Grooves
Twin helical strands form the DNA backbone. Another double helix
may be found by tracing the spaces, or grooves, between the strands.
These voids are adjacent to the base pairs and may provide a binding
site. As the strands are not directly opposite each other, the grooves are
unequally sized. One groove, the major groove, is 22 Å wide and the
other, the minor groove, is 12 Å wide.[14] The narrowness of the minor
Major and minor grooves of DNA. Minor groove
groove means that the edges of the bases are more accessible in the
is a binding site for the dye Hoechst 33258. major groove. As a result, proteins like transcription factors that can
bind to specific sequences in double-stranded DNA usually make
contacts to the sides of the bases exposed in the major groove.[15] This situation varies in unusual conformations of
DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size
that would be seen if the DNA is twisted back into the ordinary B form.

Base pairing
Further information: Base pair
In a DNA double helix, each type of nucleobase on one strand normally interacts with just one type of nucleobase on
the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with
A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the
double helix is called a base pair. As hydrogen bonds are not covalent, they can be broken and rejoined relatively
easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical
force or high temperature.[16] As a result of this complementarity, all the information in the double-stranded
sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and
specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[3]
DNA 59

Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent
hydrogen bonds between the pairs are shown as dashed lines.
The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC
forming three hydrogen bonds (see figures, left). DNA with high GC-content is more stable than DNA with low
GC-content. Although it is often stated that this is due to the added stability of an additional hydrogen bond, this is
incorrect. DNA with high GC-content is more stable due to intra-strand base stacking interactions.
As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by
noncovalent bonds; this double stranded structure (dsDNA) is maintained largely by the intrastrand base stacking
interactions, which are strongest for G,C stacks. The two strands can come apart – a process known as melting – to
form two ss DNA molecules. Melting occurs when conditions favor ssDNA; such conditions are high temperature,
low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely
used). The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence
(since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be
measured in various ways; a common way is the "melting temperature", which is the temperature at which 50% of
the ds molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the
concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double
helix that determine the strength of the association between the two strands of DNA. Long DNA helices with a high
GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting
strands.[17] In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow
box in some promoters, tend to have a high AT content, making the strands easier to pull apart.[18]
In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the
hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix
melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA
molecules (ssDNA) have no single common shape, but some conformations are more stable than others.[19]

Sense and antisense

Further information: Sense (molecular biology)
A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into
protein.[20] The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense
sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense
sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these
RNAs are not entirely clear.[21] One proposal is that antisense RNAs are involved in regulating gene expression
through RNA-RNA base pairing.[22]
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between
sense and antisense strands by having overlapping genes.[23] In these cases, some DNA sequences do double duty,
encoding one protein when read along one strand, and a second protein when read in the opposite direction along the
DNA 60

other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[24] while in viruses,
overlapping genes increase the amount of information that can be encoded within the small viral genome.[25]

Supercoiling
Further information: DNA supercoil
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand
usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become
more tightly or more loosely wound.[26] If the DNA is twisted in the direction of the helix, this is positive
supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is
negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling
that is introduced by enzymes called topoisomerases.[27] These enzymes are also needed to relieve the twisting
stresses introduced into DNA strands during processes such as transcription and DNA replication.[28]

Alternate DNA structures

Further information: Molecular Structure of Nucleic Acids: A
Structure for Deoxyribose Nucleic Acid, Molecular models of DNA,
and DNA structure
DNA exists in many possible conformations that include A-DNA,
B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have
been directly observed in functional organisms.[10] The conformation
that DNA adopts depends on the hydration level, DNA sequence, the From left to right, the structures of A, B and Z
DNA
amount and direction of supercoiling, chemical modifications of the
bases, the type and concentration of metal ions, as well as the presence
of polyamines in solution.[29]

The first published reports of A-DNA X-ray diffraction patterns— and also B-DNA used analyses based on
Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA.[30] [31]
An alternate analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray
diffraction/scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions.[32] In the same
journal, James D. Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray
diffraction patterns to suggest that the structure was a double-helix.[5]
Although the `B-DNA form' is most common under the conditions found in cells,[33] it is not a well-defined
conformation but a family of related DNA conformations[34] that occur at the high hydration levels present in living
cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a
significant degree of disorder.[35] [36]
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a
narrower, deeper major groove. The A form occurs under non-physiological conditions in partially dehydrated
samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in
enzyme-DNA complexes.[37] [38] Segments of DNA where the bases have been chemically modified by methylation
may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a
left-handed spiral, the opposite of the more common B form.[39] These unusual structures can be recognized by
specific Z-DNA binding proteins and may be involved in the regulation of transcription.[40]
DNA 61

Alternate DNA chemistry

For a number of years exobiologists have proposed the existence of a shadow biosphere, a postulated microbial
biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One
of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA.
A December 2010 NASA press conference stated that the bacterium GFAJ-1, which has evolved in an arsenic-rich
environment, is the first terrestrial lifeform found which may have this ability. The bacterium was found in Mono
Lake, east of Yosemite National Park. GFAJ-1 is a rod-shaped extremophile bacterium in the family
Halomonadaceae that, when starved of phosphorus, may be capable of incorporating the usually poisonous element
arsenic in its DNA.[41] This discovery may lend weight to the long-standing idea that extraterrestrial life could have a
different chemical makeup from life on Earth.[41] [42] The research was carried out by a team led by Felisa
Wolfe-Simon, a geomicrobiologist and geobiochemist, a Postdoctoral Fellow of the NASA Astrobiology Institute
with Arizona State University. This finding has, however, faced strong criticism from the scientific community;
scientists have argued that there is no evidence that arsenic is actually incorporated into biomolecules.[42] [43]
Independent conformation of this finding has also not yet been possible.

Quadruplex structures
Further information: G-quadruplex
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these
regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally
replicate DNA cannot copy the extreme 3′ ends of chromosomes.[44] These specialized chromosome caps also help
protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected.[45]
In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a
simple TTAGGG sequence.[46]
These guanine-rich sequences may stabilize chromosome ends by
forming structures of stacked sets of four-base units, rather than the
usual base pairs found in other DNA molecules. Here, four guanine
bases form a flat plate and these flat four-base units then stack on top
of each other, to form a stable G-quadruplex structure.[48] These
structures are stabilized by hydrogen bonding between the edges of the
bases and chelation of a metal ion in the centre of each four-base
unit.[49] Other structures can also be formed, with the central set of
four bases coming from either a single strand folded around the bases,
or several different parallel strands, each contributing one base to the
central structure.
DNA quadruplex formed by telomere repeats.
The looped conformation of the DNA backbone
In addition to these stacked structures, telomeres also form large loop [47]
is very different from the typical DNA helix.
structures called telomere loops, or T-loops. Here, the single-stranded
DNA curls around in a long circle stabilized by telomere-binding
proteins.[50] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of
double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two
strands. This triple-stranded structure is called a displacement loop or D-loop.[48]
DNA 62

Single branch Multiple branches

Branched DNA can form networks containing multiple branches.

Branched DNA
Further information: Branched DNA and DNA nanotechnology
In DNA fraying occurs when non-complementary regions exist at the end of an otherwise complementary
double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains
adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest
example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple
branches are also possible.[51] Branched DNA can be used in nanotechnology to construct geometric shapes, see the
section on uses in technology below.

Vibration
DNA may carry out low-frequency collective motion as observed by the Raman spectroscopy[52] [53]
and analyzed
with a quasi-continuum model.[54] [55]

Chemical modifications

cytosine 5-methylcytosine thymine

Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine.

Base modifications
Further information: DNA methylation
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin.
Base modifications can be involved in packaging, with regions that have low or no gene expression usually
containing high levels of methylation of cytosine bases. For example, cytosine methylation, produces
5-methylcytosine, which is important for X-chromosome inactivation.[56] The average level of methylation varies
between organisms – the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher
levels, with up to 1% of their DNA containing 5-methylcytosine.[57] Despite the importance of 5-methylcytosine, it
can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations.[58] Other base
modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain,[59] and
the glycosylation of uracil to produce the "J-base" in kinetoplastids.[60] [61]
DNA 63

Damage
Further information: Mutation
DNA can be damaged by many sorts of mutagens, which change the
DNA sequence. Mutagens include oxidizing agents, alkylating agents
and also high-energy electromagnetic radiation such as ultraviolet light
and X-rays. The type of DNA damage produced depends on the type of
mutagen. For example, UV light can damage DNA by producing
thymine dimers, which are cross-links between pyrimidine bases.[63]
On the other hand, oxidants such as free radicals or hydrogen peroxide
produce multiple forms of damage, including base modifications,
particularly of guanosine, and double-strand breaks.[64] A typical
human cell contains about 150,000 bases that have suffered oxidative
damage.[65] Of these oxidative lesions, the most dangerous are
double-strand breaks, as these are difficult to repair and can produce
point mutations, insertions and deletions from the DNA sequence, as
well as chromosomal translocations.[66]

Many mutagens fit into the space between two adjacent base pairs, this
is called intercalation. Most intercalators are aromatic and planar A covalent adduct between a metabolically
activated form of benzo[a]pyrene, the major
molecules; examples include ethidium bromide, acridines, [62]
mutagen in tobacco smoke, and DNA
daunomycin, and doxorubicin. In order for an intercalator to fit
between base pairs, the bases must separate, distorting the DNA
strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and
mutations.[67] As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen.[68]
Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts which induce errors in replication.[69]
Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in
chemotherapy to inhibit rapidly growing cancer cells.[70]

Biological functions
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of
chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA
arranged into 46 chromosomes.[71] The information carried by DNA is held in the sequence of pieces of DNA called
genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in
transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA
sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then
used to make a matching protein sequence in a process called translation, which depends on the same interaction
between RNA nucleotides. In alternative fashion, a cell may simply copy its genetic information in a process called
DNA replication. The details of these functions are covered in other articles; here we focus on the interactions
between DNA and other molecules that mediate the function of the genome.
DNA 64

Genes and genomes

Further information: Cell nucleus, Chromatin, Chromosome, Gene, Noncoding DNA
Genomic DNA is tightly and orderly packed in the process called DNA condensation to fit the small available
volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, as well as small amounts in mitochondria and
chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the
nucleoid.[72] The genetic information in a genome is held within genes, and the complete set of this information in an
organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular
characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory
sequences such as promoters and enhancers, which control the transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about
1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of
non-coding repetitive sequences.[73] The reasons for the presence of so much noncoding DNA in eukaryotic
genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing
puzzle known as the "C-value enigma".[74] However, DNA sequences that do not code protein may still encode
functional non-coding RNA molecules, which are involved in the regulation of gene expression.[75]
Some noncoding DNA sequences play structural roles in
chromosomes. Telomeres and centromeres typically contain few genes,
but are important for the function and stability of chromosomes.[45] [77]
An abundant form of noncoding DNA in humans are pseudogenes,
which are copies of genes that have been disabled by mutation.[78]
These sequences are usually just molecular fossils, although they can
occasionally serve as raw genetic material for the creation of new
genes through the process of gene duplication and divergence.[79]

T7 RNA polymerase (blue) producing a mRNA

[76] Transcription and translation
(green) from a DNA template (orange).
Further information: Genetic code, Transcription (genetics), Protein
biosynthesis
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism.
Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines
one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid
sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic
code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG,
TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then
decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which
carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (
combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible
codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA,
TGA and TAG codons.
DNA 65

Replication
Further information: DNA replication
Cell division is essential for an
organism to grow, but, when a cell
divides, it must replicate the DNA in
its genome so that the two daughter
cells have the same genetic
information as their parent. The
double-stranded structure of DNA
provides a simple mechanism for DNA DNA replication. The double helix is unwound by a helicase and topoisomerase. Next,
replication. Here, the two strands are one DNA polymerase produces the leading strand copy. Another DNA polymerase binds
separated and then each strand's to the lagging strand. This enzyme makes discontinuous segments (called Okazaki
fragments) before DNA ligase joins them together.
complementary DNA sequence is
recreated by an enzyme called DNA
polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base
pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′
direction, different mechanisms are used to copy the antiparallel strands of the double helix.[80] In this way, the base
on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

Interactions with proteins

All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the
protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the
polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.

DNA-binding proteins
Further information: DNA-binding protein

Interaction of DNA (shown in orange) with histones (shown in blue). These proteins' basic amino acids bind to the
acidic phosphate groups on DNA.
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within
chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact
structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins
called histones, while in prokaryotes multiple types of proteins are involved.[81] [82] The histones form a disk-shaped
complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its
surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the
acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence.[83]
Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.[84]
DNA 66

These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA
more or less accessible to transcription factors and changing the rate of transcription.[85] Other non-specific
DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted
DNA.[86] These proteins are important in bending arrays of nucleosomes and arranging them into the larger
structures that make up chromosomes.[87]
A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA.
In humans, replication protein A is the best-understood member of this family and is used in processes where the
double helix is separated, including DNA replication, recombination and DNA repair.[88] These binding proteins
seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
In contrast, other proteins have evolved to bind to particular DNA sequences.
The most intensively studied of these are the various transcription factors, which
are proteins that regulate transcription. Each transcription factor binds to one
particular set of DNA sequences and activates or inhibits the transcription of
genes that have these sequences close to their promoters. The transcription
factors do this in two ways. Firstly, they can bind the RNA polymerase
responsible for transcription, either directly or through other mediator proteins;
this locates the polymerase at the promoter and allows it to begin
transcription.[90] Alternatively, transcription factors can bind enzymes that
modify the histones at the promoter; this will change the accessibility of the
DNA template to the polymerase.[91]

As these DNA targets can occur throughout an organism's genome, changes in

the activity of one type of transcription factor can affect thousands of genes.[92] The lambda repressor
helix-turn-helix transcription factor
Consequently, these proteins are often the targets of the signal transduction [89]
bound to its DNA target
processes that control responses to environmental changes or cellular
differentiation and development. The specificity of these transcription factors'
interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing
them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are
most accessible.[15]

DNA-modifying enzymes

Nucleases and ligases

Nucleases are enzymes that cut DNA strands by catalyzing the

hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse
nucleotides from the ends of DNA strands are called exonucleases,
while endonucleases cut within strands. The most frequently used
nucleases in molecular biology are the restriction endonucleases, which
The restriction enzyme EcoRV (green) in a
complex with its substrate DNA
[93] cut DNA at specific sequences. For instance, the EcoRV enzyme
shown to the left recognizes the 6-base sequence 5′-GAT|ATC-3′ and
makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting the
phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.[94] In technology,
these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands.[95] Ligases are particularly important in lagging
strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a
complete copy of the DNA template. They are also used in DNA repair and genetic recombination.[95]
DNA 67

Topoisomerases and helicases

Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of
supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate,
thereby reducing its level of supercoiling; the enzyme then seals the DNA break.[27] Other types of these enzymes
are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining
the helix.[96] Topoisomerases are required for many processes involving DNA, such as DNA replication and
transcription.[28]
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates,
predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single
strands.[97] These enzymes are essential for most processes where enzymes need to access the DNA bases.

Polymerases
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their
products are copies of existing polynucleotide chains – which are called templates. These enzymes function by
adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in a DNA strand. As a consequence, all
polymerases work in a 5′ to 3′ direction.[98] In the active site of these enzymes, the incoming nucleoside triphosphate
base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their
template. Polymerases are classified according to the type of template that they use.
In DNA replication, a DNA-dependent DNA polymerase makes a copy of a DNA sequence. Accuracy is vital in this
process, so many of these polymerases have a proofreading activity. Here, the polymerase recognizes the occasional
mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is
detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.[99] In most organisms, DNA
polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the
DNA clamp or helicases.[100]
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand
into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by
retroviruses, and telomerase, which is required for the replication of telomeres.[44] [101] Telomerase is an unusual
polymerase because it contains its own RNA template as part of its structure.[45]
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into
RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and
separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a
region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent
DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome,
operates as part of a large protein complex with multiple regulatory and accessory subunits.[102]
DNA 68

Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are
coloured red, blue, green and yellow.[103]
Further information: Genetic recombination
A DNA helix usually does not interact with other
segments of DNA, and in human cells the different
chromosomes even occupy separate areas in the
nucleus called "chromosome territories".[104] This
physical separation of different chromosomes is
important for the ability of DNA to function as a stable
repository for information, as one of the few times
chromosomes interact is during chromosomal crossover
when they recombine. Chromosomal crossover is when
two DNA helices break, swap a section and then rejoin.
Recombination involves the breakage and rejoining of two
Recombination allows chromosomes to exchange
chromosomes (M and F) to produce two re-arranged chromosomes
genetic information and produces new combinations of
(C1 and C2).
genes, which increases the efficiency of natural
selection and can be important in the rapid evolution of
new proteins.[105] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to
double-strand breaks.[106]

The most common form of chromosomal crossover is homologous recombination, where the two chromosomes
involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce
chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known
as recombinases, such as RAD51.[107] The first step in recombination is a double-stranded break either caused by an
endonuclease or damage to the DNA.[108] A series of steps catalyzed in part by the recombinase then leads to joining
of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to
the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be
moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted
by cleavage of the junction and re-ligation of the released DNA.[109]
DNA 69

Evolution
Further information: RNA world hypothesis
DNA contains the genetic information that allows all modern living things to function, grow and reproduce.
However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been
proposed that the earliest forms of life may have used RNA as their genetic material.[98] [110] RNA may have acted
as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part
of ribozymes.[111] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics
may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur,
since the number of different bases in such an organism is a trade-off between a small number of bases increasing
replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[112]
However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible.
This is because DNA will survive in the environment for less than one million years and slowly degrades into short
fragments in solution.[113] Claims for older DNA have been made, most notably a report of the isolation of a viable
bacterium from a salt crystal 250 million years old,[114] but these claims are controversial.[115] [116]
On August 8, 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting
building blocks of DNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially in
outer space.[117] [118] [119]

Uses in technology

Genetic engineering
Further information: Molecular biology, nucleic acid methods and genetic engineering
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to
manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and
biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a
man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into
organisms in the form of plasmids or in the appropriate format, by using a viral vector.[120] The genetically modified
organisms produced can be used to produce products such as recombinant proteins, used in medical research,[121] or
be grown in agriculture.[122] [123]

Forensics
Further information: DNA profiling
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching
DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, but may also be called
"genetic fingerprinting". In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem
repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for
identifying a matching DNA.[124] However, identification can be complicated if the scene is contaminated with DNA
from several people.[125] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[126] and first
used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[127]
The development of forensic science,and the ability to now obtain genetic matching on minute samples of blood,
skin, saliva or hair has led to a re-examination of a number of cases. Evidence can now be uncovered that was not
scientifically possible at the time of the original examination. Combined with the removal of the double jeopardy
law, this allows cases to be reopened where previous trials have failed to produce sufficient evidence to convince a
jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The
most obvious defence to DNA matches obtained forensically is to claim that cross-contamination of evidence has
DNA 70

taken place. This has resulted in meticulous strict handling procedures with new cases of serious crime. DNA
profiling is also be used to identify victims of mass casualty incidents.[128] As well as positively identifying bodies or
body parts in serious accidents, DNA profiling is being successfully used to identify individual victims in mass war
graves - matching to family members.

Bioinformatics
Further information: Bioinformatics
Bioinformatics involves the manipulation, searching, and data mining of biological data, and this includes DNA
sequence data. The development of techniques to store and search DNA sequences have led to widely applied
advances in computer science, especially string searching algorithms, machine learning and database theory.[129]
String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence
of letters, were developed to search for specific sequences of nucleotides.[130] The DNA sequenced may be aligned
with other DNA sequences to identify homologous sequences and locate the specific mutations that make them
distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships
and protein function.[131] Data sets representing entire genomes' worth of DNA sequences, such as those produced
by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and
regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated
with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict
the presence of particular gene products and their possible functions in an organism even before they have been
isolated experimentally.[132] Entire genomes may also be compared which can shed light on the evolutionary history
of particular organism and permit the examination of complex evolutionary events.

DNA nanotechnology
Further information: DNA
nanotechnology
DNA nanotechnology uses the unique
molecular recognition properties of
DNA and other nucleic acids to create
self-assembling branched DNA
complexes with useful properties.[133]
DNA is thus used as a structural
material rather than as a carrier of
biological information. This has led to
the creation of two-dimensional
periodic lattices (both tile-based as The DNA structure at left (schematic shown) will self-assemble into the structure
well as using the "DNA origami" visualized by atomic force microscopy at right. DNA nanotechnology is the field that
seeks to design nanoscale structures using the molecular recognition properties of DNA
method) as well as three-dimensional
molecules. Image from Strong, 2004 (doi:10.1371/journal.pbio.0020073).
structures in the shapes of
polyhedra.[134] Nanomechanical
devices and algorithmic self-assembly have also been demonstrated,[135] and these DNA structures have been used to
template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins.[136]

History and anthropology

Further information: Phylogenetics and Genetic genealogy
DNA 71

Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by
comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.[137] This
field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared,
population geneticists can learn the history of particular populations. This can be used in studies ranging from
ecological genetics to anthropology; For example, DNA evidence is being used to try to identify the Ten Lost Tribes
of Israel.[138] [139]
DNA has also been used to look at modern family relationships, such as establishing family relationships between
the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal
investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes
has matched relatives of the guilty individual.[140]

History of DNA research

Further information: History of molecular biology
DNA was first isolated by the Swiss physician Friedrich Miescher
who, in 1869, discovered a microscopic substance in the pus of
discarded surgical bandages. As it resided in the nuclei of cells, he
called it "nuclein".[141] In 1878, Albrecht Kossel isolated the
non-protein component of "nuclein", nucleic acid, and later isolated its
five primary nucleobases.[142] In 1919, Phoebus Levene identified the
base, sugar and phosphate nucleotide unit.[143] Levene suggested that
DNA consisted of a string of nucleotide units linked together through
the phosphate groups. However, Levene thought the chain was short
and the bases repeated in a fixed order. In 1937 William Astbury James D. Watson and Francis Crick (right),
produced the first X-ray diffraction patterns that showed that DNA had co-originators of the double-helix model, with
Maclyn McCarty (left).
a regular structure.[144]

In 1927 Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" which
would be made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a
template".[145] In 1928, Frederick Griffith discovered that traits of the "smooth" form of the Pneumococcus could be
transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough"
form.[146] This system provided the first clear suggestion that DNA carries genetic information—the
Avery–MacLeod–McCarty experiment—when Oswald Avery, along with coworkers Colin MacLeod and Maclyn
McCarty, identified DNA as the transforming principle in 1943.[147] DNA's role in heredity was confirmed in 1952,
when Alfred Hershey and Martha Chase in the Hershey–Chase experiment showed that DNA is the genetic material
of the T2 phage.[148]

In 1953, James D. Watson and Francis Crick suggested what is now accepted as the first correct double-helix model
of DNA structure in the journal Nature.[5] Their double-helix, molecular model of DNA was then based on a single
X-ray diffraction image (labeled as "Photo 51")[149] taken by Rosalind Franklin and Raymond Gosling in May 1952,
as well as the information that the DNA bases are paired — also obtained through private communications from
Erwin Chargaff in the previous years. Chargaff's rules played a very important role in establishing double-helix
configurations for B-DNA as well as A-DNA.
Experimental evidence supporting the Watson and Crick model were published in a series of five articles in the same
issue of Nature.[150] Of these, Franklin and Gosling's paper was the first publication of their own X-ray diffraction
data and original analysis method that partially supported the Watson and Crick model;[31] [151] this issue also
contained an article on DNA structure by Maurice Wilkins and two of his colleagues, whose analysis and in vivo
B-DNA X-ray patterns also supported the presence in vivo of the double-helical DNA configurations as proposed by
DNA 72

Crick and Watson for their double-helix molecular model of DNA in the previous two pages of Nature.[32] In 1962,
after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.[152]
However, Nobel rules of the time allowed only living recipients, but a vigorous debate continues on who should
receive credit for the discovery.[153]
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the
relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[154] Final confirmation of
the replication mechanism that was implied by the double-helical structure followed in 1958 through the
Meselson–Stahl experiment.[155] Further work by Crick and coworkers showed that the genetic code was based on
non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall
Warren Nirenberg to decipher the genetic code.[156] These findings represent the birth of molecular biology.

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Accessed 22 December 06

Further reading
• Berry, Andrew; Watson, James D. (2003). DNA: the secret of life. New York: Alfred A. Knopf.
ISBN 0-375-41546-7.
• Calladine, Chris R.; Drew, Horace R.; Luisi, Ben F. and Travers, Andrew A. (2003). Understanding DNA: the
molecule & how it works. Amsterdam: Elsevier Academic Press. ISBN 0-12-155089-3.
• Dennis, Carina; Julie Clayton (2003). 50 years of DNA. Basingstoke: Palgrave Macmillan. ISBN 1-4039-1479-6.
• Judson, Horace F. 1979. The Eighth Day of Creation: Makers of the Revolution in Biology. Touchstone Books,
ISBN 0-671-22540-5. 2nd edition: Cold Spring Harbor Laboratory Press, 1996 paperback: ISBN 0-87969-478-5.
• Olby, Robert C. (1994). The path to the double helix: the discovery of DNA. New York: Dover Publications.
ISBN 0-486-68117-3., first published in October 1974 by MacMillan, with foreword by Francis Crick;the
definitive DNA textbook,revised in 1994 with a 9 page postscript
• Micklas, David. 2003. DNA Science: A First Course. Cold Spring Harbor Press: ISBN 978-0879696368
• Ridley, Matt (2006). Francis Crick: discoverer of the genetic code. Ashland, OH: Eminent Lives, Atlas Books.
ISBN 0-06-082333-X.
• Olby, Robert C. (2009). Francis Crick: A Biography. Plainview, N.Y: Cold Spring Harbor Laboratory Press.
ISBN 0-87969-798-9.
• Rosenfeld, Israel. 2010. DNA: A Graphic Guide to the Molecule that Shook the World. Columbia University
Press: ISBN 978-0231142717
• Schultz, Mark and Zander Cannon. 2009. The Stuff of Life: A Graphic Guide to Genetics and DNA. Hill and
Wang: ISBN 0809089475
DNA 78

• Stent, Gunther Siegmund; Watson, James D. (1980). The double helix: a personal account of the discovery of the
structure of DNA. New York: Norton. ISBN 0-393-95075-1.
• Watson, James D. 2004. DNA: The Secret of Life. Random House: ISBN 978-0099451846
• Wilkins, Maurice (2003). The third man of the double helix the autobiography of Maurice Wilkins. Cambridge,
Eng: University Press. ISBN 0-19-860665-6.

External links
• DNA (http://www.dmoz.org/Science/Biology/Biochemistry_and_Molecular_Biology/Biomolecules/
Nucleic_Acids/DNA//) at the Open Directory Project
• DNA binding site prediction on protein (http://pipe.scs.fsu.edu/displar.html)
• DNA coiling to form chromosomes (http://biostudio.com/c_ education mac.htm)
• DNA the Double Helix Game (http://nobelprize.org/educational_games/medicine/dna_double_helix/) From
the official Nobel Prize web site
• DNA under electron microscope (http://www.fidelitysystems.com/Unlinked_DNA.html)
• Dolan DNA Learning Center (http://www.dnalc.org/)
• Double Helix: 50 years of DNA (http://www.nature.com/nature/dna50/archive.html), Nature
• Proteopedia DNA (http://www.proteopedia.org/wiki/index.php/DNA)
• Double Helix 1953–2003 (http://www.ncbe.reading.ac.uk/DNA50/) National Centre for Biotechnology
Education
• Francis Crick and James Watson talking on the BBC in 1962, 1972, and 1974 (http://www.bbc.co.uk/bbcfour/
audiointerviews/profilepages/crickwatson1.shtml)
• Genetic Education Modules for Teachers (http://www.genome.gov/10506718)—DNA from the Beginning
Study Guide
• Guide to DNA cloning (http://www.blackwellpublishing.com/trun/artwork/Animations/cloningexp/
cloningexp.html)
• Olby R (2003). "Quiet debut for the double helix" (http://chem-faculty.ucsd.edu/joseph/CHEM13/DNA1.
pdf). Nature 421 (6921): 402–5. doi:10.1038/nature01397. PMID 12540907.
• DNA from the Beginning (http://www.dnaftb.org/dnaftb/) Another DNA Learning Center site on DNA, genes,
and heredity from Mendel to the human genome project.
• DNA Lab, demonstrates how to extract DNA from wheat using readily available equipment and supplies. (http://
ca.youtube.com/watch?v=iyb7fwduuGM)
• PDB Molecule of the Month pdb23_1 (http://www.rcsb.org/pdb/static.do?p=education_discussion/
molecule_of_the_month/pdb23_1.html)
• Rosalind Franklin's contributions to the study of DNA (http://mason.gmu.edu/~emoody/rfranklin.html)
• The Register of Francis Crick Personal Papers 1938 – 2007 (http://orpheus.ucsd.edu/speccoll/testing/html/
mss0660a.html#abstract) at Mandeville Special Collections Library, University of California, San Diego
• U.S. National DNA Day (http://www.genome.gov/10506367)—watch videos and participate in real-time chat
with top scientists
• Clue to chemistry of heredity found (http://www.nytimes.com/packages/pdf/science/dna-article.pdf) The
New York Times June 1953. First American newspaper coverage of the discovery of the DNA structure
• An Introduction to DNA and Chromosomes (http://hopes.stanford.edu/basics/dna/b0.html) from HOPES:
Huntington's Disease Outreach Project for Education at Stanford
 79

Proteins and amino acids

Protein
Proteins (pronounced /ˈproʊtiːnz/) are biochemical compounds
consisting of one or more polypeptides typically folded into a globular
or fibrous form, facilitating a biological function. A polypeptide is a
single linear polymer chain of amino acids bonded together by peptide
bonds between the carboxyl and amino groups of adjacent amino acid
residues. The sequence of amino acids in a protein is defined by the
sequence of a gene, which is encoded in the genetic code. In general,
the genetic code specifies 20 standard amino acids; however, in certain
organisms the genetic code can include selenocysteine—and in certain
archaea—pyrrolysine. Shortly after or even during synthesis, the
residues in a protein are often chemically modified by posttranslational
modification, which alters the physical and chemical properties,
folding, stability, activity, and ultimately, the function of the proteins.
A representation of the 3D structure of the protein
Sometimes proteins have non-peptide groups attached, which can be myoglobin showing colored alpha helices. This
called prosthetic groups or cofactors. Proteins can also work together protein was the first to have its structure solved
to achieve a particular function, and they often associate to form stable by X-ray crystallography. Towards the
right-center among the coils, a prosthetic group
protein complexes.
called a heme group is shown colored largely in
green.
One of the most distinguishing features of polypeptides is their ability
to fold into a globular state. The extent to which proteins fold into a
defined structure varies widely. Some proteins fold into a highly rigid structure with small fluctuations and are
therefore considered to be single structure. Other proteins undergo large rearrangements from one conformation to
another. This conformational change is often associated with a signaling event. Thus, the structure of a protein serves
as a medium through which to regulate either the function of a protein or activity of an enzyme. Not all proteins
require a folding process in order to function, as some function in an unfolded state.

Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of
organisms and participate in virtually every process within cells. Many proteins are enzymes that catalyze
biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such as
actin and myosin in muscle and the proteins in the cytoskeleton, which form a system of scaffolding that maintains
cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle.
Proteins are also necessary in animals' diets, since animals cannot synthesize all the amino acids they need and must
obtain essential amino acids from food. Through the process of digestion, animals break down ingested protein into
free amino acids that are then used in metabolism.

Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist
Jöns Jacob Berzelius in 1838. Early nutritional scientists such as the German Carl von Voit believed that protein was
the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh
makes flesh."[1] The central role of proteins as enzymes in living organisms was however not fully appreciated until
1926, when James B. Sumner showed that the enzyme urease was in fact a protein.[2] The first protein to be
sequenced was insulin, by Frederick Sanger, who won the Nobel Prize for this achievement in 1958. The first protein
Protein 80

structures to be solved were hemoglobin and myoglobin, by Max Perutz and Sir John Cowdery Kendrew,
respectively, in 1958.[3] [4] The three-dimensional structures of both proteins were first determined by X-ray
diffraction analysis; Perutz and Kendrew shared the 1962 Nobel Prize in Chemistry for these discoveries. Proteins
may be purified from other cellular components using a variety of techniques such as ultracentrifugation,
precipitation, electrophoresis, and chromatography; the advent of genetic engineering has made possible a number of
methods to facilitate purification. Methods commonly used to study protein structure and function include
immunohistochemistry, site-directed mutagenesis, nuclear magnetic resonance and mass spectrometry. Distributed
computing is a relatively new tool researchers are using to examine the infamously complex interactions that govern
protein folding; the statistical analysis techniques employed to calculate a protein's probable tertiary structure from
its amino acid sequence (primary structure) are well-suited for the distributed computing environment, which has
made this otherwise prohibitively expensive and time consuming problem significantly more manageable.

Biochemistry
Most proteins consist of linear polymers built from series of up
to 20 different L-α-amino acids. All proteinogenic amino acids
possess common structural features, including an α-carbon to
which an amino group, a carboxyl group, and a variable side
chain are bonded. Only proline differs from this basic structure
as it contains an unusual ring to the N-end amine group, which
forces the CO–NH amide moiety into a fixed conformation.[5]
The side chains of the standard amino acids, detailed in the list
of standard amino acids, have a great variety of chemical
structures and properties; it is the combined effect of all of the
amino acid side chains in a protein that ultimately determines its Chemical structure of the peptide bond (bottom) and the
three-dimensional structure and its chemical reactivity.[6] The three-dimensional structure of a peptide bond between an
amino acids in a polypeptide chain are linked by peptide bonds. alanine and an adjacent amino acid (top/inset)

Once linked in the protein chain, an individual amino acid is

called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein
backbone.[7]

The peptide bond has two resonance forms that

contribute some double-bond character and inhibit
rotation around its axis, so that the alpha carbons are
roughly coplanar. The other two dihedral angles in the
Resonance structures of the peptide bond that links individual amino peptide bond determine the local shape assumed by the
acids to form a protein polymer
protein backbone.[8] The end of the protein with a free
carboxyl group is known as the C-terminus or carboxy
terminus, whereas the end with a free amino group is known as the N-terminus or amino terminus. The words
protein, polypeptide, and peptide are a little ambiguous and can overlap in meaning. Protein is generally used to
refer to the complete biological molecule in a stable conformation, whereas peptide is generally reserved for a short
amino acid oligomers often lacking a stable three-dimensional structure. However, the boundary between the two is
not well defined and usually lies near 20–30 residues.[9] Polypeptide can refer to any single linear chain of amino
acids, usually regardless of length, but often implies an absence of a defined conformation.
Protein 81

Synthesis
Proteins are assembled from amino acids using information encoded in
genes. Each protein has its own unique amino acid sequence that is
specified by the nucleotide sequence of the gene encoding this protein.
The genetic code is a set of three-nucleotide sets called codons and
each three-nucleotide combination designates an amino acid, for
example AUG (adenine-uracil-guanine) is the code for methionine.
Because DNA contains four nucleotides, the total number of possible
codons is 64; hence, there is some redundancy in the genetic code, with
some amino acids specified by more than one codon.[10] Genes A ribosome produces a protein using mRNA as
encoded in DNA are first transcribed into pre-messenger RNA template.
(mRNA) by proteins such as RNA polymerase. Most organisms then
process the pre-mRNA (also known as a primary transcript) using
various forms of Post-transcriptional modification to form the mature
mRNA, which is then used as a template for protein synthesis by the
ribosome. In prokaryotes the mRNA may either be used as soon as it is
produced, or be bound by a ribosome after having moved away from
the nucleoid. In contrast, eukaryotes make mRNA in the cell nucleus The DNA sequence of a gene encodes the amino
and then translocate it across the nuclear membrane into the cytoplasm, acid sequence of a protein.

where protein synthesis then takes place. The rate of protein synthesis
is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second.[11]

The process of synthesizing a protein from an mRNA template is known as translation. The mRNA is loaded onto
the ribosome and is read three nucleotides at a time by matching each codon to its base pairing anticodon located on
a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme
aminoacyl tRNA synthetase "charges" the tRNA molecules with the correct amino acids. The growing polypeptide is
often termed the nascent chain. Proteins are always biosynthesized from N-terminus to C-terminus.[10]
The size of a synthesized protein can be measured by the number of amino acids it contains and by its total
molecular mass, which is normally reported in units of daltons (synonymous with atomic mass units), or the
derivative unit kilodalton (kDa). Yeast proteins are on average 466 amino acids long and 53 kDa in mass.[9] The
largest known proteins are the titins, a component of the muscle sarcomere, with a molecular mass of almost 3,000
kDa and a total length of almost 27,000 amino acids.[12]

Chemical synthesis
Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis, which rely on
organic synthesis techniques such as chemical ligation to produce peptides in high yield.[13] Chemical synthesis
allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent
probes to amino acid side chains.[14] These methods are useful in laboratory biochemistry and cell biology, though
generally not for commercial applications. Chemical synthesis is inefficient for polypeptides longer than about 300
amino acids, and the synthesized proteins may not readily assume their native tertiary structure. Most chemical
synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction.[15]
Protein 82

Structure
Further information: Protein structure prediction
Most proteins fold into unique
3-dimensional structures. The shape into
which a protein naturally folds is known as
its native conformation.[16] Although many
proteins can fold unassisted, simply through
the chemical properties of their amino acids,
others require the aid of molecular
chaperones to fold into their native
states.[17] Biochemists often refer to four The crystal structure of the chaperonin. Chaperonins assist protein folding.
distinct aspects of a protein's structure:[18]

• Primary structure: the amino acid

sequence.
• Secondary structure: regularly repeating
local structures stabilized by hydrogen
bonds. The most common examples are
the alpha helix, beta sheet and turns.
Because secondary structures are local,
many regions of different secondary
structure can be present in the same Three possible representations of the three-dimensional structure of the protein
protein molecule. triose phosphate isomerase. Left: all-atom representation colored by atom type.
Middle: Simplified representation illustrating the backbone conformation, colored
• Tertiary structure: the overall shape of a by secondary structure. Right: Solvent-accessible surface representation colored by
single protein molecule; the spatial residue type (acidic residues red, basic residues blue, polar residues green,
relationship of the secondary structures to nonpolar residues white)

one another. Tertiary structure is

generally stabilized by nonlocal interactions, most commonly the formation of a hydrophobic core, but also
through salt bridges, hydrogen bonds, disulfide bonds, and even posttranslational modifications. The term
"tertiary structure" is often used as synonymous with the term fold. The tertiary structure is what controls the
basic function of the protein.
• Quaternary structure: the structure formed by several protein molecules (polypeptide chains), usually called
protein subunits in this context, which function as a single protein complex.
Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several
related structures while they perform their functions. In the context of these functional rearrangements, these tertiary
or quaternary structures are usually referred to as "conformations", and transitions between them are called
conformational changes. Such changes are often induced by the binding of a substrate molecule to an enzyme's
active site, or the physical region of the protein that participates in chemical catalysis. In solution proteins also
undergo variation in structure through thermal vibration and the collision with other molecules.[19]
Protein 83

Proteins can be informally divided into three

main classes, which correlate with typical
tertiary structures: globular proteins, fibrous
proteins, and membrane proteins. Almost all
globular proteins are soluble and many are
enzymes. Fibrous proteins are often
structural, such as collagen, the major Molecular surface of several proteins showing their comparative sizes. From left to
right are: immunoglobulin G (IgG, an antibody), hemoglobin, insulin (a hormone),
component of connective tissue, or keratin,
adenylate kinase (an enzyme), and glutamine synthetase (an enzyme).
the protein component of hair and nails.
Membrane proteins often serve as receptors
or provide channels for polar or charged molecules to pass through the cell membrane.[20]

A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence
promoting their own dehydration, are called dehydrons.[21]

Structure determination
Discovering the tertiary structure of a protein, or the quaternary structure of its complexes, can provide important
clues about how the protein performs its function. Common experimental methods of structure determination include
X-ray crystallography and NMR spectroscopy, both of which can produce information at atomic resolution.
However, NMR experiments are able to provide information from which a subset of distances between pairs of
atoms can be estimated, and the final possible conformations for a protein are determined by solving a distance
geometry problem. Dual polarisation interferometry is a quantitative analytical method for measuring the overall
protein conformation and conformational changes due to interactions or other stimulus. Circular dichroism is another
laboratory technique for determining internal beta sheet/ helical composition of proteins. Cryoelectron microscopy is
used to produce lower-resolution structural information about very large protein complexes, including assembled
viruses;[22] a variant known as electron crystallography can also produce high-resolution information in some cases,
especially for two-dimensional crystals of membrane proteins.[23] Solved structures are usually deposited in the
Protein Data Bank (PDB), a freely available resource from which structural data about thousands of proteins can be
obtained in the form of Cartesian coordinates for each atom in the protein.[24]

Many more gene sequences are known than protein structures. Further, the set of solved structures is biased toward
proteins that can be easily subjected to the conditions required in X-ray crystallography, one of the major structure
determination methods. In particular, globular proteins are comparatively easy to crystallize in preparation for X-ray
crystallography. Membrane proteins, by contrast, are difficult to crystallize and are underrepresented in the PDB.[25]
Structural genomics initiatives have attempted to remedy these deficiencies by systematically solving representative
structures of major fold classes. Protein structure prediction methods attempt to provide a means of generating a
plausible structure for proteins whose structures have not been experimentally determined.

Cellular functions
Proteins are the chief actors within the cell, said to be carrying out the duties specified by the information encoded in
genes.[9] With the exception of certain types of RNA, most other biological molecules are relatively inert elements
upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other
macromolecules such as DNA and RNA make up only 3% and 20%, respectively.[26] The set of proteins expressed
in a particular cell or cell type is known as its proteome.
Protein 84

The chief characteristic of proteins that also allows their diverse set of
functions is their ability to bind other molecules specifically and
tightly. The region of the protein responsible for binding another
molecule is known as the binding site and is often a depression or
"pocket" on the molecular surface. This binding ability is mediated by
the tertiary structure of the protein, which defines the binding site
pocket, and by the chemical properties of the surrounding amino acids'
side chains. Protein binding can be extraordinarily tight and specific;
for example, the ribonuclease inhibitor protein binds to human The enzyme hexokinase is shown as a
angiogenin with a sub-femtomolar dissociation constant (<10−15 M) conventional ball-and-stick molecular model. To
but does not bind at all to its amphibian homolog onconase (>1 M). scale in the top right-hand corner are two of its
substrates, ATP and glucose.
Extremely minor chemical changes such as the addition of a single
methyl group to a binding partner can sometimes suffice to nearly
eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates
against the very similar side chain of the amino acid isoleucine.[27]

Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other
copies of the same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that
consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate
enzymatic activity, control progression through the cell cycle, and allow the assembly of large protein complexes
that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even
be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins
allows the construction of enormously complex signaling networks.[28] Importantly, as interactions between proteins
are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that
are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to
understand important aspects of cellular function, and ultimately the properties that distinguish particular cell
types.[29] [30]

Enzymes
The best-known role of proteins in the cell is as enzymes, which catalyze chemical reactions. Enzymes are usually
highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions
involved in metabolism, as well as manipulating DNA in processes such as DNA replication, DNA repair, and
transcription. Some enzymes act on other proteins to add or remove chemical groups in a process known as
posttranslational modification. About 4,000 reactions are known to be catalyzed by enzymes.[31] The rate
acceleration conferred by enzymatic catalysis is often enormous—as much as 1017-fold increase in rate over the
uncatalyzed reaction in the case of orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with
the enzyme).[32]
The molecules bound and acted upon by enzymes are called substrates. Although enzymes can consist of hundreds
of amino acids, it is usually only a small fraction of the residues that come in contact with the substrate, and an even
smaller fraction—three to four residues on average—that are directly involved in catalysis.[33] The region of the
enzyme that binds the substrate and contains the catalytic residues is known as the active site.
Protein 85

Cell signaling and ligand binding

Many proteins are involved in the process of cell signaling and signal
transduction. Some proteins, such as insulin, are extracellular proteins
that transmit a signal from the cell in which they were synthesized to
other cells in distant tissues. Others are membrane proteins that act as
receptors whose main function is to bind a signaling molecule and
induce a biochemical response in the cell. Many receptors have a
binding site exposed on the cell surface and an effector domain within
the cell, which may have enzymatic activity or may undergo a
conformational change detected by other proteins within the cell.[34]

Antibodies are protein components of an adaptive immune system

whose main function is to bind antigens, or foreign substances in the
body, and target them for destruction. Antibodies can be secreted into
the extracellular environment or anchored in the membranes of
specialized B cells known as plasma cells. Whereas enzymes are
limited in their binding affinity for their substrates by the necessity of
conducting their reaction, antibodies have no such constraints. An
antibody's binding affinity to its target is extraordinarily high.[35] Ribbon diagram of a mouse antibody against
cholera that binds a carbohydrate antigen
Many ligand transport proteins bind particular small biomolecules and
transport them to other locations in the body of a multicellular
organism. These proteins must have a high binding affinity when their ligand is present in high concentrations, but
must also release the ligand when it is present at low concentrations in the target tissues. The canonical example of a
ligand-binding protein is haemoglobin, which transports oxygen from the lungs to other organs and tissues in all
vertebrates and has close homologs in every biological kingdom.[36] Lectins are sugar-binding proteins which are
highly specific for their sugar moieties. Lectins typically play a role in biological recognition phenomena involving
cells and proteins.[37] Receptors and hormones are highly specific binding proteins.

Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane
to small molecules and ions. The membrane alone has a hydrophobic core through which polar or charged molecules
cannot diffuse. Membrane proteins contain internal channels that allow such molecules to enter and exit the cell.
Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium
channels often discriminate for only one of the two ions.[38]

Structural proteins
Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are
fibrous proteins; for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long,
stiff fibers that make up the cytoskeleton, which allows the cell to maintain its shape and size. Collagen and elastin
are critical components of connective tissue such as cartilage, and keratin is found in hard or filamentous structures
such as hair, nails, feathers, hooves, and some animal shells.[39]
Other proteins that serve structural functions are motor proteins such as myosin, kinesin, and dynein, which are
capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms
and the sperm of many multicellular organisms which reproduce sexually. They also generate the forces exerted by
contracting muscles.[40]
Protein 86

Methods of study
As some of the most commonly studied biological molecules, the activities and structures of proteins are examined
both in vitro and in vivo. In vitro studies of purified proteins in controlled environments are useful for learning how a
protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's
catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments on
proteins' activities within cells or even within whole organisms can provide complementary information about where
a protein functions and how it is regulated.

Protein purification
In order to perform in vitro analysis, a protein must be purified away from other cellular components. This process
usually begins with cell lysis, in which a cell's membrane is disrupted and its internal contents released into a
solution known as a crude lysate. The resulting mixture can be purified using ultracentrifugation, which fractionates
the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular
organelles, and nucleic acids. Precipitation by a method known as salting out can concentrate the proteins from this
lysate. Various types of chromatography are then used to isolate the protein or proteins of interest based on
properties such as molecular weight, net charge and binding affinity.[41] The level of purification can be monitored
using various types of gel electrophoresis if the desired protein's molecular weight and isoelectric point are known,
by spectroscopy if the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has
enzymatic activity. Additionally, proteins can be isolated according their charge using electrofocusing.[42]
For natural proteins, a series of purification steps may be necessary to obtain protein sufficiently pure for laboratory
applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that
make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino
acid sequence, often a series of histidine residues (a "His-tag"), is attached to one terminus of the protein. As a result,
when the lysate is passed over a chromatography column containing nickel, the histidine residues ligate the nickel
and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags
have been developed to help researchers purify specific proteins from complex mixtures.[43]
Protein 87

Cellular localization
The study of proteins in vivo is often concerned
with the synthesis and localization of the protein
within the cell. Although many intracellular
proteins are synthesized in the cytoplasm and
membrane-bound or secreted proteins in the
endoplasmic reticulum, the specifics of how
proteins are targeted to specific organelles or
cellular structures is often unclear. A useful
technique for assessing cellular localization uses
genetic engineering to express in a cell a fusion
protein or chimera consisting of the natural
protein of interest linked to a "reporter" such as
green fluorescent protein (GFP).[44] The fused
protein's position within the cell can be cleanly
and efficiently visualized using microscopy,[45]
as shown in the figure opposite.

Other methods for elucidating the cellular

location of proteins requires the use of known
compartmental markers for regions such as the
ER, the Golgi, lysosomes/vacuoles,
mitochondria, chloroplasts, plasma membrane,
etc. With the use of fluorescently tagged versions
of these markers or of antibodies to known Proteins in different cellular compartments and structures tagged with green
fluorescent protein (here, white)
markers, it becomes much simpler to identify the
localization of a protein of interest. For example,
indirect immunofluorescence will allow for fluorescence colocalization and demonstration of location. Fluorescent
dyes are used to label cellular compartments for a similar purpose.[46]

Other possibilities exist, as well. For example, immunohistochemistry usually utilizes an antibody to one or more
proteins of interest that are conjugated to enzymes yielding either luminescent or chromogenic signals that can be
compared between samples, allowing for localization information. Another applicable technique is cofractionation in
sucrose (or other material) gradients using isopycnic centrifugation.[47] While this technique does not prove
colocalization of a compartment of known density and the protein of interest, it does increase the likelihood, and is
more amenable to large-scale studies.

Finally, the gold-standard method of cellular localization is immunoelectron microscopy. This technique also uses an
antibody to the protein of interest, along with classical electron microscopy techniques. The sample is prepared for
normal electron microscopic examination, and then treated with an antibody to the protein of interest that is
conjugated to an extremely electro-dense material, usually gold. This allows for the localization of both
ultrastructural details as well as the protein of interest.[48]
Through another genetic engineering application known as site-directed mutagenesis, researchers can alter the
protein sequence and hence its structure, cellular localization, and susceptibility to regulation. This technique even
allows the incorporation of unnatural amino acids into proteins, using modified tRNAs,[49] and may allow the
rational design of new proteins with novel properties.[50]
Protein 88

Proteomics and bioinformatics

The total complement of proteins present at a time in a cell or cell type is known as its proteome, and the study of
such large-scale data sets defines the field of proteomics, named by analogy to the related field of genomics. Key
experimental techniques in proteomics include 2D electrophoresis,[51] which allows the separation of a large number
of proteins, mass spectrometry,[52] which allows rapid high-throughput identification of proteins and sequencing of
peptides (most often after in-gel digestion), protein microarrays,[53] which allow the detection of the relative levels
of a large number of proteins present in a cell, and two-hybrid screening, which allows the systematic exploration of
protein–protein interactions.[54] The total complement of biologically possible such interactions is known as the
interactome.[55] A systematic attempt to determine the structures of proteins representing every possible fold is
known as structural genomics.[56]
The large amount of genomic and proteomic data available for a variety of organisms, including the human genome,
allows researchers to efficiently identify homologous proteins in distantly related organisms by sequence alignment.
Sequence profiling tools can perform more specific sequence manipulations such as restriction enzyme maps, open
reading frame analyses for nucleotide sequences, and secondary structure prediction. From this data phylogenetic
trees can be constructed and evolutionary hypotheses developed using special software like ClustalW regarding the
ancestry of modern organisms and the genes they express. The field of bioinformatics seeks to assemble, annotate,
and analyze genomic and proteomic data, applying computational techniques to biological problems such as gene
finding and cladistics.

Structure prediction and simulation

Complementary to the field of structural genomics, protein structure prediction seeks to develop efficient ways to
provide plausible models for proteins whose structures have not yet been determined experimentally.[57] The most
successful type of structure prediction, known as homology modeling, relies on the existence of a "template"
structure with sequence similarity to the protein being modeled; structural genomics' goal is to provide sufficient
representation in solved structures to model most of those that remain.[58] Although producing accurate models
remains a challenge when only distantly related template structures are available, it has been suggested that sequence
alignment is the bottleneck in this process, as quite accurate models can be produced if a "perfect" sequence
alignment is known.[59] Many structure prediction methods have served to inform the emerging field of protein
engineering, in which novel protein folds have already been designed.[60] A more complex computational problem is
the prediction of intermolecular interactions, such as in molecular docking and protein–protein interaction
prediction.[61]
The processes of protein folding and binding can be simulated using such technique as molecular mechanics, in
particular, molecular dynamics and Monte Carlo, which increasingly take advantage of parallel and distributed
computing (Folding@Home project;[62] molecular modeling on GPU). The folding of small alpha-helical protein
domains such as the villin headpiece[63] and the HIV accessory protein[64] have been successfully simulated in silico,
and hybrid methods that combine standard molecular dynamics with quantum mechanics calculations have allowed
exploration of the electronic states of rhodopsins.[65]

Nutrition
Further information: Protein (nutrient)
Most microorganisms and plants can biosynthesize all 20 standard amino acids, while animals (including humans)
must obtain some of the amino acids from the diet.[26] The amino acids that an organism cannot synthesize on its
own are referred to as essential amino acids. Key enzymes that synthesize certain amino acids are not present in
animals — such as aspartokinase, which catalyzes the first step in the synthesis of lysine, methionine, and threonine
from aspartate. If amino acids are present in the environment, microorganisms can conserve energy by taking up the
amino acids from their surroundings and downregulating their biosynthetic pathways.
Protein 89

In animals, amino acids are obtained through the consumption of foods containing protein. Ingested proteins are then
broken down into amino acids through digestion, which typically involves denaturation of the protein through
exposure to acid and hydrolysis by enzymes called proteases. Some ingested amino acids are used for protein
biosynthesis, while others are converted to glucose through gluconeogenesis, or fed into the citric acid cycle. This
use of protein as a fuel is particularly important under starvation conditions as it allows the body's own proteins to be
used to support life, particularly those found in muscle.[66] Amino acids are also an important dietary source of
nitrogen.

History and etymology

Further information: History of molecular biology
Proteins were recognized as a distinct class of biological molecules in the eighteenth century by Antoine Fourcroy
and others, distinguished by the molecules' ability to coagulate or flocculate under treatments with heat or acid.
Noted examples at the time included albumin from egg whites, blood serum albumin, fibrin, and wheat gluten. Dutch
chemist Gerardus Johannes Mulder carried out elemental analysis of common proteins and found that nearly all
proteins had the same empirical formula, C400H620N100O120P1S1.[67] He came to the erroneous conclusion that they
might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was
proposed in 1838 by Mulder's associate Jöns Jacob Berzelius; protein is derived from the Greek word πρωτεῖος
(proteios), meaning "primary",[68] "in the lead", or "standing in front".[69] Mulder went on to identify the products of
protein degradation such as the amino acid leucine for which he found a (nearly correct) molecular weight of 131
Da.[67]
The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to
study. Hence, early studies focused on proteins that could be purified in large quantities, e.g., those of blood, egg
white, various toxins, and digestive/metabolic enzymes obtained from slaughterhouses. In the 1950s, the Armour
Hot Dog Co. purified 1 kg of pure bovine pancreatic ribonuclease A and made it freely available to scientists; this
gesture helped ribonuclease A become a major target for biochemical study for the following decades.[67]
Linus Pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen
bonding, an idea first put forth by William Astbury in 1933.[70] Later work by Walter Kauzmann on denaturation,[71]
[72]
based partly on previous studies by Kaj Linderstrøm-Lang,[73] contributed an understanding of protein folding
and structure mediated by hydrophobic interactions. In 1949 Fred Sanger correctly determined the amino acid
sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather
than branched chains, colloids, or cyclols.[74] The first atomic-resolution structures of proteins were solved by X-ray
crystallography in the 1960s and by NMR in the 1980s. As of 2009, the Protein Data Bank has over 55,000
atomic-resolution structures of proteins.[75] In more recent times, cryo-electron microscopy of large macromolecular
assemblies[76] and computational protein structure prediction of small protein domains[77] are two methods
approaching atomic resolution.
Protein 90

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28–32. doi:10.1016/S1367-5931(02)00015-7. PMID 12547423.
[57] Zhang Y (2008). "Progress and challenges in protein structure prediction". Current Opinions in Structural Biology 18 (3): 342–48.
doi:10.1016/j.sbi.2008.02.004. PMC 2680823. PMID 18436442.
[58] Xiang Z (2006). "Advances in homology protein structure modeling". Current Protein and Peptide Science 7 (3): 217–27.
doi:10.2174/138920306777452312. PMC 1839925. PMID 16787261.
[59] Zhang Y, Skolnick J (2005). "The protein structure prediction problem could be solved using the current PDB library" (http:/ / www. pnas.
org/ cgi/ pmidlookup?view=long& pmid=15653774). Proceedings of the National Academy of Sciences U.S.A. 102 (4): 1029–34.
doi:10.1073/pnas.0407152101. PMC 545829. PMID 15653774. .
[60] Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BL, Baker D (2003). "Design of a novel globular protein fold with atomic-level
accuracy" (http:/ / www. sciencemag. org/ cgi/ pmidlookup?view=long& pmid=14631033). Science 302 (5649): 1364–68.
Bibcode 2003Sci...302.1364K. doi:10.1126/science.1089427. PMID 14631033. .
[61] Ritchie DW (2008). "Recent progress and future directions in protein–protein docking". Current Protein and Peptide Science 9 (1): 1–15.
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[62] Scheraga HA, Khalili M, Liwo A (2007). "Protein-folding dynamics: overview of molecular simulation techniques". Annual Review of
Physical Chemistry 58: 57–83. doi:10.1146/annurev.physchem.58.032806.104614. PMID 17034338.
[63] Zagrovic B, Snow CD, Shirts MR, Pande VS (2002). "Simulation of folding of a small alpha-helical protein in atomistic detail using
worldwide-distributed computing". Journal of Molecular Biology 323 (5): 927–37. doi:10.1016/S0022-2836(02)00997-X. PMID 12417204.
[64] Herges T, Wenzel W (2005). "In silico folding of a three helix protein and characterization of its free-energy landscape in an all-atom force
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[65] Hoffmann M, Wanko M, Strodel P, König PH, Frauenheim T, Schulten K, Thiel W, Tajkhorshid E, Elstner M (2006). "Color tuning in
rhodopsins: the mechanism for the spectral shift between bacteriorhodopsin and sensory rhodopsin II". Journal of the American Chemical
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[66] Brosnan J (June 2003). "Interorgan amino acid transport and its regulation" (http:/ / jn. nutrition. org/ cgi/ content/ full/ 133/ 6/ 2068S).
Journal of Nutrition 133 (6 Suppl 1): 2068S–72S. PMID 12771367. .
[67] Perrett D (2007). "From 'protein' to the beginnings of clinical proteomics". Proteomics – Clinical Applications 1 (8): 720–38.
doi:10.1002/prca.200700525. PMID 21136729.
[68] New Oxford Dictionary of English
[69] Reynolds JA, Tanford C (2003). Nature's Robots: A History of Proteins (Oxford Paperbacks). New York, New York: Oxford University
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[70] Pauling L, Corey RB, Branson HR (1951). "The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain"
(http:/ / www. pnas. org/ site/ misc/ Protein8. pdf) (PDF). Proceedings of the National Academy of Sciences U.S.A. 37 (5): 235–40.
Bibcode 1951PNAS...37..235P. doi:10.1073/pnas.37.5.235. PMC 1063348. PMID 14834145. .
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References
• Branden C, Tooze J (1999). Introduction to Protein Structure. New York: Garland Pub. ISBN 0-8153-2305-0.
• Murray RF, Harper HW, Granner DK, Mayes PA, Rodwell VW (2006). Harper's Illustrated Biochemistry. New
York: Lange Medical Books/McGraw-Hill. ISBN 0-07-146197-3.
• Van Holde KE, Mathews CK (1996). Biochemistry. Menlo Park, California: Benjamin/Cummings Pub. Co., Inc.
ISBN 0-8053-3931-0.

External links

Databases and projects

• Comparative Toxicogenomics Database (http://ctd.mdibl.org/) curates protein–chemical interactions, as well
as gene/protein–disease relationships and chemical-disease relationships.
• Bioinformatic Harvester (http://harvester.fzk.de) A Meta search engine (29 databases) for gene and protein
information.
• The Protein Databank (http://www.rcsb.org) (see also PDB Molecule of the Month (http://www.rcsb.org/
pdb/static.do?p=education_discussion/molecule_of_the_month/index.html), presenting short accounts on
selected proteins from the PDB)
• Proteopedia – Life in 3D (http://www.proteopedia.org): rotatable, zoomable 3D model with wiki annotations
for every known protein molecular structure.
• UniProt the Universal Protein Resource (http://www.expasy.uniprot.org)
• neXtProt – Exploring the universe of human proteins (http://www.nextprot.org): human-centric protein
knowledge resource
• The Protein Naming Utility (http://www.jcvi.org/pn-utility)
• Human Protein Atlas (http://www.proteinatlas.org)
• NCBI Entrez Protein database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=protein)
• NCBI Protein Structure database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=structure)
• Human Protein Reference Database (http://www.hprd.org/)
Protein 93

• Human Proteinpedia (http://www.humanproteinpedia.org/)

• Folding@Home (Stanford University) (http://folding.stanford.edu/)

Tutorials and educational websites

• "An Introduction to Proteins" (http://hopes.stanford.edu/basics/proteins/p0.html) from HOPES (Huntington's
Disease Outreach Project for Education at Stanford)
• Proteins: Biogenesis to Degradation – The Virtual Library of Biochemistry and Cell Biology (http://www.
biochemweb.org/proteins.shtml)

Amino acid
Amino acids (pronounced /əˈmiːnoʊ ..., əˈmaɪnoʊ ..., ˈæmɪnoʊ .../)
are molecules containing an amine group, a carboxylic acid group
and a side-chain that varies between different amino acids. The
key elements of an amino acid are carbon, hydrogen, oxygen, and
nitrogen. They are particularly important in biochemistry, where
the term usually refers to alpha-amino acids.

An alpha-amino acid has the generic formula H2NCHRCOOH,

where R is an organic substituent;[1] the amino group is attached to
the carbon atom immediately adjacent to the carboxylate group
The generic structure of an alpha amino acid in its
(the α–carbon). Other types of amino acid exist when the amino
unionized form
group is attached to a different carbon atom; for example, in
gamma-amino acids (such as gamma-amino-butyric acid) the
carbon atom to which the amino group attaches is separated from the carboxylate group by two other carbon atoms.
The various alpha-amino acids differ in which side-chain (R-group) is attached to their alpha carbon, and can vary in
size from just one hydrogen atom in glycine to a large heterocyclic group in tryptophan.

Amino acids are critical to life, and have many functions in metabolism. One particularly important function is to
serve as the building blocks of proteins, which are linear chains of amino acids. Amino acids can be linked together
in varying sequences to form a vast variety of proteins.[2] Twenty-two amino acids
Amino acid 94

are naturally incorporated into polypeptides and

are called proteinogenic or standard amino
acids. Of these, 20 are encoded by the universal
genetic code. Nine standard amino acids are
called "essential" for humans because they
cannot be created from other compounds by the
human body, and so must be taken in as food.

Due to their central role in biochemistry, amino

acids are important in nutrition and are
commonly used in nutrition supplements,
fertilizers, food technology and industry. In
industry, applications include the production of
biodegradable plastics, drugs, and chiral
catalysts.

The 21 amino acids found in eukaryotes, grouped according to their

side-chains' pKas and charge at physiological pH 7.4

History
The first few amino acids were discovered in the early 19th century. In 1806, the French chemists Louis-Nicolas
Vauquelin and Pierre Jean Robiquet isolated a compound in asparagus that proved to be asparagine, the first amino
acid to be discovered.[3] [4] Another amino acid that was discovered in the early 19th century was cystine, in 1810,[5]
although its monomer, cysteine, was discovered much later, in 1884.[4] [6] Glycine and leucine were also discovered
around this time, in 1820.[7] Usage of the term amino acid in the English language is from 1898.[8]
Amino acid 95

General structure
Further information: Proteinogenic amino acid
In the structure shown at the top of the page, R represents a side-chain specific to
each amino acid. The carbon atom next to the carboxyl group is called the α–carbon
and amino acids with a side-chain bonded to this carbon are referred to as alpha
amino acids. These are the most common form found in nature. In the alpha amino
acids, the α–carbon is a chiral carbon atom, with the exception of glycine.[9] In
amino acids that have a carbon chain attached to the α–carbon (such as lysine,
shown to the right) the carbons are labeled in order as α, β, γ, δ, and so on.[10] In
some amino acids, the amine group is attached to the β or γ-carbon, and these are
therefore referred to as beta or gamma amino acids.

Amino acids are usually classified by the properties of their side-chain into four
groups. The side-chain can make an amino acid a weak acid or a weak base, and a
hydrophile if the side-chain is polar or a hydrophobe if it is nonpolar.[9] The
chemical structures of the 22 standard amino acids, along with their chemical
Lysine with the carbon atoms in
properties, are described more fully in the article on these proteinogenic amino the side-chain labeled
acids.

The phrase "branched-chain amino acids" or BCAA refers to the amino acids having aliphatic side-chains that are
non-linear; these are leucine, isoleucine, and valine. Proline is the only proteinogenic amino acid whose side-group
links to the α-amino group and, thus, is also the only proteinogenic amino acid containing a secondary amine at this
position.[9] In chemical terms, proline is, therefore, an imino acid, since it lacks a primary amino group,[11] although
it is still classed as an amino acid in the current biochemical nomenclature,[12] and may also be called an
"N-alkylated alpha-amino acid".[13]

Isomerism
Of the standard α-amino acids, all but glycine can exist in either of two
optical isomers, called L or D amino acids, which are mirror images of
each other (see also Chirality). While L-amino acids represent all of the
amino acids found in proteins during translation in the ribosome,
D-amino acids are found in some proteins produced by enzyme
posttranslational modifications after translation and translocation to the
endoplasmic reticulum, as in exotic sea-dwelling organisms such as
The two optical isomers of alanine, D-Alanine
cone snails.[14] They are also abundant components of the
and L-Alanine
peptidoglycan cell walls of bacteria,[15] and D-serine may act as a
neurotransmitter in the brain.[16] The L and D convention for amino
acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the
isomer of glyceraldehyde from which that amino acid can, in theory, be synthesized (D-glyceraldehyde is
dextrorotary; L-glyceraldehyde is levorotary). In alternative fashion, the (S) and (R) designators are used to indicate
the absolute stereochemistry. Almost all of the amino acids in proteins are (S) at the α carbon, with cysteine being
(R) and glycine non-chiral.[17] Cysteine is unusual since it has a sulfur atom at the second position in its side-chain,
which has a larger atomic mass than the groups attached to the first carbon, which is attached to the α-carbon in the
other standard amino acids, thus the (R) instead of (S).
Amino acid 96

Zwitterions
The amine and carboxylic acid
functional groups found in amino acids
allow them to have amphiprotic
properties.[9] Carboxylic acid groups
(-CO2H) can be deprotonated to
become negative carboxylates (-CO2- ),
and α-amino groups (NH2-) can be
protonated to become positive
+
α-ammonium groups ( NH3-). At pH An amino acid in its (1) unionized and (2) zwitterionic forms
values greater than the pKa of the
carboxylic acid group (mean for the 20 common amino acids is about 2.2, see the table of amino acid structures
above), the negative carboxylate ion predominates. At pH values lower than the pKa of the α-ammonium group
(mean for the 20 common α-amino acids is about 9.4), the nitrogen is predominantly protonated as a positively
charged α-ammonium group. Thus, at pH between 2.2 and 9.4, the predominant form adopted by α-amino acids
contains a negative carboxylate and a positive α-ammonium group, as shown in structure (2) on the right, so has net
zero charge. This molecular state is known as a zwitterion, from the German Zwitter meaning hermaphrodite or
hybrid.[18] Below pH 2.2, the predominant form will have a neutral carboxylic acid group and a positive
α-ammonium ion (net charge +1), and above pH 9.4, a negative carboxylate and neutral α-amino group (net charge
-1). The fully neutral form (structure (1) on the right) is a very minor species in aqueous solution throughout the pH
range (less than 1 part in 107). Amino acids also exist as zwitterions in the solid phase, and crystallize with salt-like
properties unlike typical organic acids or amines.

Isoelectric point
At pH values between the two pKa values, the zwitterion predominates, but coexists in dynamic equilibrium with
small amounts of net negative and net positive ions. At the exact midpoint between the two pKa values, the trace
amount of net negative and trace of net positive ions exactly balance, so that average net charge of all forms present
is zero.[19] This pH is known as the isoelectric point pI, so pI = ½(pKa1 + pKa2). The individual amino acids all have
slightly different pKa values, so have different isoelectric points. For amino acids with charged side-chains, the pKa
of the side-chain is involved. Thus for Asp, Glu with negative side-chains, pI = ½(pKa1 + pKaR), where pKaR is the
side-chain pKa. Cysteine also has potentially negative side-chain with pKaR = 8.14, so pI should be calculated as for
Asp and Glu, even though the side-chain is not significantly charged at neutral pH. For His, Lys, and Arg with
positive side-chains, pI = ½(pKaR + pKa2). Amino acids have zero mobility in electrophoresis at their isoelectric
point, although this behaviour is more usually exploited for peptides and proteins than single amino acids.
Zwitterions have minimum solubility at their isolectric point and some amino acids (in particular, with non-polar
side-chains) can be isolated by precipitation from water by adjusting the pH to the required isoelectric point.
Amino acid 97

Occurrence and functions in biochemistry

Standard amino acids

Amino acids are the structural units that
make up proteins. They join together to
form short polymer chains called peptides or
longer chains called either polypeptides or
proteins. These polymers are linear and
unbranched, with each amino acid within
the chain attached to two neighboring amino
acids. The process of making proteins is
called translation and involves the
step-by-step addition of amino acids to a
growing protein chain by a ribozyme that is A polypeptide is an unbranched chain of amino acids.
[20]
called a ribosome. The order in which the
amino acids are added is read through the genetic code from an mRNA template, which is a RNA copy of one of the
organism's genes.

Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino
acids.[9] Of these, 20 are encoded by the universal genetic code. The remaining 2, selenocysteine and pyrrolysine, are
incorporated into proteins by unique synthetic mechanisms. Selenocysteine is incorporated when the mRNA being
translated includes a SECIS element, which causes the UGA codon to encode selenocysteine instead of a stop
codon.[21] Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is
coded for with the codon UAG, which is normally a stop codon in other organisms.[22] This UAG codon is followed
by a PYLIS downstream sequence.[23]

Non-standard amino acids

Aside from the 22 standard amino acids, there are many other amino acids
that are called non-proteinogenic or non-standard. Those either are not
found in proteins (for example carnitine, GABA), or are not produced
directly and in isolation by standard cellular machinery (for example,
hydroxyproline and selenomethionine).
Non-standard amino acids that are found in proteins are formed by
post-translational modification, which is modification after translation
The amino acid selenocysteine during protein synthesis. These modifications are often essential for the
function or regulation of a protein; for example, the carboxylation of
glutamate allows for better binding of calcium cations,[24] and the hydroxylation of proline is critical for maintaining
connective tissues.[25] Another example is the formation of hypusine in the translation initiation factor EIF5A,
through modification of a lysine residue.[26] Such modifications can also determine the localization of the protein,
e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.[27]
Amino acid 98

Some nonstandard amino acids are not found in

proteins. Examples include lanthionine,
2-aminoisobutyric acid, dehydroalanine, and the
neurotransmitter gamma-aminobutyric acid.
Nonstandard amino acids often occur as intermediates
in the metabolic pathways for standard amino acids —
for example, ornithine and citrulline occur in the urea
cycle, part of amino acid catabolism (see below).[28] A
rare exception to the dominance of α-amino acids in β-alanine and its α-alanine isomer

biology is the β-amino acid beta alanine

(3-aminopropanoic acid), which is used in plants and microorganisms in the synthesis of pantothenic acid (vitamin
B5), a component of coenzyme A.[29]

In human nutrition
Further information: Protein in nutrition and Amino acid synthesis
When taken up into the human body from the diet, the 22 standard amino acids either are used to synthesize proteins
and other biomolecules or are oxidized to urea and carbon dioxide as a source of energy.[30] The oxidation pathway
starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The
other product of transamidation is a keto acid that enters the citric acid cycle.[31] Glucogenic amino acids can also be
converted into glucose, through gluconeogenesis.[32]
Pyrrolysine trait is restricted to several microbes, and only one organism has both Pyl and Sec. Of the 22 standard
amino acids, 9 are called essential amino acids because the human body cannot synthesize them from other
compounds at the level needed for normal growth, so they must be obtained from food.[33] In addition, cysteine,
taurine, tyrosine, histidine, and arginine are semiessential amino-acids in children, because the metabolic pathways
that synthesize these amino acids are not fully developed.[34] [35] The amounts required also depend on the age and
health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.

Essential Nonessential

Histidine Alanine

Isoleucine Arginine*

Leucine Asparagine

Lysine Aspartic acid

Methionine Cysteine*

Phenylalanine Glutamic acid

Threonine Glutamine*

Tryptophan Glycine

Valine Ornithine*

Proline*

Selenocysteine*

Serine*

Taurine*

Tyrosine*

(*) Essential only in certain cases.[36] [37]

Amino acid 99

Non-protein functions
Further information: Amino acid neurotransmitter
In humans, non-protein amino acids also have important roles as metabolic intermediates, such as in the biosynthesis
of the neurotransmitter gamma-aminobutyric acid. Many amino acids are used to synthesize other molecules, for
example:
• Tryptophan is a precursor of the neurotransmitter serotonin.[38]
• Tyrosine is a precursor of the neurotransmitter dopamine.
• Glycine is a precursor of porphyrins such as heme.[39]
• Arginine is a precursor of nitric oxide.[40]
• Ornithine and S-adenosylmethionine are precursors of polyamines.[41]
• Aspartate, glycine, and glutamine are precursors of nucleotides.[42]
• Phenylalanine is a precursor of various phenylpropanoids, which are important in plant metabolism.
However, not all of the functions of other abundant non-standard amino acids are known. For example, taurine is a
major amino acid in muscle and brain tissues, but, although many functions have been proposed, its precise role in
the body has not been determined.[43]
Some non-standard amino acids are used as defenses against herbivores in plants.[44] For example canavanine is an
analogue of arginine that is found in many legumes,[45] and in particularly large amounts in Canavalia gladiata
(sword bean).[46] This amino acid protects the plants from predators such as insects and can cause illness in people if
some types of legumes are eaten without processing.[47] The non-protein amino acid mimosine is found in other
species of legume, particularly Leucaena leucocephala.[48] This compound is an analogue of tyrosine and can poison
animals that graze on these plants.

Uses in technology
Amino acids are used for a variety of applications in industry, but their main use is as additives to animal feed. This
is necessary, since many of the bulk components of these feeds, such as soybeans, either have low levels or lack
some of the essential amino acids: Lysine, methionine, threonine, and tryptophan are most important in the
production of these feeds.[49] In this industry, amino acids are also used to chelate metal cations in order to improve
the absorption of minerals from supplements, which may be required to improve the health or production of these
animals.[50]
The food industry is also a major consumer of amino acids, in particular, glutamic acid, which is used as a flavor
enhancer,[51] and Aspartame (aspartyl-phenylalanine-1-methyl ester) as a low-calorie artificial sweetener.[52] Similar
technology to that used for animal nutrition is employed in the human nutrition industry to alleviate symptoms of
mineral deficiencies, such as anemia, by improving mineral absorption and reducing negative side effects from
inorganic mineral supplementation. [53]
The chelating ability of amino acids has been used in fertilizers for agriculture to facilitate the delivery of minerals to
plants in order to correct mineral deficiencies, such as iron chlorosis. These fertilizers are also used to prevent
deficiencies from occurring and improving the overall health of the plants.[54] The remaining production of amino
acids is used in the synthesis of drugs and cosmetics.[49]
Amino acid 100

Amino acid derivative Pharmaceutical application

5-HTP (5-hydroxytryptophan) [55]

Experimental treatment for depression.

L-DOPA (L-dihydroxyphenylalanine) [56]

Treatment for Parkinsonism.

Eflornithine [57]
Drug that inhibits ornithine decarboxylase and is used in the treatment of sleeping sickness.

Expanded genetic code

Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a
corresponding transfer-RNA:aminoacyl – tRNA-synthetase pair to encode it with diverse physicochemical and
biological properties in order to be used as a tool to exploring protein structure and function or to create novel or
enhanced proteins.[58] [59]

Chemical building blocks

Further information: Asymmetric synthesis
Amino acids are important as low-cost feedstocks. These compounds are used in chiral pool synthesis as
enantiomerically-pure building blocks.[60]
Amino acids have been investigated as precursors chiral catalysts, e.g., for asymmetric hydrogenation reactions,
although no commercial applications exist.[61]

Biodegradable plastics
Further information: Biodegradable plastics and Biopolymers
Amino acids are under development as components of a range of biodegradable polymers. These materials have
applications as environmentally friendly packaging and in medicine in drug delivery and the construction of
prosthetic implants. These polymers include polypeptides, polyamides, polyesters, polysulfides, and polyurethanes
with amino acids either forming part of their main chains or bonded as side-chains. These modifications alter the
physical properties and reactivities of the polymers.[62] An interesting example of such materials is polyaspartate, a
water-soluble biodegradable polymer that may have applications in disposable diapers and agriculture.[63] Due to its
solubility and ability to chelate metal ions, polyaspartate is also being used as a biodegradeable anti-scaling agent
and a corrosion inhibitor.[64] [65] In addition, the aromatic amino acid tyrosine is being developed as a possible
replacement for toxic phenols such as bisphenol A in the manufacture of polycarbonates.[66]

Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most
of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation
and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the
carboxylic acid group.[67] The combination of these functional groups allow amino acids to be effective polydentate
ligands for metal-amino acid chelates.[68] The multiple side-chains of amino acids can also undergo chemical
reactions.[69] The types of these reactions are determined by the groups on these side-chains and are, therefore,
different between the various types of amino acid.
Amino acid 101

Chemical synthesis
Several methods exist to synthesize
amino acids. One of the oldest methods
begins with the bromination at the
The Strecker amino acid synthesis α-carbon of a carboxylic acid.
Nucleophilic substitution with
ammonia then converts the alkyl bromide to the amino acid.[70] In alternative fashion, the Strecker amino acid
synthesis involves the treatment of an aldehyde with potassium cyanide and ammonia, this produces an α-amino
nitrile as an intermediate. Hydrolysis of the nitrile in acid then yields a α-amino acid.[71] Using ammonia or
ammonium salts in this reaction gives unsubstituted amino acids, while substituting primary and secondary amines
will yield substituted amino acids.[72] Likewise, using ketones, instead of aldehydes, gives α,α-disubstituted amino
[73]
acids. The classical synthesis gives racemic mixtures of α-amino acids as products, but several alternative
procedures using asymmetric auxiliaries [74] or asymmetric catalysts [75] [76] have been developed.[77]

At the current time, the most-adopted method is an automated synthesis on a solid support (e.g., polystyrene beads),
using protecting groups (e.g., Fmoc and t-Boc) and activating groups (e.g., DCC and DIC).

Peptide bond formation

As both the amine and carboxylic acid
groups of amino acids can react to
form amide bonds, one amino acid
molecule can react with another and
become joined through an amide
linkage. This polymerization of amino
acids is what creates proteins. This
condensation reaction yields the newly
formed peptide bond and a molecule of
water. In cells, this reaction does not
occur directly; instead the amino acid
is first activated by attachment to a
transfer RNA molecule through an
ester bond. This aminoacyl-tRNA is
produced in an ATP-dependent
reaction carried out by an aminoacyl
tRNA synthetase.[78] This
The condensation of two amino acids to form a peptide bond
aminoacyl-tRNA is then a substrate for
the ribosome, which catalyzes the
attack of the amino group of the elongating protein chain on the ester bond.[79] As a result of this mechanism, all
proteins made by ribosomes are synthesized starting at their N-terminus and moving towards their C-terminus.

However, not all peptide bonds are formed in this way. In a few cases, peptides are synthesized by specific enzymes.
For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This
peptide is synthesized in two steps from free amino acids.[80] In the first step gamma-glutamylcysteine synthetase
condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the
glutamate (the gamma carbon of this side-chain) and the amino group of the cysteine. This dipeptide is then
condensed with glycine by glutathione synthetase to form glutathione.[81]
Amino acid 102

In chemistry, peptides are synthesized by a variety of reactions. One of the most-used in solid-phase peptide
synthesis uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the
growing peptide chain, which is attached to a solid resin support.[82] The ability to easily synthesize vast numbers of
different peptides by varying the types and order of amino acids (using combinatorial chemistry) has made peptide
synthesis particularly important in creating libraries of peptides for use in drug discovery through high-throughput
screening.[83]

Biosynthesis
In plants, nitrogen is first assimilated into organic compounds in the form of glutamate, formed from
alpha-ketoglutarate and ammonia in the mitochondrion. In order to form other amino acids, the plant uses
transaminases to move the amino group to another alpha-keto carboxylic acid. For example, aspartate
aminotransferase converts glutamate and oxaloacetate to alpha-ketoglutarate and aspartate.[84] Other organisms use
transaminases for amino acid synthesis, too.
Nonstandard amino acids are usually formed through modifications to standard amino acids. For example,
homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the
intermediate metabolite S-adenosyl methionine,[43] while hydroxyproline is made by a posttranslational modification
of proline.[85]
Microorganisms and plants can synthesize many uncommon amino acids. For example, some microbes make
2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged derivative of alanine. Both of these amino acids
are found in peptidic lantibiotics such as alamethicin.[86] While in plants, 1-aminocyclopropane-1-carboxylic acid is
a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.[87]

Catabolism
Degradation of an amino acid often involves
deamination by moving its amino group to
alpha-ketoglutarate, forming glutamate. This
process involves transaminases, often the
same as those used in amination during
synthesis. In many vertebrates, the amino
group is then removed through the urea
cycle and is excreted in the form of urea.
However, amino acid degradation can
produce uric acid or ammonia instead. For
example, serine dehydratase converts serine
to pyruvate and ammonia.[89]
Catabolism of proteinogenic amino acids. Amino acids can be classified according
[88]
to the properties of their main products as either of the following: Glucogenic,
Physicochemical properties of with the products having the ability to form glucose by gluconeogenesisKetogenic,
amino acids with the products not having the ability to form glucose. These products may still
be used for ketogenesis or lipid synthesis.Amino acids catabolized into both
The 20 amino acids encoded directly by the glucogenic and ketogenic products.
genetic code can be divided into several
groups based on their properties. Important factors are charge, hydrophilicity or hydrophobicity, size, and functional
groups.[9] These properties are important for protein structure and protein–protein interactions. The water-soluble
proteins tend to have their hydrophobic residues (Leu, Ile, Val, Phe, and Trp) buried in the middle of the protein,
whereas hydrophilic side-chains are exposed to the aqueous solvent. The integral membrane proteins tend to have
outer rings of exposed hydrophobic amino acids that anchor them into the lipid bilayer. In the case part-way between
Amino acid 103

these two extremes, some peripheral membrane proteins have a patch of hydrophobic amino acids on their surface
that locks onto the membrane. In similar fashion, proteins that have to bind to positively-charged molecules have
surfaces rich with negatively charged amino acids like glutamate and aspartate, while proteins binding to
negatively-charged molecules have surfaces rich with positively charged chains like lysine and arginine. There are
different hydrophobicity scales of amino acid residues.[90]
Some amino acids have special properties such as cysteine, that can form covalent disulfide bonds to other cysteine
residues, proline that forms a cycle to the polypeptide backbone, and glycine that is more flexible than other amino
acids.
Many proteins undergo a range of posttranslational modifications, when additional chemical groups are attached to
the amino acids in proteins. Some modifications can produce hydrophobic lipoproteins,[91] or hydrophilic
glycoproteins.[92] These type of modification allow the reversible targeting of a protein to a membrane. For example,
the addition and removal of the fatty acid palmitic acid to cysteine residues in some signaling proteins causes the
proteins to attach and then detach from cell membranes.[93]

Table of standard amino acid abbreviations and properties

Amino Acid [94] [94]

3-Letter 1-Letter Side-chain Side-chain charge Hydropathy Absorbance ε at λmax (x10−3
[94] [94] [95] [96] [96]
polarity (pH 7.4) index λmax(nm) M−1 cm−1)

Alanine Ala A nonpolar neutral 1.8

Arginine Arg R polar positive −4.5

Asparagine Asn N polar neutral −3.5

Aspartic acid Asp D polar negative −3.5

Cysteine Cys C polar neutral 2.5 250 0.3

Glutamic acid Glu E polar negative −3.5

Glutamine Gln Q polar neutral −3.5

Glycine Gly G nonpolar neutral −0.4

Histidine His H polar positive(10%) −3.2 211 5.9

neutral(90%)

Isoleucine Ile I nonpolar neutral 4.5

Leucine Leu L nonpolar neutral 3.8

Lysine Lys K polar positive −3.9

Methionine Met M nonpolar neutral 1.9

Phenylalanine Phe F nonpolar neutral 2.8 257, 206, 188 0.2, 9.3, 60.0

Proline Pro P nonpolar neutral −1.6

Serine Ser S polar neutral −0.8

Threonine Thr T polar neutral −0.7

Tryptophan Trp W nonpolar neutral −0.9 280, 219 5.6, 47.0

Tyrosine Tyr Y polar neutral −1.3 274, 222, 193 1.4, 8.0, 48.0

Valine Val V nonpolar neutral 4.2

In addition, there are two additional amino acids that are incorporated by overriding stop codons:
Amino acid 104

21st and 22nd amino acids 3-Letter 1-Letter

Selenocysteine Sec U

Pyrrolysine Pyl O

In addition to the specific amino acid codes, placeholders are used in cases where chemical or crystallographic
analysis of a peptide or protein cannot conclusively determine the identity of a residue.

Ambiguous Amino Acids 3-Letter 1-Letter

Asparagine or aspartic acid Asx B

Glutamine or glutamic acid Glx Z

Leucine or Isoleucine Xle J

Unspecified or unknown amino acid Xaa X

Unk is sometimes used instead of Xaa, but is less standard.

In addition, many non-standard amino acids have a specific code. For example, several peptide drugs, such as
Bortezomib and MG132, are artificially synthesized and retain their protecting groups, which have specific codes.
Bortezomib is Pyz-Phe-boroLeu, and MG132 is Z-Leu-Leu-Leu-al. To aid in the analysis of protein structure,
photocrosslinking amino acid analogues are available. These include photoleucine (pLeu) and photomethionine
(pMet).[97]

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[86] Whitmore L, Wallace BA (May 2004). "Analysis of peptaibol sequence composition: implications for in vivo synthesis and channel
formation". European Biophysics Journal 33 (3): 233–7. doi:10.1007/s00249-003-0348-1. PMID 14534753.
[87] Alexander L, Grierson D (October 2002). "Ethylene biosynthesis and action in tomato: a model for climacteric fruit ripening". Journal of
Experimental Botany 53 (377): 2039–55. doi:10.1093/jxb/erf072. PMID 12324528.
[88] Chapter 20 (Amino Acid Degradation and Synthesis) in: Denise R., PhD. Ferrier. Lippincott's Illustrated Reviews: Biochemistry
(Lippincott's Illustrated Reviews). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2265-9.
[89] Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2002). Biochemistry. San Francisco: W.H. Freeman. pp. 639–49.
ISBN 0-7167-4684-0.
[90] Urry, Dan W. (2004). "The change in Gibbs free energy for hydrophobic association: Derivation and evaluation by means of inverse
temperature transitions". Chemical Physics Letters 399 (1–3): 177–83. doi:10.1016/S0009-2614(04)01565-9.
[91] Magee T, Seabra MC (April 2005). "Fatty acylation and prenylation of proteins: what's hot in fat". Current Opinion in Cell Biology 17 (2):
190–6. doi:10.1016/j.ceb.2005.02.003. PMID 15780596.
[92] Pilobello KT, Mahal LK (June 2007). "Deciphering the glycocode: the complexity and analytical challenge of glycomics". Current Opinion
in Chemical Biology 11 (3): 300–5. doi:10.1016/j.cbpa.2007.05.002. PMID 17500024.
[93] Smotrys JE, Linder ME (2004). "Palmitoylation of intracellular signaling proteins: regulation and function". Annual Review of Biochemistry
73 (1): 559–87. doi:10.1146/annurev.biochem.73.011303.073954. PMID 15189153.
[94] Hausman, Robert E.; Cooper, Geoffrey M. (2004). The cell: a molecular approach. Washington, D.C: ASM Press. p. 51.
ISBN 0-87893-214-3.
[95] Kyte J, Doolittle RF (May 1982). "A simple method for displaying the hydropathic character of a protein". Journal of Molecular Biology
157 (1): 105–32. doi:10.1016/0022-2836(82)90515-0. PMID 7108955.
[96] Freifelder, D. (1983). Physical Biochemistry (2nd ed.). W. H. Freeman and Company. ISBN 0-7167-1315-2.
[97] Suchanek M, Radzikowska A, Thiele C (April 2005). "Photo-leucine and photo-methionine allow identification of protein-protein
interactions in living cells". Nature Methods 2 (4): 261–7. doi:10.1038/nmeth752. PMID 15782218.

Further reading
• Doolittle, R.F. (1989) Redundancies in protein sequences. In Predictions of Protein Structure and the Principles
of Protein Conformation (Fasman, G.D. ed) Plenum Press, New York, pp. 599–623
• David L. Nelson and Michael M. Cox, Lehninger Principles of Biochemistry, 3rd edition, 2000, Worth Publishers,
ISBN 1-57259-153-6
• Meierhenrich, U.J.: Amino acids and the asymmetry of life, Springer-Verlag, Berlin, New York, 2008. ISBN
978-3-540-76885-2
• Morelli, Robert J. "Studies of amino acid absorption from the small intestine." San Francisco: Morelli, 1952.
Amino acid 108

External links
• Amino acids overview (http://www.peptideguide.com/amino-acids/index.html) physical-chemistry properties,
3D structures, etc.
• List of Standard Amino Acids (http://www.unc.edu/~bzafer/aminoacids/) The Detailed PDF List of Standard
Amino Acids (including 3D depictions)
• Nomenclature and Symbolism for Amino Acids and Peptides (http://www.chem.qmul.ac.uk/iupac/
AminoAcid/) IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)
• Molecular Expressions: The Amino Acid Collection (http://micro.magnet.fsu.edu/aminoacids/index.html) –
Has detailed information and microscopy photographs of each amino acid.
• Amino acid properties (http://www.russell.embl.de/aas/) – Properties of the amino acids (a tool aimed mostly
at molecular geneticists trying to understand the meaning of mutations)
• Synthesis of Amino Acids and Derivatives (http://www.organic-chemistry.org/synthesis/C1C/nitrogen/
alpha-amino-acids2.shtm)
• Learn the 20 proteinogenic amino acids online (http://www.mathiasbader.de/studium/biology/index.
php?lng=en)
• The origin of the single-letter code for the amino acids (http://www.biology.arizona.edu/biochemistry/
problem_sets/aa/Dayhoff.html)
• Amino acid solution’s pH, titration and isoelectric point calculation free spreadsheet (http://www2.iq.usp.br/
docente/gutz/Curtipot_.html)
• Interactive Amino Map Web Application at DNA.UTAH.EDU (http://www.dna.utah.edu/utensils/amino.
php)

Properties of the twenty amino acids

Proteinogenic amino acids are those amino acids that can be found in proteins and require cellular machinery coded
for in the genetic code [1] of any organism for their isolated production. There are 22 standard amino acids, but only
21 are found in eukaryotes. Of the 22, 20 are directly encoded by the universal genetic code. Humans can synthesize
11 of these 20 from each other or from other molecules of intermediary metabolism. The other 9 must be consumed
in the diet, and so are called essential amino acids; those are histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, threonine, tryptophan, and valine. The remaining two, selenocysteine and pyrrolysine, are
incorporated into proteins by unique synthetic mechanisms.
The word proteinogenic means "protein building". Proteinogenic amino acids can be assembled into a polypeptide
(the subunit of a protein) through a process called translation (the second stage of protein biosynthesis, part of the
overall process of gene expression).
In contrast, non-proteinogenic amino acids are either not found in proteins (like carnitine, GABA, or L-DOPA), or
are not produced directly and in isolation by standard cellular machinery (like hydroxyproline and
selenomethionine). The latter often results from posttranslational modification of proteins.
There are clear reasons why organisms have not evolved to incorporate certain non-proteinogenic amino acids into
proteins: for example, ornithine and homoserine cyclize against the peptide backbone and fragment the protein with
relatively short half-lives, while others are toxic because they can be mistakenly incorporated into proteins, such as
the arginine analog canavanine.
Non-proteinogenic amino acids are found in nonribosomal peptides, which are not produced by the ribosome during
translation.
Properties of the twenty amino acids 109

Structures
The following illustrates the structures and abbreviations of the 21 amino acids that are directly encoded for protein
synthesis by the genetic code of eukaryotes. The structures given below are standard chemical structures, not the
typical zwitterion forms that exist in aqueous solutions.

Grouped table of 21 amino acids' structures, nomenclature, and their side

groups' pKa's.

L-Alanine L-Arginine L-Asparagine L-Aspartic acid

(Ala / A) (Arg / R) (Asn / N) (Asp / D)

L-Cysteine L-Glutamic acid L-Glutamine Glycine

(Cys / C) (Glu / E) (Gln / Q) (Gly / G)
Properties of the twenty amino acids 110

L-Histidine L-Isoleucine L-Leucine L-Lysine

(His / H) (Ile / I) (Leu / L) (Lys / K)

L-Methionine L-Phenylalanine L-Proline L-Serine

(Met / M) (Phe / F) (Pro / P) (Ser / S)

L-Threonine L-Tryptophan L-Tyrosine L-Valine

(Thr / T) (Trp / W) (Tyr / Y) (Val / V)

IUPAC/IUBMB now also recommends standard abbreviations for the following two amino acids:

L-Selenocysteine L-Pyrrolysine
(Sec / U) (Pyl / O)
Properties of the twenty amino acids 111

Non-specific abbreviations
Sometimes the specific identity of an amino acid cannot be determined unambiguously. Certain protein sequencing
techniques do not distinguish among certain pairs. Thus, the following codes are used:
• Asx (B) is "asparagine or aspartic acid"
• Glx (Z) is "glutamic acid or glutamine"
• Xle (J) is "leucine or isoleucine"
In addition, the symbol X is used to indicate an amino acid that is completely unidentified.

Chemical properties
Following is a table listing the one-letter symbols, the three-letter symbols, and the chemical properties of the
side-chains of the standard amino acids. The masses listed are based on weighted averages of the elemental isotopes
at their natural abundances. Note that forming a peptide bond results in elimination of a molecule of water, so the
mass of an amino acid unit within a protein chain is reduced by 18.01524 Da.
General chemical properties

Amino Acid Short Abbrev. Avg. Mass (Da) pI pK1 pK2

(α-COOH) (α-+NH )
3

Alanine A Ala 89.09404 6.01 2.35 9.87

Cysteine C Cys 121.15404 5.05 1.92 10.70

Aspartic acid D Asp 133.10384 2.85 1.99 9.90

Glutamic acid E Glu 147.13074 3.15 2.10 9.47

Phenylalanine F Phe 165.19184 5.49 2.20 9.31

Glycine G Gly 75.06714 6.06 2.35 9.78

Histidine H His 155.15634 7.60 1.80 9.33

Isoleucine I Ile 131.17464 6.05 2.32 9.76

Lysine K Lys 146.18934 9.60 2.16 9.06

Leucine L Leu 131.17464 6.01 2.33 9.74

Methionine M Met 149.20784 5.74 2.13 9.28

Asparagine N Asn 132.11904 5.41 2.14 8.72

Pyrrolysine O Pyl

Proline P Pro 115.13194 6.30 1.95 10.64

Glutamine Q Gln 146.14594 5.65 2.17 9.13

Arginine R Arg 174.20274 10.76 1.82 8.99

Serine S Ser 105.09344 5.68 2.19 9.21

Threonine T Thr 119.12034 5.60 2.09 9.10

Selenocysteine U Sec 168.053 5.47

Valine V Val 117.14784 6.00 2.39 9.74

Tryptophan W Trp 204.22844 5.89 2.46 9.41

Tyrosine Y Tyr 181.19124 5.64 2.20 9.21

Properties of the twenty amino acids 112

Side chain properties

Amino Acid Short Abbrev. Side chain Hydro- pKa Polar pH Small Tiny Aromatic van der
phobic or Waals
Aliphatic volume

Alanine A Ala -CH3 X - - - X X - 67

Cysteine C Cys -CH2SH X 8.18 - acidic X - - 86

Aspartic acid D Asp -CH2COOH - 3.90 X acidic X - - 91

Glutamic acid E Glu -CH2CH2COOH - 4.07 X acidic - - - 109

Phenylalanine F Phe -CH2C6H5 X - - - - - Aromatic 135

Glycine G Gly -H X - - - X X - 48

Histidine H His -CH2-C3H3N2 - 6.04 X weak basic - - Aromatic 118

Isoleucine I Ile -CH(CH3)CH2CH3 X - - - - - Aliphatic 124

Lysine K Lys -(CH2)4NH2 - 10.54 X basic - - - 135

Leucine L Leu -CH2CH(CH3)2 X - - - - - Aliphatic 124

Methionine M Met -CH2CH2SCH3 X - - - - - - 124

Asparagine N Asn -CH2CONH2 - - X - X - - 96

Pyrrolysine O Pyl

Proline P Pro -CH2CH2CH2- X - - - X - - 90

Glutamine Q Gln -CH2CH2CONH2 - - X - - - - 114

Arginine R Arg -(CH2)3NH-C(NH)NH2 - 12.48 X strongly - - - 148

basic

Serine S Ser -CH2OH - - X - X X - 73

Threonine T Thr -CH(OH)CH3 - - X weak acidic X - - 93

Selenocysteine U Sec -CH2SeH X 5.73 - - X - -

Valine V Val -CH(CH3)2 X - - - X - Aliphatic 105

Tryptophan W Trp -CH2C8H6N X - - - - - Aromatic 163

Tyrosine Y Tyr -CH2-C6H4OH - 10.46 X - - - Aromatic 141

Note: The pKa values of amino acids are typically slightly different when the amino acid is inside a protein. Protein
pKa calculations are sometimes used to calculate the change in the pKa value of an amino acid in this situation.

Gene expression and biochemistry

Properties of the twenty amino acids 113

Amino Acid Short Abbrev. Codon(s) Occurrence Essential‡ in humans

in human
proteins
(%)

Alanine A Ala GCU, GCC, GCA, GCG 7.8 -

Cysteine C Cys UGU, UGC 1.9 Conditionally

Aspartic acid D Asp GAU, GAC 5.3 -

Glutamic acid E Glu GAA, GAG 6.3 Conditionally

Phenylalanine F Phe UUU, UUC 3.9 Yes

Glycine G Gly GGU, GGC, GGA, GGG 7.2 Conditionally

Histidine H His CAU, CAC 2.3 Yes

Isoleucine I Ile AUU, AUC, AUA 5.3 Yes

Lysine K Lys AAA, AAG 5.9 Yes

Leucine L Leu UUA, UUG, CUU, CUC, CUA, CUG 9.1 Yes

Methionine M Met AUG 2.3 Yes

Asparagine N Asn AAU, AAC 4.3 -

Pyrrolysine O Pyl UAG* -

Proline P Pro CCU, CCC, CCA, CCG 5.2 -

Glutamine Q Gln CAA, CAG 4.2 -

Arginine R Arg CGU, CGC, CGA, CGG, AGA, AGG 5.1 Conditionally

Serine S Ser UCU, UCC, UCA, UCG, AGU, AGC 6.8 -

Threonine T Thr ACU, ACC, ACA, ACG 5.9 Yes

Selenocysteine U Sec UGA** -

Valine V Val GUU, GUC, GUA, GUG 6.6 Yes

Tryptophan W Trp UGG 1.4 Yes

Tyrosine Y Tyr UAU, UAC 3.2 Conditionally

Stop codon† - Term UAA, UAG, UGA - -

* UAG is normally the amber stop codon, but encodes pyrrolysine if a PYLIS element is present.
** UGA is normally the opal (or umber) stop codon, but encodes selenocysteine if a SECIS element is present.
† The stop codon is not an amino acid, but is included for completeness.
‡ An essential amino acid cannot be synthesized in humans and must, therefore, be supplied in the diet.
Conditionally essential amino acids are not normally required in the diet, but must be supplied exogenously to
specific populations that do not synthesize it in adequate amounts.
Properties of the twenty amino acids 114

Mass spectrometry
In mass spectrometry of peptides and proteins, it is useful to know the masses of the residues. The mass of the
peptide or protein is the sum of the residue masses plus the mass of water.[2]

Amino Acid Short Abbrev. Formula Mon. Mass§ (Da) Avg. Mass (Da)

Alanine A Ala C3H5NO 71.03711 71.0788

Cysteine C Cys C3H5NOS 103.00919 103.1388

Aspartic acid D Asp C4H5NO3 115.02694 115.0886

Glutamic acid E Glu C5H7NO3 129.04259 129.1155

Phenylalanine F Phe C9H9NO 147.06841 147.1766

Glycine G Gly C2H3NO 57.02146 57.0519

Histidine H His C6H7N3O 137.05891 137.1411

Isoleucine I Ile C6H11NO 113.08406 113.1594

Lysine K Lys C6H12N2O 128.09496 128.1741

Leucine L Leu C6H11NO 113.08406 113.1594

Methionine M Met C5H9NOS 131.04049 131.1986

Asparagine N Asn C4H6N2O2 114.04293 114.1039

Pyrrolysine O Pyl C12H21N3O3 255.15829 255.3172

Proline P Pro C5H7NO 97.05276 97.1167

Glutamine Q Gln C5H8N2O2 128.05858 128.1307

Arginine R Arg C6H12N4O 156.10111 156.1875

Serine S Ser C3H5NO2 87.03203 87.0782

Threonine T Thr C4H7NO2 101.04768 101.1051

Selenocysteine U Sec C3H5NOSe 150.95364 150.0388

Valine V Val C5H9NO 99.06841 99.1326

Tryptophan W Trp C11H10N2O 186.07931 186.2132

Tyrosine Y Tyr C9H9NO2 163.06333 163.1760

§ Monoisotopic mass

Stoichiometry and metabolic cost in cell

Following table lists the abundance of amino acids in E.coli cell and the metabolic cost (ATP) for synthesis the
amino acids. Negative numbers indicate the metabolic processes are energy favorable and do not cost net ATP of the
cell.[3] Note that the abundance of amino acids include amino acids in free-form and in polymerization form
(proteins).
Properties of the twenty amino acids 115

Amino acid ATP cost in ATP cost in

Abundance
synthesis synthesis
(# of molecules
under aerobic under anaerobic
(×108)
condition condition
per E. coli cell)

Alanine 2.9 -1 1

Cysteine 0.52 11 15

Aspartic acid 1.4 0 2

Glutamic acid 1.5 -7 -1

Phenylalanine 1.1 -6 2

Glycine 3.5 -2 2

Histidine 0.54 1 7

Isoleucine 1.7 7 11

Lysine 2.0 5 9

Leucine 2.6 -9 1

Methionine 0.88 21 23

Asparagine 1.4 3 5

Proline 1.3 -2 4

Glutamine 1.5 -6 0

Arginine 1.7 5 13

Serine 1.2 -2 2

Threonine 1.5 6 8

Tryptophan 0.33 -7 7

Tyrosine 0.79 -8 2

Valine 2.4 -2 2

Remarks

Amino Acid Abbrev. Remarks

Alanine A Ala Very abundant, very versatile. More stiff than glycine, but small enough to pose only small steric limits for the
protein conformation. It behaves fairly neutrally, and can be located in both hydrophilic regions on the protein
outside and the hydrophobic areas inside.

Asparagine or B Asx A placeholder when either amino acid may occupy a position.
aspartic acid

Cysteine C Cys The sulfur atom bonds readily to heavy metal ions. Under oxidizing conditions, two cysteines can join together in a
disulfide bond to form the amino acid cystine. When cystines are part of a protein, insulin for example, the tertiary
structure is stabilized, which makes the protein more resistant to denaturation; therefore, disulfide bonds are common
in proteins that have to function in harsh environments including digestive enzymes (e.g., pepsin and chymotrypsin)
and structural proteins (e.g., keratin). Disulfides are also found in peptides too small to hold a stable shape on their
own (eg. insulin).

Aspartic acid D Asp Behaves similarly to glutamic acid. Carries a hydrophilic acidic group with strong negative charge. Usually is located
on the outer surface of the protein, making it water-soluble. Binds to positively-charged molecules and ions, often
used in enzymes to fix the metal ion. When located inside of the protein, aspartate and glutamate are usually paired
with arginine and lysine.
Properties of the twenty amino acids 116

Glutamic acid E Glu Behaves similar to aspartic acid. Has longer, slightly more flexible side chain.

Phenylalanine F Phe Essential for humans. Phenylalanine, tyrosine, and tryptophan contain large rigid aromatic group on the side-chain.
These are the biggest amino acids. Like isoleucine, leucine and valine, these are hydrophobic and tend to orient
towards the interior of the folded protein molecule. Phenylalanine can be converted into Tyrosine.

Glycine G Gly Because of the two hydrogen atoms at the α carbon, glycine is not optically active. It is the smallest amino acid,
rotates easily, adds flexibility to the protein chain. It is able to fit into the tightest spaces, e.g., the triple helix of
collagen. As too much flexibility is usually not desired, as a structural component it is less common than alanine.

Histidine H His In even slightly acidic conditions protonation of the nitrogen occurs, changing the properties of histidine and the
polypeptide as a whole. It is used by many proteins as a regulatory mechanism, changing the conformation and
behavior of the polypeptide in acidic regions such as the late endosome or lysosome, enforcing conformation change
in enzymes. However only a few histidines are needed for this, so it is comparatively scarce.

Isoleucine I Ile Essential for humans. Isoleucine, leucine and valine have large aliphatic hydrophobic side chains. Their molecules
are rigid, and their mutual hydrophobic interactions are important for the correct folding of proteins, as these chains
tend to be located inside of the protein molecule.

Leucine or J Xle A placeholder when either amino acid may occupy a position
isoleucine

Lysine K Lys Essential for humans. Behaves similarly to arginine. Contains a long flexible side-chain with a positively-charged
end. The flexibility of the chain makes lysine and arginine suitable for binding to molecules with many negative
charges on their surfaces. E.g., DNA-binding proteins have their active regions rich with arginine and lysine. The
strong charge makes these two amino acids prone to be located on the outer hydrophilic surfaces of the proteins;
when they are found inside, they are usually paired with a corresponding negatively-charged amino acid, e.g.,
aspartate or glutamate.

Leucine L Leu Essential for humans. Behaves similar to isoleucine and valine. See isoleucine.

Methionine M Met Essential for humans. Always the first amino acid to be incorporated into a protein; sometimes removed after
translation. Like cysteine, contains sulfur, but with a methyl group instead of hydrogen. This methyl group can be
activated, and is used in many reactions where a new carbon atom is being added to another molecule.

Asparagine N Asn Similar to aspartic acid. Asn contains an amide group where Asp has a carboxyl.

Pyrrolysine O Pyl Similar to lysine, with a pyrroline ring attached.

Proline P Pro Contains an unusual ring to the N-end amine group, which forces the CO-NH amide sequence into a fixed
conformation. Can disrupt protein folding structures like α helix or β sheet, forcing the desired kink in the protein
chain. Common in collagen, where it often undergoes a posttranslational modification to hydroxyproline.

Glutamine Q Gln Similar to glutamic acid. Gln contains an amide group where Glu has a carboxyl. Used in proteins and as a storage
for ammonia. The most abundant Amino Acid in the body.

Arginine R Arg Functionally similar to lysine.

Serine S Ser Serine and threonine have a short group ended with a hydroxyl group. Its hydrogen is easy to remove, so serine and
threonine often act as hydrogen donors in enzymes. Both are very hydrophilic, therefore the outer regions of soluble
proteins tend to be rich with them.

Threonine T Thr Essential for humans. Behaves similarly to serine.

Selenocysteine U Sec Selenated form of cysteine, which replaces sulfur.

Valine V Val Essential for humans. Behaves similarly to isoleucine and leucine. See isoleucine.

Tryptophan W Trp Essential for humans. Behaves similarly to phenylalanine and tyrosine (see phenylalanine). Precursor of serotonin.
Naturally fluorescent.

Unknown X Xaa Placeholder when the amino acid is unknown or unimportant.

Tyrosine Y Tyr Behaves similarly to phenylalanine (precursor to Tyrosine) and tryptophan (see phenylalanine). Precursor of melanin,
epinephrine, and thyroid hormones. Naturally fluorescent, although fluorescence is usually quenched by energy
transfer to tryptophans.

Glutamic acid Z Glx A placeholder when either amino acid may occupy a position.
or glutamine
Properties of the twenty amino acids 117

Catabolism

[4]
Amino acids can be classified according to the properties of their main products as either of the following:
Glucogenic, with the products having the ability to form glucose by gluconeogenesisKetogenic, with the
products not having the ability to form glucose. These products may still be used for ketogenesis or lipid
synthesis.Amino acids catabolized into both glucogenic and ketogenic products.

References
[1] Ambrogelly A, Palioura S, Söll D (Jan 2007). "Natural expansion of the genetic code" (http:/ / www. nature. com/ nchembio/ journal/ v3/ n1/
abs/ nchembio847. html). Nat Chem Biol 3 (1): 29–35. doi:10.1038/nchembio847. PMID 17173027. .
[2] "The amino acid masses" (http:/ / education. expasy. org/ student_projects/ isotopident/ htdocs/ aa-list. html). ExPASy. . Retrieved
2009-01-06.
[3] Physical Biology of the Cell (Garland Science) p. 178
[4] Chapter 20 (Amino Acid Degradation and Synthesis) in: Denise R., PhD. Ferrier. Lippincott's Illustrated Reviews: Biochemistry (Lippincott's
Illustrated Reviews). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2265-9.

• Nelson, David L.; Cox, Michael M. (2000). Lehninger Principles of Biochemistry (3rd ed.). Worth Publishers.
ISBN 1-57259-153-6.
• Kyte, J.; Doolittle, R. F. (1982). "A simple method for displaying the hydropathic character of a protein". J. Mol.
Biol. 157 (1): 105–132. doi:10.1016/0022-2836(82)90515-0. PMID 7108955.
• Meierhenrich, Uwe J. (2008). Amino acids and the asymmetry of life (1st ed.). Springer.
ISBN 978-3-540-76885-2.
Myoglobin 118

Myoglobin
Myoglobin

[1]
Model of helical domains in myoglobin.

Available structures

PDB 1m6c [2], 1m6m [3], 1mdn [4], 1mnh [5], 1mni [6], 1mnj [7], 1mnk [8], 1mno [9], 1mwc [10], 1mwd [11], 1myg [12], 1myh
[13] [14] [15] [16] [17] [18] [19]
, 1myi , 1myj , 1pmb , 1yca , 1ycb , 2mm1

Identifiers

Symbols [20]
MB ; MGC13548; PVALB

External IDs [21] [22] [23] [24]

OMIM:  160000 MGI:  96922 HomoloGene:  3916 GeneCards: MB Gene

Gene Ontology

Molecular function • oxygen transporter activity [25]

[26]
• iron ion binding
[27]
• oxygen binding
[28]
• heme binding
[29]
• metal ion binding

Biological process [30]

• response to hypoxia
[31]
• transport
[32]
• oxygen transport
[33]
• enucleate erythrocyte differentiation
[34] [35]
Sources: Amigo / QuickGO

RNA expression pattern

[36]
More reference expression data

Orthologs

Species Human Mouse

Myoglobin 119

Entrez [37] [38]

4151 17189

Ensembl [39] [40]

ENSG00000198125 ENSMUSG00000018893

UniProt [41] [42]

P02144 Q3UVB1

RefSeq (mRNA) [43] [44]

NM_005368 NM_013593

RefSeq (protein) [45] [46]

NP_005359 NP_038621

Location (UCSC) Chr 22: Chr 15:

[47] [48]
34.33 – 34.35 Mb 76.84 – 76.88 Mb

PubMed search [49] [50]

Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost
all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the
red blood cells. The only time myoglobin is found in the bloodstream is when it is released following muscle injury.
It is an abnormal finding, and can be diagnostically relevant when found in blood. [51]
Myoglobin (abbreviated Mb) is a single-chain globular protein of 153[52] or 154[53] amino acids, containing a heme
(iron-containing porphyrin) prosthetic group in the center around which the remaining apoprotein folds. It has eight
alpha helices and a hydrophobic core. It has a molecular weight of 17,699 daltons (with heme), and is the primary
oxygen-carrying pigment of muscle tissues.[53] Unlike the blood-borne hemoglobin, to which it is structurally
related,[54] this protein does not exhibit cooperative binding of oxygen, since positive cooperativity is a property of
multimeric/oligomeric proteins only. Instead, the binding of oxygen by myoglobin is unaffected by the oxygen
pressure in the surrounding tissue. Myoglobin is often cited as having an "instant binding tenacity" to oxygen given
its hyperbolic oxygen dissociation curve. High concentrations of myoglobin in muscle cells allow organisms to hold
their breaths longer. Diving mammals such as whales and seals have muscles with particularly high myoglobin
abundance.[51]
Myoglobin was the first protein to have its three-dimensional structure revealed.[55] In 1958, John Kendrew and
associates successfully determined the structure of myoglobin by high-resolution X-ray crystallography.[56] For this
discovery, John Kendrew shared the 1962 Nobel Prize in chemistry with Max Perutz.[57] Despite being one of the
most studied proteins in biology, its true physiological function is not yet conclusively established: mice genetically
engineered to lack myoglobin are viable, but showed a 30% reduction in cardiac systolic output. They adapted to this
deficiency through hypoxic genetic mechanisms and increased vasodilation.[58] In humans myoglobin is encoded by
the MB gene.[59]
Myoglobin 120

Meat color
Myoglobin forms pigments responsible for making meat red. The color
that meat takes is partly determined by the oxidation states of the iron
atom in myoglobin and the oxygen species attached to it. When meat is
in its raw state, the iron atom is in the +2 oxidation state, and is bound
to a dioxygen molecule (O2). Meat cooked well done is brown because
the iron atom is now in the +3 oxidation state, having lost an electron,
and is now coordinated by a water molecule. Under some conditions,
meat can also remain pink all through cooking, despite being heated to
high temperatures. If meat has been exposed to nitrites, it will remain
pink because the iron atom is bound to NO, nitric oxide (true of, e.g.,
An X-ray diffraction image for the protein corned beef or cured hams). Grilled meats can also take on a pink
myoglobin "smoke ring" that comes from the iron binding to a molecule of carbon
monoxide to give metmyoglobin.[60] Raw meat packed in a carbon
monoxide atmosphere also shows this same pink "smoke ring" due to the same coordination chemistry. Notably, the
surface of this raw meat also displays the pink color, which is usually associated in consumers' minds with fresh
meat. This artificially-induced pink color can persist in the meat for a very long time, reportedly up to one year.[61]
Hormel and Cargill are both reported to use this meat-packing process, and meat treated this way has been in the
consumer market since 2003.[62] Myoglobin is found in Type I muscle, Type II A and Type II B, but most texts
consider myoglobin not to be found in smooth muscle.

Role in disease
Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of
myoglobin. The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may
cause acute renal failure.[63] It is not the myoglobin itself that is toxic (it is a protoxin) but the ferrihemate portion
that is dissociated from myoglobin in acidic environments (e.g., acidic urine, lysozymes).
Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest
pain.[64] However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB,
cTnT, ECG, and clinical signs should be taken into account to make the diagnosis.

Structure and bonding

Myoglobin contains a porphyrin ring with an iron center. There is a proximal histidine group attached directly to the
iron center, and a distal histidine group on the opposite face, not bonded to the iron.
Many functional models of myoglobin have been studied. One of the most important is that of picket fence porphyrin
by James Collman. This model was used to show the importance of the distal prosthetic group. It serves three
functions:
1. To form hydrogen bonds with the dioxygen moiety, increasing the O2 binding constant
2. To prevent the binding of carbon monoxide, whether from within or without the body. Carbon monoxide binds to
iron in an end-on fashion, and is hindered by the presence of the distal histidine, which forces it into a bent
conformation. CO binds to heme 23,000 times better than O2, but only 200 times better in hemoglobin and
myoglobin. Oxygen binds in a bent fashion, which can fit with the distal histidine.[65]
3. To prevent irreversible dimerization of the oxymyoglobin with another deoxymyoglobin species
Myoglobin 121

References
[1] PDB 1MBO (http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1MBO); Takano T (March 1977). "Structure of myoglobin
refined at 2.0 Å resolution. II. Structure of deoxymyoglobin from sperm whale". J. Mol. Biol. 110 (3): 569–84.
doi:10.1016/S0022-2836(77)80112-5. PMID 845960.
[2] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1m6c
[3] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1m6m
[4] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mdn
[5] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mnh
[6] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mni
[7] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mnj
[8] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mnk
[9] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mno
[10] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mwc
[11] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1mwd
[12] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1myg
[13] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1myh
[14] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1myi
[15] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1myj
[16] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1pmb
[17] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1yca
[18] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1ycb
[19] http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=2mm1
[20] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=6915
[21] http:/ / omim. org/ entry/ 160000
[22] http:/ / www. informatics. jax. org/ searches/ accession_report. cgi?id=MGI:96922
[23] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=homologene& dopt=HomoloGene& list_uids=3916
[24] http:/ / www. genecards. org/ cgi-bin/ carddisp. pl?id_type=entrezgene& id=4151
[25] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005344
[26] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0005506
[27] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0019825
[28] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0020037
[29] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0046872
[30] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0001666
[31] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0006810
[32] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0015671
[33] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?view=details& search_constraint=terms& depth=0& query=GO:0043353
[34] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ gp-assoc. cgi?gp=UniProtKB:P02144
[35] http:/ / www. ebi. ac. uk/ QuickGO/ GProtein?ac=P02144
[36] http:/ / biogps. org/ gene/ 4151/
[37] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=4151& rn=1
[38] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& cmd=retrieve& dopt=default& list_uids=17189& rn=1
[39] http:/ / www. ensembl. org/ Homo_sapiens/ geneview?gene=ENSG00000198125;db=core
[40] http:/ / www. ensembl. org/ Mus_musculus/ geneview?gene=ENSMUSG00000018893;db=core
[41] http:/ / www. uniprot. org/ uniprot/ P02144
[42] http:/ / www. uniprot. org/ uniprot/ Q3UVB1
[43] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_005368
[44] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NM_013593
[45] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_005359
[46] http:/ / www. ncbi. nlm. nih. gov/ entrez/ viewer. fcgi?val=NP_038621
[47] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Human& db=hg18& position=chr22:34332757-34349347
[48] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?org=Mouse& db=mm8& position=chr15:76842742-76877925
[49] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=4151
[50] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?db=gene& cmd=Link& LinkName=gene_pubmed& from_uid=17189
[51] Nelson, D. L.; Cox, M. M. (2000). Lehninger Principles of Biochemistry (3rd ed.). New York: Worth Publishers. p. 206. ISBN 071676203X.
[52] Hendgen-Cotta, U.; Kelm, M.; Rassaf, T. (2009). "A highlight of myoglobin diversity: the nitrite reductase activity during myocardial
ischemia-reperfusion". Nitric oxide : biology and chemistry / official journal of the Nitric Oxide Society 22 (2): 75–82.
doi:10.1016/j.niox.2009.10.003. PMID 19836457.
Myoglobin 122

[53] George A. Ordway and Daniel J. Garry (2004). "Myoglobin: an essential hemoprotein in striated muscle". Journal of Experimental Biology
207 (Pt 20): 3441–6. doi:10.1242/jeb.01172. PMID 15339940.
[54] Harvey Lodish, Arnold Berk, Lawrence S. Zipursky, Paul Matsudaira, David Baltimore and James Darnell (2000). "Evolutionary tree
showing the globin protein family members myoglobin and hemoglobin" (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search&
db=books& doptcmdl=GenBookHL& term=myoglobin+ AND+ mcb[book]+ AND+ 105134[uid]& rid=mcb. figgrp. 540). Molecular Cell
Biology (4th ed.). W. H. Freeman. ISBN 0-7167-3136-3. .
[55] (U.S.) National Science Foundation: Protein Data Bank Chronology (Jan. 21, 2004) (http:/ / www. nsf. gov/ news/ news_summ.
jsp?cntn_id=100689). Retrieved 3.17.2010
[56] JC Kendrew, G Bodo, HM Dintzis, RG Parrish, H Wyckoff, and DC Phillips (1958). "A Three-Dimensional Model of the Myoglobin
Molecule Obtained by X-Ray Analysis". Nature 181 (4610): 662–6. Bibcode 1958Natur.181..662K. doi:10.1038/181662a0. PMID 13517261.
[57] The Nobel Prize in Chemistry 1962 (http:/ / nobelprize. org/ chemistry/ laureates/ 1962/ index. html)
[58] Mammen PP, Kanatous SB, Yuhanna IS, Shaul PW, Garry MG, Balaban RS, Garry DJ (2003). "Hypoxia-induced left ventricular
dysfunction in myoglobin-deficient mice". American Journal of Physiology. Heart and Circulatory Physiology 285 (5): H2132–41.
doi:10.1152/ajpheart.00147.2003. PMID 12881221.
[59] Akaboshi E (1985). "Cloning of the human myoglobin gene". Gene 33 (3): 241–9. doi:10.1016/0378-1119(85)90231-8. PMID 2989088.
[60] McGee, H (2004). On Food and Cooking: The Science and Lore of the Kitchen. New York: Scribner. p. 148. ISBN 0-684-80001-2.
[61] Minneapolis Star Tribune, Nov. 14, 2007 http:/ / www. startribune. com/ 10223/ story/ 1548852. html
[62] Minneapolis Star Tribune, October 31, 2007 http:/ / www. startribune. com/ 535/ story/ 1518775. html
[63] Toshio Naka, Daryl Jones, Ian Baldwin, Nigel Fealy, Samantha Bates, Hermann Goehl, Stanislao Morgera, Hans H. Neumayer and Rinaldo
Bellomo (2005). "Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report". Critical Care 9
(2): R90–5. doi:10.1186/cc3034. PMC 1175920. PMID 15774055.
[64] M. Weber, M. Rau, K. Madlener, A. Elsaesser, D. Bankovic, V. Mitrovic and C. Hamm (2005). "Diagnostic utility of new immunoassays
for the cardiac markers cTnI, myoglobin and CK-MB mass". Clinical Biochemistry 38 (11): 1027–30. doi:10.1016/j.clinbiochem.2005.07.011.
PMID 16125162.
[65] J. P. Collman, J. I. Brauman, T. R. Halbert, and K. S. Suslick (1976). "Nature of Oxygen and Carbon Monoxide Binding to
Metalloporphyrins and Heme Proteins" (http:/ / www. pnas. org/ cgi/ content/ abstract/ 73/ 10/ 3333). Proceedings of the National Academy of
Sciences of the United States of America 73 (10): 3333–7. doi:10.1073/pnas.73.10.3333. PMC 431107. PMID 1068445. .

Further reading
• J. P. Collman, R. Boulatov, C. J. Sunderland and L. Fu (2004). "Functional Analogues of Cytochrome c Oxidase,
Myoglobin, and Hemoglobin". Chem. Rev. 104 (2): 561–588. doi:10.1021/cr0206059. PMID 14871135.
• Reeder, BJ; Svistunenko DA, Cooper CE, Wilson MT (December 2004). "The radical and redox chemistry of
myoglobin and hemoglobin: from in vitro studies to human pathology". Antioxid Redox Signal 6 (6): 954–66.
doi:10.1089/ars.2004.6.954. PMID 15548893.
• Schlieper, G; Kim JH, Molojavyi A, Jacoby C, Laussmann T, Flogel U, Godecke A, Schrader J (April 2004).
"Adaptation of the myoglobin knockout mouse to hypoxic stress". Am J Physiol Regul Integr Comp Physiol 286
(4): R786–92. doi:10.1152/ajpregu.00043.2003. PMID 14656764.
• Takano, T (1977). "Structure of myoglobin refined at 2-0 A resolution. II. Structure of deoxymyoglobin from
sperm whale". J. Mol. Biol. 110 (3): 569–584. doi:10.1016/S0022-2836(77)80112-5. PMID 845960.
• Roy, A; Sen S, Chakraborti AS (February 2004). "In vitro nonenzymatic glycation enhances the role of
myoglobin as a source of oxidative stress". Free Radic Res. 38 (2): 139–46.
doi:10.1080/10715160310001638038. PMID 15104207.
• Stewart, JM; Blakely JA, Karpowicz PA, Kalanxhi E, Thatcher BJ, Martin BM (March 2004). "Unusually weak
oxygen binding, physical properties, partial sequence, autoxidation rate and a potential phosphorylation site of
beluga whale (Delphinapterus leucas) myoglobin". Comp Biochem Physiol B Biochem Mol Biol 137 (3): 401–12.
doi:10.1016/j.cbpc.2004.01.007. PMID 15050527.
• Wu, G; Wainwright LM, Poole RK (2003). "Microbial globins". Adv Microb Physiol 47: 255–310.
doi:10.1016/S0065-2911(03)47005-7. PMID 14560666.
Myoglobin 123

External links
• The Myoglobin Protein (http://macromoleculeinsights.com/myoglobin.php)
• Protein Database featured molecule (http://pdbdev.sdsc.edu:48346/pdb/molecules/mb1.html)
• Online 'Mendelian Inheritance in Man' (OMIM) 160000 (http://omim.org/entry/160000) human genetics
• Which Cut Is Older? (It's a Trick Question) (http://www.nytimes.com/2006/02/21/national/21meat.html)
New York Times, February 21, 2006 article regarding meat industry use of carbon monoxide to keep meat
looking red.
• Stores React to Meat Reports (http://www.nytimes.com/2006/03/01/dining/01meat.html) New York Times,
March 1, 2006 article on the use of carbon monoxide to make meat appear fresh.
Hemoglobin 124

Hemoglobin
Hemoglobin, human, adult
(heterotetramer, (αβ)2)

Structure of human hemoglobin. The protein's α and β subunits are in red and blue, and the iron-containing heme groups in green. From PDB 1GZX [1]Proteopedia Hemoglobin [2]

Protein type metalloprotein, globulin

Function oxygen-transport

Cofactor(s) heme (4)

Subunit Gene Chromosomal

Name Locus

Hb-α1 HBA1 [3]

Chr. 16 p13.3

Hb-α2 HBA2 [3]

Chr. 16 p13.3

Hb-β HBB [4]

Chr. 11 p15.5

Hemoglobin (English pronunciation: /hiːməˈɡloʊbɪn/; also rendered as haemoglobin and abbreviated Hb or Hgb) is the
iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates,[5] with the exception of the
fish family Channichthyidae,[6] as well as the tissues of some invertebrates. Hemoglobin in the blood carries oxygen
from the respiratory organs (lungs or gills) to the rest of the body (i.e., the tissues) where it releases the oxygen to
burn nutrients to provide energy to power the functions of the organism, and collects the resultant carbon dioxide to
bring it back to the respiratory organs to be dispensed from the organism.
In mammals, the protein makes up about 97% of the red blood cells' dry content, and around 35% of the total content
(including water). Hemoglobin has an oxygen binding capacity of 1.34 ml O2 per gram of hemoglobin,[7] which
increases the total blood oxygen capacity seventy-fold compared to dissolved oxygen in blood. The mammalian
hemoglobin molecule can bind (carry) up to four oxygen molecules.[8]
Hemoglobin is involved in the transport of other gases: it carries some of the body's respiratory carbon dioxide
(about 10% of the total) as carbaminohemoglobin, in which CO2 is bound to the globin protein. The molecule also
carries the important regulatory molecule nitric oxide bound to a globin protein thiol group, releasing it at the same
time as oxygen.[9]
Hemoglobin is also found outside red blood cells and their progenitor lines. Other cells that contain hemoglobin
include the A9 dopaminergic neurons in the substantia nigra, macrophages, alveolar cells, and mesangial cells in the
kidney. In these tissues, hemoglobin has a non-oxygen-carrying function as an antioxidant and a regulator of iron
Hemoglobin 125

metabolism.[10]
Hemoglobin and hemoglobin-like molecules are also found in many invertebrates, fungi, and plants. In these
organisms, hemoglobins may carry oxygen, or they may act to transport and regulate other things such as carbon
dioxide, nitric oxide, hydrogen sulfide and sulfide. A variant of the molecule, called leghemoglobin, is used to
scavenge oxygen, to keep it from poisoning anaerobic systems, such as nitrogen-fixing nodules of leguminous
plants.

Research history
The oxygen-carrying protein hemoglobin was discovered by Hünefeld in 1840.[11] In 1851,[12] Otto Funke published
a series of articles in which he described growing hemoglobin crystals by successively diluting red blood cells with a
solvent such as pure water, alcohol or ether, followed by slow evaporation of the solvent from the resulting protein
solution.[13] Hemoglobin's reversible oxygenation was described a few years later by Felix Hoppe-Seyler.[14]
In 1959 Max Perutz determined the molecular structure of hemoglobin by X-ray crystallography.[15] [16]
This work
resulted in his sharing with John Kendrew the 1962 Nobel Prize in Chemistry.
The role of hemoglobin in the blood was elucidated by physiologist Claude Bernard. The name hemoglobin is
derived from the words heme and globin, reflecting the fact that each subunit of hemoglobin is a globular protein
with an embedded heme group. Each heme group contains one iron atom, that can bind one oxygen molecule
through ion-induced dipole forces. The most common type of hemoglobin in mammals contains four such subunits.

Genetics
Hemoglobin consists mostly of protein (the "globin" chains) subunits, and these proteins, in turn, are folded chains of
a large number of different amino acids called polypeptides. The amino acid sequence of any polypeptide created by
a cell, is in turn determined by the stretches of DNA called genes. In all proteins, it is the amino acid sequence,
which determines the protein's chemical properties and function.
There is more than one hemoglobin gene. The amino acid sequences of the globin proteins in hemoglobins usually
differ between species. These differences grow with evolutionary distance between species. For example, the most
common hemoglobin sequences in humans and chimpanzees are nearly identical, differing by only one amino acid in
both the alpha and the beta globin protein chains. These differences grow larger between less closely related species.
Even within a species, different variants of hemoglobin always exist, although one sequence is usually a "most
common" one in each species. Mutations in the genes for the hemoglobin protein in a species result in hemoglobin
variants.[17] [18] Many of these mutant forms of hemoglobin cause no disease. Some of these mutant forms of
hemoglobin, however, cause a group of hereditary diseases termed the hemoglobinopathies. The best known
hemoglobinopathy is sickle-cell disease, which was the first human disease whose mechanism was understood at the
molecular level. A (mostly) separate set of diseases called thalassemias involves underproduction of normal and
sometimes abnormal hemoglobins, through problems and mutations in globin gene regulation. All these diseases
produce anemia.[19]
Variations in hemoglobin amino acid sequences, as with other proteins, may be adaptive. For example, recent studies
have suggested genetic variants in deer mice that help explain how deer mice that live in the mountains are able to
survive in the thin air that accompanies high altitudes. A researcher from the University of Nebraska-Lincoln found
mutations in four different genes that can account for differences between deer mice that live in lowland prairies
versus the mountains. After examining wild mice captured from both highlands and lowlands, it was found that: the
genes of the two breeds are “virtually identical–except for those that govern the oxygen-carrying capacity of their
hemoglobin”. “The genetic difference enables highland mice to make more efficient use of their oxygen”, since less is
available at higher altitudes, such as those in the mountains.[20] Mammoth hemoglobin featured mutations that
allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the
Hemoglobin 126

Pleistocene.[21]

Synthesis
Hemoglobin (Hb) is synthesized in a complex series of steps. The heme part is synthesized in a series of steps in the
mitochondria and the cytosol of immature red blood cells, while the globin protein parts are synthesized by
ribosomes in the cytosol.[22] Production of Hb continues in the cell throughout its early development from the
proerythroblast to the reticulocyte in the bone marrow. At this point, the nucleus is lost in mammalian red blood
cells, but not in birds and many other species. Even after the loss of the nucleus in mammals, residual ribosomal
RNA allows further synthesis of Hb until the reticulocyte loses its RNA soon after entering the vasculature (this
hemoglobin-synthetic RNA in fact gives the reticulocyte its reticulated appearance and name).

Structure
Hemoglobin has a quaternary structure characteristic of many
multi-subunit globular proteins.[23] Most of the amino acids in
hemoglobin form alpha helices, connected by short non-helical
segments. Hydrogen bonds stabilize the helical sections inside this
protein, causing attractions within the molecule, folding each
polypeptide chain into a specific shape.[24] Hemoglobin's quaternary
structure comes from its four subunits in roughly a tetrahedral
arrangement.[23]

In most vertebrates, the hemoglobin molecule is an assembly of four

globular protein subunits. Each subunit is composed of a protein chain
tightly associated with a non-protein heme group. Each protein chain
arranges into a set of alpha-helix structural segments connected
together in a globin fold arrangement, so called because this Heme b group
arrangement is the same folding motif used in other heme/globin
proteins such as myoglobin.[25] [26] This folding pattern contains a pocket that strongly binds the heme group.

A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic ring, known as a porphyrin. This
porphyrin ring consists of four pyrrole molecules cyclically linked together (by methene bridges) with the iron ion
bound in the center.[27] The iron ion, which is the site of oxygen binding, coordinates with the four nitrogens in the
center of the ring, which all lie in one plane. The iron is bound strongly (covalently) to the globular protein via the
imidazole ring of the F8 histidine residue (also known as the proximal histidine) below the porphyrin ring. A sixth
position can reversibly bind oxygen by a coordinate covalent bond,[28] completing the octahedral group of six
ligands. Oxygen binds in an "end-on bent" geometry where one oxygen atom binds Fe and the other protrudes at an
angle. When oxygen is not bound, a very weakly bonded water molecule fills the site, forming a distorted
octahedron.
Even though carbon dioxide is carried by hemoglobin, it does not compete with oxygen for the iron-binding
positions, but is actually bound to the protein chains of the structure.
The iron ion may be either in the Fe2+ or in the Fe3+ state, but ferrihemoglobin (methemoglobin) (Fe3+) cannot bind
oxygen.[29] In binding, oxygen temporarily and reversibly oxidizes (Fe2+) to (Fe3+) while oxygen temporally turns
into superoxide, thus iron must exist in the +2 oxidation state to bind oxygen. If superoxide ion associated to Fe3+ is
protonated the hemoglobin iron will remain oxidized and incapable to bind oxygen. In such cases, the enzyme
methemoglobin reductase will be able to eventually reactivate methemoglobin by reducing the iron center.
In adult humans, the most common hemoglobin type is a tetramer (which contains 4 subunit proteins) called
hemoglobin A, consisting of two α and two β subunits non-covalently bound, each made of 141 and 146 amino acid
Hemoglobin 127

residues, respectively. This is denoted as α2β2. The subunits are structurally similar and about the same size. Each
subunit has a molecular weight of about 17,000 daltons, for a total molecular weight of the tetramer of about
64,000 daltons (64,458 g/mol).[30] Thus, 1 g/dL = 0.1551 mmol/L. Hemoglobin A is the most intensively studied of
the hemoglobin molecules.
In human infants, the hemoglobin molecule is made up of 2 α chains and 2 gamma chains. The gamma chains are
gradually replaced by β chains as the infant grows.[31]
The four polypeptide chains are bound to each other by salt bridges, hydrogen bonds, and the hydrophobic effect.

Oxygen saturation
In general, hemoglobin can be saturated with oxygen molecules (oxyhemoglobin), or desaturated with oxygen
molecules (deoxyhemoglobin).[32]

Oxyhemoglobin
Oxyhemoglobin is formed during physiological respiration when oxygen binds to the heme component of the protein
hemoglobin in red blood cells. This process occurs in the pulmonary capillaries adjacent to the alveoli of the lungs.
The oxygen then travels through the blood stream to be dropped off at cells where it is utilized in glycolysis and in
the production of ATP by the process of oxidative phosphorylation. It does not, however, help to counteract a
decrease in blood pH. Ventilation, or breathing, may reverse this condition by removal of carbon dioxide, thus
causing a shift up in pH.[33]
Hemoglobin exists in two forms, a taut form (T) and a relaxed form (R). Various factors such as low pH, high CO2
and high 2,3 BPG at the level of the tissues favor the taut form, which has low oxygen affinity and releases oxygen
in the tissues. Conversely, a high pH, low CO2, or low 2,3 BPG favors the relaxed form which can better bind
oxygen.

Deoxygenated hemoglobin
Deoxygenated hemoglobin is the form of hemoglobin without the bound oxygen. The absorption spectra of
oxyhemoglobin and deoxyhemoglobin differ. The oxyhemoglobin has significantly lower absorption of the 660 nm
wavelength than deoxyhemoglobin, while at 940 nm its absorption is slightly higher. This difference is used for
measurement of the amount of oxygen in patient's blood by an instrument called pulse oximeter. This difference also
accounts for the presentation of cyanosis, the blue to purplish color that tissues develop during hypoxia.

Iron's oxidation state in oxyhemoglobin

Assigning oxygenated hemoglobin's oxidation state is difficult because oxyhemoglobin (Hb-O2), by experimental
measurement, is diamagnetic (no net unpaired electrons), yet the low-energy electron configurations in both oxygen
and iron are paramagnetic (suggesting at least one unpaired electron in the complex). The lowest-energy form of
oxygen, and the lowest energy forms of the relevant oxidation states of iron, are these:
• Triplet oxygen, the lowest energy molecular oxygen species, has two unpaired electrons in antibonding π*
molecular orbitals.
• Iron(II) tends to exist in a high-spin configuration where unpaired electrons exist in Eg antibonding orbitals.
• Iron(III) has an odd number of electrons, and thus must have one or more unpaired electrons, in any energy state.
All of these structures are paramagnetic (have unpaired electrons), not diamagnetic. Thus, a non-intuitive (e.g., a
higher-energy for at least one species) distribution of electrons in the combination of iron and oxygen must exist, in
order to explain the observed diamagnetism and no unpaired electrons.
The three logical possibilities to produce diamagnetic (no net spin) Hb-O2 are:
Hemoglobin 128

1. Low-spin Fe2+ binds to singlet oxygen. Both low-spin iron and singlet oxygen are diamagnetic. However, the
singlet form of oxygen is the higher-energy form of the molecule.
2. Low-spin Fe3+ binds to .O2- (the superoxide ion) and the two unpaired electrons couple antiferromagnetically,
giving diamagnetic properties.
3. Low-spin Fe4+ binds to peroxide, O22-. Both are diamagnetic.
Direct experimental data:
• X-ray photoelectron spectroscopy suggests iron has an oxidation state of approximately 3.2
• infrared stretching frequencies of the O-O bond suggests a bond length fitting with superoxide (a bond order of
about 1.6, with superoxide being 1.5).
• X-ray Absorption Near Edge Structures at the iron K-edge. The energy shift of 5 eV between Deoxyhemoglobin
and Oxyhemoglobin, as for all the Methemoglobin species, strongly suggests an actual local charge closer to Fe3+
than Fe2+.[34] [35] [36]
Thus, the nearest formal oxidation state of iron in Hb-O2 is the +3 state, with oxygen in the -1 state (as superoxide
.O2-). The diamagnetism in this configuration arises from the single unpaired electron on superoxide aligning
antiferromagnetically from the single unpaired electron on iron, to give no net spin to the entire configuration, in
accordance with diamagnetic oxyhemoglobin from experiment.[37] [38]
The second choice of the three logical possibilities above for diamagnetic oxyhemoglobin being found correct by
experiment, is not surprising: singlet oxygen (possibility #1) and large separations of charge (possibility #3) are both
unfavorably high-energy states. Iron's shift to a higher oxidation state in Hb-O2 decreases the atom's size, and allows
it into the plane of the porphyrin ring, pulling on the coordinated histidine residue and initiating the allosteric
changes seen in the globulins.
Early postulates by bio-inorganic chemists claimed that possibility #1 (above) was correct and that iron should exist
in oxidation state II. This seemed particularly likely since the iron oxidation state III as methemoglobin, when not
accompanied by superoxide .O2- to "hold" the oxidation electron, was known to render hemoglobin incapable of
binding normal triplet O2 as it occurs in the air. It was thus assumed that iron remained as Fe(II) when oxygen gas
was bound in the lungs. The iron chemistry in this previous classical model was elegant, but the required presence of
the required diamagnetic high-energy singlet oxygen was never explained. It was classically argued that the binding
of an oxygen molecule placed high-spin iron(II) in an octahedral field of strong-field ligands; this change in field
would increase the crystal field splitting energy, causing iron's electrons to pair into the low-spin configuration,
which would be diamagnetic in Fe(II). This forced low-spin pairing is indeed thought to happen in iron when oxygen
binds, but is not enough to explain iron's change in size. Extraction of an additional electron from iron by oxygen is
required to explain both iron's smaller size and observed increased oxidation state, and oxygen's weaker bond.
It should be noted that the assignment of a whole-number oxidation state is a formalism, as the covalent bonds are
not required to have perfect bond orders involving whole electron-transfer. Thus, all three models for paramagnetic
Hb-O2 may contribute to some small degree (by resonance) to the actual electronic configuration of Hb-O2.
However, the model of iron in Hb-O2 being Fe(III) is more correct than the classical idea that it remains Fe(II).

Binding for ligands other than oxygen

Besides the oxygen ligand, which binds to hemoglobin in a cooperative manner, hemoglobin ligands also include
competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO2) and nitric
oxide (NO). The carbon dioxide is bound to amino groups of the globin proteins as carbaminohemoglobin, and is
thought to account for about 10% of carbon dioxide transport in mammals. Nitric oxide is bound to specific thiol
groups in the globin protein to form an S-nitrosothiol which dissociates into free nitric oxide and thiol again, as the
hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to
assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.[39]
Hemoglobin 129

Cooperative
When oxygen binds to the iron complex, it causes the iron atom to
move back toward the center of the plane of the porphyrin ring (see
moving diagram). At the same time, the imidazole side-chain of the
histidine residue interacting at the other pole of the iron is pulled
toward the porphyrin ring. This interaction forces the plane of the ring
sideways toward the outside of the tetramer, and also induces a strain
in the protein helix containing the histidine as it moves nearer to the
iron atom. This strain is transmitted to the remaining three monomers
in the tetramer, where it induces a similar conformational change in the
A schematic visual model of oxygen-binding
other heme sites such that binding of oxygen to these sites becomes
process, showing all four monomers and hemes,
easier. and protein chains only as diagramatic coils, to
In the tetrameric form of normal adult hemoglobin, the binding of facilitate visualization into the molecule. Oxygen
is not shown in this model, but, for each of the
oxygen is, thus, a cooperative process. The binding affinity of
iron atoms, it binds to the iron (red sphere) in the
hemoglobin for oxygen is increased by the oxygen saturation of the flat heme. For example, in the upper left of the
molecule, with the first oxygens bound influencing the shape of the four hemes shown, oxygen binds at the left of the
binding sites for the next oxygens, in a way favorable for binding. This iron atom shown in the upper left of diagram.
This causes the iron atom to move backward into
positive cooperative binding is achieved through steric conformational
the heme which holds it (the iron moves upward
changes of the hemoglobin protein complex as discussed above; i.e., as it binds oxygen, in this illustration), tugging
when one subunit protein in hemoglobin becomes oxygenated, a the histidine residue (modeled as a red pentagon
conformational or structural change in the whole complex is initiated, on the right of the iron) closer, as it does. This, in
turn, pulls on the protein chain holding the
causing the other subunits to gain an increased affinity for oxygen. As
histidine.
a consequence, the oxygen binding curve of hemoglobin is sigmoidal,
or S-shaped, as opposed to the normal hyperbolic curve associated with
noncooperative binding.

The dynamic mechanism of the cooperativity in hemoglobin and its relation with the low-frequency resonance has
been discussed.[40]

Competitive
Hemoglobin's oxygen-binding capacity is decreased in the presence of carbon monoxide because both gases compete
for the same binding sites on hemoglobin, carbon monoxide binding preferentially in place of oxygen.
The binding of oxygen is affected by molecules such as carbon monoxide (CO) (for example, from tobacco smoking,
car exhaust, and incomplete combustion in furnaces). CO competes with oxygen at the heme binding site.
Hemoglobin binding affinity for CO is 250 times greater than its affinity for oxygen,[41] meaning that small amounts
of CO dramatically reduce hemoglobin's ability to transport oxygen. Since Carbon Monoxide is a colorless, odorless
and tasteless gas, and poses a potentially fatal threat detectors have become commercially available to warn of
dangerous levels in residences. When hemoglobin combines with CO, it forms a very bright red compound called
carboxyhemoglobin, which may cause the skin of CO poisoning victims to appear pink in death, instead of white or
blue. When inspired air contains CO levels as low as 0.02%, headache and nausea occur; if the CO concentration is
increased to 0.1%, unconsciousness will follow. In heavy smokers, up to 20% of the oxygen-active sites can be
blocked by CO.

In similar fashion, hemoglobin also has competitive binding affinity for cyanide (CN-), sulfur monoxide (SO), nitric
oxide (NO), and sulfide(S2-), including hydrogen sulfide (H2S). All of these bind to iron in heme without changing
its oxidation state, but they nevertheless inhibit oxygen-binding, causing grave toxicity.
Hemoglobin 130

The iron atom in the heme group must initially be in the ferrous (Fe2+) oxidation state to support oxygen and other
gases' binding and transport (it temporarily switches to ferric during the time oxygen is bound, as explained above).
Initial oxidation to the ferric (Fe3+) state without oxygen converts hemoglobin into "hemiglobin" or methemoglobin
(pronounced "MET-hemoglobin"), which cannot bind oxygen. Hemoglobin in normal red blood cells is protected by
a reduction system to keep this from happening. Nitric oxide is capable of converting a small fraction of hemoglobin
to methemoglobin in red blood cells. The latter reaction is a remnant activity of the more ancient nitric oxide
dioxygenase function of globins.

Allosteric
Further information: Oxygen-hemoglobin dissociation curve
Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide is more readily dissolved in
deoxygenated blood, facilitating its removal from the body after the oxygen has been released to tissues undergoing
metabolism. This increased affinity for carbon dioxide by the venous blood is known as the Haldane effect. Through
the enzyme carbonic anhydrase, carbon dioxide reacts with water to give carbonic acid, which decomposes into
bicarbonate and protons:
CO2 + H2O → H2CO3 → HCO3- + H+
Hence blood with high carbon dioxide levels is
also lower in pH (more acidic). Hemoglobin can
bind protons and carbon dioxide, which causes a
conformational change in the protein and facilitates
the release of oxygen. Protons bind at various
places on the protein, while carbon dioxide binds
at the α-amino group.[42] Carbon dioxide binds to
hemoglobin and forms carbaminohemoglobin.[43]
This decrease in hemoglobin's affinity for oxygen
by the binding of carbon dioxide and acid is known
as the Bohr effect (shifts the O2-saturation curve to
the right). Conversely, when the carbon dioxide
levels in the blood decrease (i.e., in the lung
capillaries), carbon dioxide and protons are
The sigmoidal shape of hemoglobin's oxygen-dissociation curve results released from hemoglobin, increasing the oxygen
from cooperative binding of oxygen to hemoglobin. affinity of the protein. A reduction in the total
binding capacity of hemoglobin to oxygen (i.e.
shifting the curve down, not just to the right) due to reduced pH is called the root effect. This is seen in bony fish.

It is necessary for hemoglobin to release the oxygen that it binds; if not, there is no point in binding it. The sigmoidal
curve of hemoglobin makes it efficient in binding (taking up O2 in lungs), and efficient in unloading (unloading O2
in tissues).[44]
In people acclimated to high altitudes, the concentration of 2,3-Bisphosphoglycerate (2,3-BPG) in the blood is
increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower
oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is
called a heterotropic allosteric effect.
A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with
greater affinity than adult hemoglobin. This means that the oxygen binding curve for fetal hemoglobin is left-shifted
(i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension), in comparison to that of
adult hemoglobin. As a result, fetal blood in the placenta is able to take oxygen from maternal blood.
Hemoglobin 131

Hemoglobin also carries nitric oxide in the globin part of the molecule. This improves oxygen delivery in the
periphery and contributes to the control of respiration. NO binds reversibly to a specific cysteine residue in globin;
the binding depends on the state (R or T) of the hemoglobin. The resulting S-nitrosylated hemoglobin influences
various NO-related activities such as the control of vascular resistance, blood pressure and respiration. NO is not
released in the cytoplasm of erythrocytes but transported by an anion exchanger called AE1 out of them.[45]
A study was performed to examine the influence of the form of hemoglobin (Hb) on the partitioning of inhaled
volatile organic compounds (VOCs) into [human and animal] blood. Benzene was the prototypic VOC used in the
investigations for this research due to the similar properties it shares with many other VOCs. To be specific, this
study analyses the influence of the water solubility of Hb on the partitioning coefficient (PC) of a VOC as compared
to the influence of the “species” or form of Hb. The different forms of blood used include: human hemoglobin
(HbA), rat Hb, and sickle-cell hemoglobin (HbS). Rat Hb contains little water and is in a quasi-crystalline form,
found inside the red blood cells (RBC), meaning they are more hydrophobic than human Hb, which are
water-soluble. Sickle-cell hemoglobin (HbS) is water-soluble, however it can become water-insoluble, forming
hydrophobic polymers, when deoxygenated. The findings state that the benzene PC for rat Hb was much higher than
human that for Hb; however, the tests that measured the PCs of the oxygenated and deoxygenated forms of HbA and
HbS did not differ, indicating that the affinity of benzene was not affected by the water solubility of Hb.[46]

Types in humans
Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant
forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants such
as sickle-cell anemia are responsible for diseases, and are considered hemoglobinopathies. Other variants cause no
detectable pathology, and are thus considered non-pathological variants.[47] [48]
In the embryo:
• Gower 1 (ζ2ε2)
• Gower 2 (α2ε2) (PDB 1A9W [49])
• Hemoglobin Portland (ζ2γ2)
In the fetus:
• Hemoglobin F (α2γ2) (PDB 1FDH [50])
In adults:
• Hemoglobin A (α2β2) (PDB 1BZ0 [51]) - The most common with a normal amount over 95%
• Hemoglobin A2 (α2δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal range of
1.5-3.5%
• Hemoglobin F (α2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F-cells.
However, the level of Hb F can be elevated in persons with sickle-cell disease and beta-thalassemia.
Hemoglobin 132

Variant forms that cause disease:

• Hemoglobin H (β4) - A variant form of
hemoglobin, formed by a tetramer of β
chains, which may be present in variants
of α thalassemia.
• Hemoglobin Barts (γ4) - A variant form
of hemoglobin, formed by a tetramer of γ
chains, which may be present in variants
of α thalassemia.
• Hemoglobin S (α2βS2) - A variant form
of hemoglobin found in people with
sickle cell disease. There is a variation in
the β-chain gene, causing a change in the
properties of hemoglobin, which results
in sickling of red blood cells. Gene expression of hemoglobin before and after birth. Also identifies the types of
cells and organs in which the gene expression (data on Wood W.G., (1976). Br.
• Hemoglobin C (α2βC2) - Another variant Med. Bull. 32, 282.)
due to a variation in the β-chain gene.
This variant causes a mild chronic hemolytic anemia.
• Hemoglobin E (α2βE2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic
hemolytic anemia.
• Hemoglobin AS - A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease
gene
• Hemoglobin SC disease - Another heterozygous form with one sickle gene and another encoding Hemoglobin C.

Degradation in vertebrate animals

When red cells reach the end of their life due to aging or defects, they are broken down, the hemoglobin molecule is
broken up and the iron gets recycled. When the porphyrin ring is broken up, the fragments are normally secreted in
the bile by the liver. This process also produces one molecule of carbon monoxide for every molecule of heme
degraded.[52] This is one of the few natural sources of carbon monoxide production in the human body, and is
responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final
product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are
being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been
released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels
of the kidneys, causing kidney damage.
Hemoglobin 133

Role in disease
Hemoglobin deficiency can be caused either by decreased amount of
hemoglobin molecules, as in anemia, or by decreased ability of each
molecule to bind oxygen at the same partial pressure of oxygen.
Hemoglobinopathies (genetic defects resulting in abnormal structure of
the hemoglobin molecule)[53] may cause both. In any case, hemoglobin
deficiency decreases blood oxygen-carrying capacity. Hemoglobin
deficiency is, in general, strictly distinguished from hypoxemia,
defined as decreased partial pressure of oxygen in blood,[54] [55] [56] [57]
although both are causes of hypoxia (insufficient oxygen supply to
tissues).

Other common causes of low hemoglobin include loss of blood,

nutritional deficiency, bone marrow problems, chemotherapy, kidney
failure, or abnormal hemoglobin (such as that of sickle-cell disease).
High hemoglobin levels may be caused by exposure to high altitudes,
smoking, dehydration, or tumors.[31]
The ability of each hemoglobin molecule to carry oxygen is normally
modified by altered blood pH or CO2, causing an altered
oxygen–hemoglobin dissociation curve. However, it can also be
In sickle cell hemoglobin (HbS) glutamic acid in
position 6 (in beta chain) is mutated to valine. pathologically altered in, e.g., carbon monoxide poisoning.
This change allows the deoxygenated form of the
Decrease of hemoglobin, with or without an absolute decrease of red
hemoglobin to stick to itself.
blood cells, leads to symptoms of anemia. Anemia has many different
causes, although iron deficiency and its resultant iron deficiency
anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood
cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than
normal). Other anemias are rarer. In hemolysis (accelerated breakdown of red blood cells), associated jaundice is
caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

Some mutations in the globin chain are associated with the hemoglobinopathies, such as sickle-cell disease and
thalassemia. Other mutations, as discussed at the beginning of the article, are benign and are referred to merely as
hemoglobin variants.
There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways
of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.
To a small extent, hemoglobin A slowly combines with glucose at the terminal valine (an alpha aminoacid) of each β
chain. The resulting molecule is often referred to as Hb A1c. As the concentration of glucose in the blood increases,
the percentage of Hb A that turns into Hb A1c increases. In diabetics whose glucose usually runs high, the percent Hb
A1c also runs high. Because of the slow rate of Hb A combination with glucose, the Hb A1c percentage is
representative of glucose level in the blood averaged over a longer time (the half-life of red blood cells, which is
typically 50–55 days).
Glycosylated hemoglobin is the form of hemoglobin to which glucose is bound. The binding of glucose to amino
acids in the hemoglobin takes place spontaneously (without the help of an enzyme) in many proteins, and is not
known to serve a useful purpose. However, the binding to hemoglobin does serve as a record for average blood
glucose levels over the lifetime of red cells, which is approximately 120 days. The levels of glycosylated hemoglobin
are therefore measured in order to monitor the long-term control of the chronic disease of type 2 diabetes mellitus
(T2DM). Poor control of T2DM results in high levels of glycosylated hemoglobin in the red blood cells. The normal
Hemoglobin 134

reference range is approximately 4–5.9 %. Though difficult to obtain, values less than 7 % are recommended for
people with T2DM. Levels greater than 9 % are associated with poor control of the glycosylated hemoglobin, and
levels greater than 12 % are associated with very poor control. Diabetics who keep their glycosylated hemoglobin
levels close to 7 % have a much better chance of avoiding the complications that may accompany diabetes (than
those whose levels are 8 % or higher).[58]
Elevated levels of hemoglobin are associated with increased numbers or sizes of red blood cells, called
polycythemia. This elevation may be caused by congenital heart disease, cor pulmonale, pulmonary fibrosis, too
much erythropoietin, or polycythemia vera.[59]
Elevation in levels of hemoglobin were found in one study of the yogic practice of Yoga Nidra (yogic sleep) for half
an hour daily.[60]
A recent study done in Pondicherry, India, shows its importance in coronary artery disease.[61]

Diagnostic uses
Hemoglobin concentration measurement is among the most commonly performed blood tests, usually as part of a
complete blood count. For example it is typically tested before or after blood donation. Results are reported in g/L,
g/dL or mol/L. 1 g/dL equals about 0.6206  mmol/L.[62] Normal levels are:
• Men: 13.8 to 18.0 g/dL (138 to 182 g/L, or 8.56 to 11.3 mmol/L)
• Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)
• Children: 11 to 16 g/dL (111 to 160 g/L, or 6.83 to 9.93 mmol/L)
• Pregnant women: 11 to 12 g/dL (110 to 120 g/L, or 6.83 to 7.45 mmol/L) [63] [64]
Normal values of hemoglobin in the 1st and 3rd trimesters of pregnant women must be at least 11 g/dL and at least
10.5 g/dL during the 2nd trimester.[65]
Dehydration or hyperhydration can greatly influence measured hemoglobin levels. Albumin can indicate hydration
status.
If the concentration is below normal, this is called anemia. Anemias are classified by the size of red blood cells, the
cells that contain hemoglobin in vertebrates. The anemia is called "microcytic" if red cells are small, "macrocytic" if
they are large, and "normocytic" otherwise.
Hematocrit, the proportion of blood volume occupied by red blood cells, is typically about three times the
hemoglobin level. For example, if the hemoglobin is measured at 17, that compares with a hematocrit of 51.[66]
Laboratory hemoglobin test methods require a blood sample (arterial, venous, or capillary) and analysis on
hematology analyzer and CO-oximeter. Additionally, a new noninvasive hemoglobin (SpHb) test method called
Pulse CO-Oximetry is also available with comparable accuracy to invasive methods.[67]
Long-term control of blood sugar concentration can be measured by the concentration of Hb A1c. Measuring it
directly would require many samples because blood sugar levels vary widely through the day. Hb A1c is the product
of the irreversible reaction of hemoglobin A with glucose. A higher glucose concentration results in more Hb A1c.
Because the reaction is slow, the Hb A1c proportion represents glucose level in blood averaged over the half-life of
red blood cells, is typically 50–55 days. An Hb A1c proportion of 6.0% or less show good long-term glucose control,
while values above 7.0% are elevated. This test is especially useful for diabetics.[68]
The functional magnetic resonance imaging (fMRI) machine uses the signal from deoxyhemoglobin, which is
sensitive to magnetic fields since it is paramagnetic.
Hemoglobin 135

Analogues in non-vertebrate organisms

A variety of oxygen-transport and -binding proteins exist in organisms throughout the animal and plant kingdoms.
Organisms including bacteria, protozoans, and fungi all have hemoglobin-like proteins whose known and predicted
roles include the reversible binding of gaseous ligands. Since many of these proteins contain globins and the heme
moiety (iron in a flat porphyrin support), they are often called hemoglobins, even if their overall tertiary structure is
very different from that of vertebrate hemoglobin. In particular, the distinction of “myoglobin” and hemoglobin in
lower animals is often impossible, because some of these organisms do not contain muscles. Or, they may have a
recognizable separate circulatory system but not one that deals with oxygen transport (for example, many insects and
other arthropods). In all these groups, heme/globin-containing molecules (even monomeric globin ones) that deal
with gas-binding are referred to as oxyhemoglobins. In addition to dealing with transport and sensing of oxygen,
they may also deal with NO, CO2, sulfide compounds, and even O2 scavenging in environments that must be
anaerobic. They may even deal with detoxification of chlorinated materials in a way analogous to heme-containing
P450 enzymes and peroxidases.
The structure of hemoglobins varies across species. Hemoglobin
occurs in all kingdoms of organisms, but not in all organisms.
Primitive species such as bacteria, protozoa, algae, and plants often
have single-globin hemoglobins. Many nematode worms, molluscs,
and crustaceans contain very large multisubunit molecules, much
larger than those in vertebrates. In particular, chimeric hemoglobins
found in fungi and giant annelids may contain both globin and other
types of proteins.[69]
The giant tube worm Riftia pachyptila showing
One of the most striking occurrences and uses of hemoglobin in red hemoglobin-containing plumes
organisms is in the giant tube worm (Riftia pachyptila, also called
Vestimentifera), which can reach 2.4 meters length and populates ocean volcanic vents. Instead of a digestive tract,
these worms contain a population of bacteria constituting half the organism's weight. The bacteria react with H2S
from the vent and O2 from the water to produce energy to make food from H2O and CO2. The worms end with a
deep red fan-like structure ("plume"), which extends into the water and absorbs H2S and O2 for the bacteria, and CO2
for use as synthetic raw material similar to photosynthetic plants. The structures are bright-red due to their
containing several extraordinarily complex hemoglobins that have up to 144 globin chains, each including associated
heme structures. These hemoglobins are remarkable for being able to carry oxygen in the presence of sulfide, and
even to carry sulfide, without being completely "poisoned" or inhibited by it as hemoglobins in most other species
are.[70] [71]

Other oxygen-binding proteins

Myoglobin
Found in the muscle tissue of many vertebrates, including humans, it gives muscle tissue a distinct red or dark
gray color. It is very similar to hemoglobin in structure and sequence, but is not a tetramer; instead, it is a
monomer that lacks cooperative binding. It is used to store oxygen rather than transport it.
Hemocyanin
The second most common oxygen-transporting protein found in nature, it is found in the blood of many
arthropods and molluscs. Uses copper prosthetic groups instead of iron heme groups and is blue in color when
oxygenated.
Hemerythrin
Hemoglobin 136

Some marine invertebrates and a few species of annelid use this iron-containing non-heme protein to carry
oxygen in their blood. Appears pink/violet when oxygenated, clear when not.
Chlorocruorin
Found in many annelids, it is very similar to erythrocruorin, but the heme group is significantly different in
structure. Appears green when deoxygenated and red when oxygenated.
Vanabins
Also known as vanadium chromagens, they are found in the blood of sea squirts. There were once
hypothesized to use the rare metal vanadium as an oxygen binding prosthetic group. However, although they
do contain vanadium by preference, they apparently bind little oxygen, and thus have some other function,
which has not been elucidated (sea squirts also contain some hemoglobin). They may act as toxins.
Erythrocruorin
Found in many annelids, including earthworms, it is a giant free-floating blood protein containing many
dozens—possibly hundreds—of iron- and heme-bearing protein subunits bound together into a single protein
complex with a molecular mass greater than 3.5 million daltons.
Pinnaglobin
Only seen in the mollusc Pinna squamosa. Brown manganese-based porphyrin protein.
Leghemoglobin
In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from
oxygen by this iron heme containing oxygen-binding protein. The specific enzyme protected is nitrogenase,
which is unable to reduce nitrogen gas in the presence of free oxygen.
Coboglobin
A synthetic cobalt-based porphyrin. Coboprotein would appear colorless when oxygenated, but yellow when
in veins.

Presence in nonerythroid cells

Some nonerythroid cells (i.e., cells other than the red blood cell line) contain hemoglobin. In the brain, these include
the A9 dopaminergic neurons in the substantia nigra, astrocytes in the cerebral cortex and hippocampus, and in all
mature oligodendrocytes.[10] It has been suggested that brain hemoglobin in these cell may enable the "storage of
oxygen to provide a homeostatic mechanism in anoxic conditions, which is especially important for A9 DA neurons
that have an elevated metabolism with a high requirement for energy production".[10] It has been noted further that
"A9 dopaminergic neurons may be at particular risk since in addition to their high mitochondrial activity they are
under intense oxidative stress caused by the production of hydrogen peroxide via autoxidation and/or monoamine
oxidase (MAO)-mediated deamination of dopamine and the subsequent reaction of accessible ferrous iron to
generate highly toxic hydroxyl radicals".[10] This may explain the risk of these cells for degeneration in Parkinson's
disease.[10] The presence of iron from hemoglobin in these cells also results in the post-mortem darkness of these
cells, which is the origin of the Latin name, substantia nigra.
Outside the brain, hemoglobin has non-oxygen-carrying functions as an antioxidant and a regulator of iron
metabolism in macrophages,[72] alveolar cells,[73] and mesangial cells in the kidney.[74]
Hemoglobin 137

In history, art and music

Historically, the color of blood was associated with rust, as ancient Romans
associated the planet Mars with the god of war since Mars is orange-red. The
color of Mars is due to the iron oxide in the Martian soil, but the red in blood
is not due to the iron in hemoglobin and its oxides, which is a common
misconception. The red is due to the porphyrin moiety of hemoglobin to
which the iron is bound, not the iron itself,[75] although the ligation and redox
state of the iron can influence the pi to pi* or n to pi* electronic transitions of
the porphyrin and hence its optical characteristics.

The planet Mars

Artist Julian Voss-Andreae created a

sculpture called "Heart of Steel
(Hemoglobin)" in 2005, based on the
protein's backbone. The sculpture was
made from glass and weathering steel.
The intentional rusting of the initially
shiny work of art mirrors hemoglobin's
fundamental chemical reaction of
oxygen binding to iron.[76] [77]

Rock band Placebo recorded a song

Heart of Steel (Hemoglobin) (2005) by Julian Voss-Andreae. The images show the 5'
called "Haemoglobin" with the lyrics (1.60 m) tall sculpture right after installation, after 10 days, and after several months of
"Haemoglobin is the key to a healthy exposure to the elements.
heartbeat". French rap artist MC Solaar
also had a successful single titled "La Concubine de L'Hemoglobin" in 1994.

References
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[33] Baillie/Simpson. "Online model of the hemoglobin binding and the effects of hyperventilation" (http:/ / www. altitude. org/
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[34] Pin S, Alpert B, Michalowicz A. (Oct 1982). "Oxygen bonding in human hemoglobin and its isolated subunits: A XANES study". FEBS
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[35] S Pin, P Valat, R Cortes, A Michalowicz, and B Alpert (December 1985). "Ligand binding processes in hemoglobin. Chemical reactivity of
iron studied by XANES spectroscopy". Biophys J. 48(6): 997–10.
[36] A. Bianconi, A. Congiu-Castellanoa, M. Dell'Aricciaa, A. Giovannellia, E. Burattinib and P. J. Durhamc (August 1985). "Increase of the Fe
effective charge in hemoproteins during oxygenation process". Biochemical and Biophysical Research Communications 30 (1): 98–102.
doi:10.1016/0006-291X(85)91775-9. PMID 4038310.
[37] Childs PE (2001). "Haemoglobin - a molecular lung: 2" (http:/ / www. ul. ie/ ~childsp/ CinA/ Issue65/ TOC28_Haemoglobin. htm).
Chemistry in Action (65). ISSN 0332-2637. .
[38] Chen H, Ikeda-Saito M, Shaik S (11 2008). "Nature of the Fe-O2 bonding in oxy-myoglobin: effect of the protein" (http:/ / pubs. acs. org/
doi/ abs/ 10. 1021/ ja805434m). Journal of the American Chemical Society 130 (44): 14778–14790. doi:10.1021/ja805434m.
PMID 18847206. .
[39] Jensen, Frank B (4/9/2009). "The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow".
Journal of Experimental Biology (The Company of Biologists) 212 (Pt 21): 3387–3393. doi:10.1242/jeb.023697. PMID 19837879.
[40] Chou KC (June 1989). "Low-frequency resonance and cooperativity of hemoglobin". Trends Biochem. Sci. 14 (6): 212–3.
doi:10.1016/0968-0004(89)90026-1. PMID 2763333.
[41] Guyton A C: Medical Physiology 12ed. 2010, page 502
[42] Nelson, D. L.; Cox, M. M. (2000). Lehninger Principles of Biochemistry, 3rd ed. New York, NY: Worth Publishers. p 217
[43] Guyton, Arthur C.; John E. Hall (2006). Textbook of Medical Physiology (11 ed.). Philadelphia: Elsevier Saunders. p. 511.
ISBN 0721602401.
[44] "YouTube - Lecture - 12 Myoglobin and Hemoglobin." YouTube - Broadcast Yourself.. N.p., n.d. Web. 30 Oct. 2009.
<http://www.youtube.com/watch?v=6AfRX6oh9-E>.
[45] Rang, H.P.; Dale M.M., Ritter J.M., Moore P.K. (2003). Pharmacology, Fifth Edition. Elsevier. ISBN 0443072027.
[46] Wiester et al. "Partitioning of Benzene in Blood: Influence of Hemoglobin Type in Humans and Animals." Environmental Health
Perspectives 110.3 (2002): p255-261. EBSCO. Web. 1 Nov. 2009.
Hemoglobin 139

[47] "Hemoglobin Variants" (http:/ / www. labtestsonline. org/ understanding/ analytes/ hemoglobin_var/ glance-3. html). Lab Tests Online.
American Association for Clinical Chemistry. 2007-11-10. . Retrieved 2008-10-12.
[48] Huisman THJ (1996). "A Syllabus of Human Hemoglobin Variants" (http:/ / globin. cse. psu. edu/ html/ huisman/ variants/ ). Globin Gene
Server. Pennsylvania State University. . Retrieved 2008-10-12.
[49] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1A9W
[50] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1FDH
[51] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1BZ0
[52] Kikuchi, G.; Yoshida, T.; Noguchi, M. (2005). "Heme oxygenase and heme degradation". Biochemical and Biophysical Research
Communications 338 (1): 558–567. doi:10.1016/j.bbrc.2005.08.020. PMID 16115609.
[53] " hemoglobinopathy (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split.
jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ four/ 000048231. htm)" at Dorland's Medical Dictionary
[54] britannica.com --> blood disease (http:/ / www. britannica. com/ EBchecked/ topic/ 280141/ hypoxemia), stating hypoxemia (reduced
oxygen tension in the blood). Retrieved on May 25, 2009
[55] Biology-Online.org --> Dictionary » H » Hypoxemia (http:/ / www. biology-online. org/ dictionary/ Hypoxemia) last modified 00:05, 29
December 2008
[56] Page 430 -> Pathophysiology of acute respiratory failure (http:/ / books. google. dk/ books?id=3H3AIEtvc8YC& pg=PA430& lpg=PA430&
dq=hypoxemia+ definition+ "partial+ pressure"& source=bl& ots=p3N6uD-dVb& sig=UvR-_OjG_K-1y4yId6PIBw7owXg& hl=en&
ei=QUAaSqL0OofU-QbNw-XLDg& sa=X& oi=book_result& ct=result& resnum=6) in Trauma By William C. Wilson, Christopher M.
Grande, David B. Hoyt Edition: illustrated Published by CRC Press, 2007 ISBN 0-8247-2920-X, 9780824729202 1384 pages
[57] Hazards of hypoxemia: How to protect your patient from low oxygen levels (http:/ / findarticles. com/ p/ articles/ mi_qa3689/ is_199605/
ai_n8735092/ ) In Nursing , May 1996 by McGaffigan, Patricia A
[58] "Definition of Glycosylated Hemoglobin." Medicine Net. N.p., n.d. Web. 12 Oct. 2009.
<www.medterms.com/script/main/art.asp?articlekey=16295>.
[59] Hemoglobin (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003645. htm#What abnormal results mean) at Medline Plus
[60] Kumar, Dr. Kamakhya; The Healing Sleep, Yoga, Mind Body Spirit; Yoga Magazine, 26 York Street London, Vol. 50 page 42-44.
[61] Padmanaban P, Toora BD. Hemoglobin: Emerging marker in stable coronary artery disease. Chron Young Sci [serial online] 2011 [cited
2011 Jul 24];2:109-10. Available from: http:/ / www. cysonline. org/ text. asp?2011/ 2/ 2/ 109/ 82971.
[62] http:/ / www. unc. edu/ ~rowlett/ units/ scales/ clinical_data. html
[63] Hemoglobin Level Test (http:/ / ibdcrohns. about. com/ od/ diagnostictesting/ p/ testhemo. htm)
[64] Although other sources can have slightly differing values, such as http:/ / www. gpnotebook. co. uk/ simplepage. cfm?ID=1026883654
[65] Murray S.S. & McKinney E.S.(2006). Foundations of Maternal-Newborn Nursing.(4th ed., p 919).Philadelphia: Saunders Elsevier
[66] "Hematocrit (HCT) or Packed Cell Volume (PCV)" (http:/ / www. doctorslounge. com/ hematology/ labs/ hematocrit. htm).
DoctorsLounge.com. . Retrieved 2007-12-26.
[67] Frasca D., Dahyot-Fizelier C., Catherine K., Levrat Q., Debaene B., Mimoz O. Crit Care Med. 2011 Oct;39(10):2277-82.
[68] This Hb A1c level is only useful in individuals who have red blood cells (RBCs) with normal survivals (i.e., normal half-life). In individuals
with abnormal RBCs, whether due to abnormal hemoglobin molecules (such as Hemoglobin S in Sickle Cell Anemia) or RBC membrane
defects - or other problems, the RBC half-life is frequently shortened. In these individuals, an alternative test called "fructosamine level" can
be used. It measures the degree of glycation (glucose binding) to albumin, the most common blood protein, and reflects average blood glucose
levels over the previous 18-21 days, which is the half-life of albumin molecules in the circulation.
[69] Weber RE, Vinogradov SN (Apr 2001). "Nonvertebrate hemoglobins: functions and molecular adaptations" (http:/ / physrev. physiology.
org/ cgi/ pmidlookup?view=long& pmid=11274340). Physiol. Rev. 81 (2): 569–628. ISSN 0031-9333. PMID 11274340. .
[70] Zal F, Lallier FH, Green BN, Vinogradov SN, Toulmond A (Apr 1996). "The multi-hemoglobin system of the hydrothermal vent tube worm
Riftia pachyptila. II. Complete polypeptide chain composition investigated by maximum entropy analysis of mass spectra" (http:/ / www. jbc.
org/ cgi/ pmidlookup?view=long& pmid=8621529). J. Biol. Chem. 271 (15): 8875–81. doi:10.1074/jbc.271.15.8875. ISSN 0021-9258.
PMID 8621529. .
[71] Minic Z, Hervé G (Aug 2004). "Biochemical and enzymological aspects of the symbiosis between the deep-sea tubeworm Riftia pachyptila
and its bacterial endosymbiont". Eur. J. Biochem. 271 (15): 3093–102. doi:10.1111/j.1432-1033.2004.04248.x. ISSN 0014-2956.
PMID 15265029.
[72] Liu L, Zeng M, Stamler JS (June 1999). "Hemoglobin induction in mouse macrophages". Proceedings of the National Academy of Sciences
of the United States of America 96 (12): 6643–7. doi:10.1073/pnas.96.12.6643. PMC 21968. PMID 10359765.
[73] Newton DA, Rao KM, Dluhy RA, Baatz JE (March 2006). "Hemoglobin Is Expressed by Alveolar Epithelial Cells" (http:/ / www. jbc. org/
cgi/ reprint/ 281/ 9/ 5668). Journal of Biological Chemistry 281 (9): 5668–76. doi:10.1074/jbc.M509314200. PMID 16407281. .
[74] Nishi H, Inagi R, Kato H, et al. (August 2008). "Hemoglobin Is Expressed by Mesangial Cells and Reduces Oxidant Stress" (http:/ / www.
pubmedcentral. nih. gov/ articlerender. fcgi?tool=pubmed& pubmedid=18448584). Journal of the American Society of Nephrology 19 (8):
1500–8. doi:10.1681/ASN.2007101085. PMC 2488266. PMID 18448584. .
[75] Boh, Larry (2001). Pharmacy Practice Manual: A Guide to the Clinical Experience. Lippincott Williams & Wilkins. ISBN 0781725410.
[76] Holden, Constance (30 September 2005). "Blood and Steel" (http:/ / www. sciencemag. org/ cgi/ reprint/ 309/ 5744/ 2160d. pdf) (pdf).
Science 309 (5744): 2160. doi:10.1126/science.309.5744.2160d. .
[77] Moran L, Horton RA, Scrimgeour G, Perry M (2011). Principles of Biochemistry. Boston, MA: Pearson. pp. 127. ISBN 0-321-70733-8.
Hemoglobin 140

Further reading
• Campbell, MK (1999). Biochemistry (Third Edition). Harcourt.
ISBN 0-03-024426-9
• Eshaghian, S; Horwich, TB; Fonarow, GC (January 2006). "An
unexpected inverse relationship between HbA1c levels and
mortality in patients with diabetes and advanced systolic heart
failure". Am Heart J 151 (1): 91. doi:10.1016/j.ahj.2005.10.008.
PMID 16368297.
• Ganong, WF (2003). Review of Medical Physiology
(Twenty-First Edition). Lange. ISBN 0-07-140236-5.
• Hager, T (1995). Force of Nature: The Life of Linus Pauling.
Simon and Schuster. ISBN 0-684-80909-5.
• Hardison, RC (June 11, 1996). "A brief history of hemoglobins: plant,
animal, protist, and bacteria" (http:/ / www. pubmedcentral. gov/
articlerender. fcgi?tool=pubmed& pubmedid=8650150). Proc Natl Acad
Sci USA 93 (12): 5675–9. doi:10.1073/pnas.93.12.5675. PMC 39118.
PMID 8650150. PMID 8650150.
• Kneipp, J; Balakrishnan, G; Chen, R, Shen TJ, Sahu SC, Ho NT,
Giovannelli JL, Simplaceanu V, Ho C, Spiro TG (November 22, 2005).
"Dynamics of allostery in hemoglobin: roles of the penultimate tyrosine
H bonds". J Mol Biol. PMID 16368110.
• Steinberg, MH (2001). Disorders of Hemoglobin: Genetics,
Pathophysiology, and Clinical Management (http:/ / books. google. com/
books?vid=ISBN0521632668). Cambridge University Press.
ISBN 0-521-63266-8.

External links
• Interactive hemoglobin saturation curves (http://www.altitude.org/hemoglobin_saturation.php)
• Interactive models of hemoglobin (http://www.ufp.pt/~pedros/anim/2frame-hben.htm) (Requires MDL
Chime (http://www.mdl.com/products/framework/chime/))
• Hemoglobin. Гемоглобин. Норма гемоглобина в крови (http://medzeit.ru/analizy/krov/
norma-gemoglobina-v-krovi.html)
• National Anemia Action Council (http://www.anemia.org/) - anemia.org
• New hemoglobin type causes mock diagnosis with pulse oxymeters (http://www.life-of-science.net/medicine/
news/new-hemoglobin-type-discovered-causing-mock-diagnosis-of-cardiac-insufficiency.html)
 141

Enzyme mechanisms

Enzyme catalysis
Enzyme catalysis is the catalysis of chemical reactions by specialized proteins known as enzymes. Catalysis of
biochemical reactions in the cell is vital due to the very low reaction rates of the uncatalysed reactions.
The mechanism of enzyme catalysis is similar in principle to other types of chemical catalysis. By providing an
alternative reaction route and by stabilizing intermediates the enzyme reduces the energy required to reach the
highest energy transition state of the reaction. The reduction of activation energy (Ea) increases the number of
reactant molecules with enough energy to reach the activation energy and form the product.

Stabilization of the transition state by an enzyme.

Induced fit
The favored model for the
enzyme-substrate interaction is the
induced fit model.[1] This model
proposes that the initial interaction
between enzyme and substrate is
relatively weak, but that these weak
interactions rapidly induce
conformational changes in the enzyme
that strengthen binding. Diagrams to show the induced fit hypothesis of enzyme action.
Enzyme catalysis 142

Catalysis by induced fit

The advantages of the induced fit mechanism arise due to the
stabilizing effect of strong enzyme binding. There are two
different mechanisms of substrate binding: uniform binding, which
has strong substrate binding, and differential binding, which has
strong transition state binding. The stabilizing effect of uniform
binding increases both substrate and transition state binding
affinity, while differential binding increases only transition state
binding affinity. Both are used by enzymes and have been
evolutionarily chosen to minimize the Ea of the reaction. Enzymes
which are saturated, that is, have a high affinity substrate binding,
require differential binding to reduce the Ea, whereas small
substrate unbound enzymes may use either differential or uniform
binding.
These effects have led to most proteins using the differential
binding mechanism to reduce the Ea, so most proteins have high
affinity of the enzyme to the transition state. Differential binding is
carried out by the induced fit mechanism - the substrate first binds
weakly, then the enzyme changes conformation increasing the
affinity to the transition state and stabilizing it, so reducing the
The different mechanisms of substrate binding
activation energy to reach it.
It is important to clarify, however, that the induced fit concept cannot be used to rationalize catalysis. That is, the
chemical catalysis is defined as the reduction of Ea‡ (when the system is already in the ES‡) relative to Ea‡ in the
uncatalyzed reaction in water (without the enzyme). The induced fit only suggests that the barrier is lower in the
closed form of the enzyme but does not tell us what the reason for the barrier reduction is.
Induced fit may be beneficial to the fidelity of molecular recognition in the presence of competition and noise via the
conformational proofreading mechanism .[2]

Mechanisms of transition state stabilization

These conformational changes also bring catalytic residues in the active site close to the chemical bonds in the
substrate that will be altered in the reaction. After binding takes place, one or more mechanisms of catalysis lowers
the energy of the reaction's transition state, by providing an alternative chemical pathway for the reaction. There are
six possible mechanisms of "over the barrier" catalysis as well as a "through the barrier" mechanism:

Catalysis by bond strain

This is the principal effect of induced fit binding, where the affinity of the enzyme to the transition state is greater
than to the substrate itself. This induces structural rearrangements which strain substrate bonds into a position closer
to the conformation of the transition state, so lowering the energy difference between the substrate and transition
state and helping catalyze the reaction.
However, the strain effect is, in fact, a ground state destabilization effect, rather than transition state stabilization
effect.[3] [4] Furthermore, enzymes are very flexible and they cannot apply large strain effect.[5]
In addition to bond strain in the substrate, bond strain may also be induced within the enzyme itself to activate
residues in the active site.
Enzyme catalysis 143

For example:

Substrate, bound substrate, and transition state conformations of lysozyme.

The substrate, on binding, is distorted from the typical 'chair' hexose ring into the 'sofa' conformation, which is similar in shape to the transition
state.

Catalysis by proximity and orientation

This increases the rate of the reaction as enzyme-substrate interactions align reactive chemical groups and hold them
close together. This reduces the entropy of the reactants and thus makes reactions such as ligations or addition
reactions more favorable, there is a reduction in the overall loss of entropy when two reactants become a single
product.
This effect is analogous to an effective increase in concentration of the reagents. The binding of the reagents to the
enzyme gives the reaction intramolecular character, which gives a massive rate increase.

For example:

Similar reactions will occur far faster if the reaction is intramolecular.

The effective concentration of acetate in the intramolecular reaction can be estimated as k2/k1 = 2 x 105 Molar.

However, the situation might be more complex, since modern computational studies have established that traditional
examples of proximity effects cannot be related directly to enzyme entropic effects.[6] [7] [8] Also, the original
entropic proposal[9] has been found to largely overestimate the contribution of orientation entropy to catalysis.[10]
Enzyme catalysis 144

Catalysis involving proton donors or acceptors (Acid/Base Catalysis)

Proton donors and acceptors, i.e. acids and bases, may donate and accept protons in order to stabilize developing
charges in the transition state. This typically has the effect of activating nucleophile and electrophile groups, or
stabilizing leaving groups. Histidine is often the residue involved in these acid/base reactions, since it has a pKa
close to neutral pH and can therefore both accept and donate protons.
Many reaction mechanisms involving acid/base catalysis assume a substantially altered pKa. This alteration of pKa
is possible through the local environment of the residue.

Conditions Acids Bases

Hydrophobic environment Increase pKa Decrease pKa

Adjacent residues of like charge Increase pKa Decrease pKa

Salt bridge (and hydrogen Decrease pKa Increase pKa

bond) formation

The pKa is can be modified significantly by the environment, to the extent that residues which are basic in solution
may act as proton donors, and vice versa.

For example:

Serine protease catalytic mechanism

The initial step of the serine protease catalytic mechanism involves the histidine of the active site accepting a proton from the serine residue. This
prepares the serine as a nucleophile to attack the amide bond of the substrate. This mechanism includes donation of a proton from serine (a base,
pKa 14) to histidine (an acid, pKa 6), made possible due to the local environment of the bases.

It is important to clarify that the modification of the pKa’s is a pure part of the electrostatic mechanism.[4]
Furthermore, the catalytic effect of the above example is mainly associated with the reduction of the pKa of the oxy
anion and the increase in the pKa of the histidine, while the proton transfer from the serine to the histidine is not
catalyzed significantly, since it is not the rate determining barrier.[11]
Enzyme catalysis 145

Electrostatic catalysis
Stabilization of charged transition states can also be by residues in the active site forming ionic bonds (or partial
ionic charge interactions) with the intermediate. These bonds can either come from acidic or basic side chains found
on amino acids such as lysine, arginine, aspartic acid or glutamic acid or come from metal cofactors such as zinc.
Metal ions are particularly effective and can reduce the pKa of water enough to make it an effective nucleophile.
Systematic computer simulation studies established that electrostatic effects give, by far, the largest contribution to
catalysis.[4] In particular, it has been found that enzyme provides an environment which is more polar than water,
and that the ionic transition states are stabilized by fixed dipoles. This is very different from transition state
stabilization in water, where the water molecules must pay with "reorganization energy".[12] in order to stabilize
ionic and charged states. Thus, the catalysis is associated with the fact that the enzyme polar groups are preorganized
[13]

For example:

Carboxypeptidase catalytic mechanism

The tetrahedral intermediate is stabilised by a partial ionic bond between the Zn2+ ion and the negative charge on the oxygen.

Covalent catalysis
Covalent catalysis involves the substrate forming a transient covalent bond with residues in the active site or with a
cofactor. This adds an additional covalent intermediate to the reaction, and helps to reduce the energy of later
transition states of the reaction. The covalent bond must, at a later stage in the reaction, be broken to regenerate the
enzyme. This mechanism is found in enzymes such as proteases like chymotrypsin and trypsin, where an
acyl-enzyme intermediate is formed. Schiff base formation using the free amine from a lysine residue is another
mechanism, as seen in the enzyme aldolase during glycolysis.
Some enzymes utilize non-amino acid cofactors such as pyridoxal phosphate (PLP) or thiamine pyrophosphate
(TPP) to form covalent intermediates with reactant molecules.[14] [15] Such covalent intermediates function to reduce
the energy of later transition states, similar to how covalent intermediates formed with active site amino acid
residues allow stabilization, but the capabilities of cofactors allow enzymes to carryout reactions that amino acid side
residues alone could not. Enzymes utilizing such cofactors include the PLP-dependent enzyme aspartate
transaminase and the TPP-dependent enzyme pyruvate dehydrogenase.[16] [17]
It is important to clarify that covalent catalysis does correspond in most cases to simply the use of a specific
mechanism rather than to true catalysis.[4] For example, the energetics of the covalent bond to the serine molecule in
chymotrypsin should be compared to the well-understood covalent bond to the nucleophile in the uncatalyzed
solution reaction. A true proposal of a covalent catalysis (where the barrier is lower than the corresponding barrier in
Enzyme catalysis 146

solution) would require, for example, a partial covalent bond to the transition state by an enzyme group (e.g., a very
strong hydrogen bond), and such effects do not contribute significantly to catalysis.

Quantum tunneling
These traditional "over the barrier" mechanisms have been challenged in some cases by models and observations of
"through the barrier" mechanisms (quantum tunneling). Some enzymes operate with kinetics which are faster than
what would be predicted by the classical ΔG‡. In "through the barrier" models, a proton or an electron can tunnel
through activation barriers.[18] [19] Quantum tunneling for protons has been observed in tryptamine oxidation by
aromatic amine dehydrogenase.[20]
Interestingly, quantum tunneling does not appear to provide a major catalytic advantage, since the tunneling
contributions are similar in the catalyzed and the uncatalyzed reactions in solution.[19] [21] [22] [23] However, the
tunneling contribution (typically enhancing rate constants by a factor of ~1000[20] compared to the rate of reaction
for the classical 'over the barrier' route) is likely crucial to the viability of biological organisms. This emphasizes the
general importance of tunneling reactions in biology.
In 1971-1972 the first quantum-mechanical model of enzyme catalysis was formulated.[24] [25]

Examples of catalytic mechanisms

In reality, most enzyme mechanisms involve a combination of several different types of catalysis.

Triose phosphate isomerase

Triose phosphate isomerase (EC 5.3.1.1 [26]) catalyses the reversible interconvertion of the two triose phosphates
isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate.

Trypsin
[27]
Trypsin (EC 3.4.21.4 ) is a serine protease that cleaves protein substrates at lysine and arginine amino acid
residues.

Aldolase
Aldolase (EC 4.1.2.13 [28]) catalyses the breakdown of fructose 1,6-bisphosphate (F-1,6-BP) into glyceraldehyde
3-phosphate and dihydroxyacetone phosphate (DHAP).

References
[1] Koshland DE (February 1958). "Application of a Theory of Enzyme Specificity to Protein Synthesis". Proc. Natl. Acad. Sci. U.S.A. 44 (2):
98–104. doi:10.1073/pnas.44.2.98. PMC 335371. PMID 16590179.
[2] Savir Y & Tlusty T (2007). Scalas, Enrico. ed. "Conformational Proofreading: The Impact of Conformational Changes on the Specificity of
Molecular Recognition" (http:/ / www. weizmann. ac. il/ complex/ tlusty/ papers/ PLoSONE2007. pdf). PLoS ONE 2 (5): e468.
doi:10.1371/journal.pone.0000468. PMC 1868595. PMID 17520027. .
[3] Jencks W.P. "Catalysis in Chemistry and Enzymology" 1987, Dover, New York
[4] Warshel, A.; Sharma, P.K.; Kato, M.; Xiang, Y.; Liu, H.; Olsson, M.H.M. (2006). "Electrostatic Basis of Enzyme Catalysis". Chem. Rev. 106
(8): 3210–3235. doi:10.1021/cr0503106. PMID 16895325.
[5] Warshel, A.; Levitt, M. (1976). "Theoretical Studies of Enzymatic Reactions: Dielectric Electrostatic and Steric Stabilization of the
Carbonium Ion in the Reaction of Lysozyme". J. Mol. Biol. 103 (2): 227–49. doi:10.1016/0022-2836(76)90311-9. PMID 985660.
[6] Stanton, R.V.; Perakyla, M.; Bakowies, D.; Kollman, P.A. (1998). "Combined ab initio and Free Energy Calculations To Study Reactions in
Enzymes and Solution: Amide Hydrolysis in Trypsin and Aqueous Solution". J. Am. Chem. Soc 120 (14): 3448–3457. doi:10.1021/ja972723x.
[7] Kuhn, B.; Kollman, P.A. (2000). "QM-FE and Molecular Dynamics Calculations on Catechol O-Methyltransferase: Free Energy of
Activation in the Enzyme and in Aqueous Solution and Regioselectivity of the Enzyme-Catalyzed Reaction". J. Am. Chem. Soc 122 (11):
2586–2596. doi:10.1021/ja992218v.
Enzyme catalysis 147

[8] Bruice, T.C.; Lightstone, F.C. (1999). "Ground State and Transition State Contributions to the Rates of Intramolecular and Enzymatic
Reactions". Acc. Chem. Res. 32 (2): 127–136. doi:10.1021/ar960131y.
[9] Page, M.I.; Jencks, W.P.. "Entropic Contributions to Rate Accelerations in Enzymic and Intramolecular Reactions and the Chelate Effect".
Proc. Natl. Acad. Sci. USA 1971 (68): 1678–1683. doi:10.1073/pnas.68.8.1678. PMC 389269. PMID 5288752.
[10] Warshel, A.; Parson, W.W. (2001). "Dynamics of Biochemical and Biophysical Reactions: Insight from Computer Simulations". Quart. Rev.
Biophys 34: 563–679.
[11] Warshel, A.; Naray-Szabo, G.; Sussman, F.; Hwang, J.-K. (1989). "How do Serine Proteases Really Work?". Biochemistry 1989 (28):
3629–37. doi:10.1021/bi00435a001. PMID 2665806.
[12] Marcus R. A. "On the Theory of Electron-Transfer Reactions. VI. Unified Treatment for Homogeneous and Electrode Reactions" J. Chem.
Phys. 1965 43:679-701
[13] Warshel A. "Energetics of Enzyme Catalysis", Proc. Natl. Acad. Sci. USA, 1978 75: 5250
[14] Toney, M. D. "Reaction specificity in pyridoxal enzymes." Archives of biochemistry and biophysics (2005) 433: 279-287
[15] Micronutrient Information Center, Oregon State University (http:/ / lpi. oregonstate. edu/ infocenter/ vitamins/ thiamin/ )
[16] Voet, Donald; Judith Voet (2004). Biochemistry. John Wiley & Sons Inc. pp. 986–989. ISBN 0-471-25090-2.
[17] Voet, Donald; Judith Voet (2004). Biochemistry. John Wiley & Sons Inc. pp. 604–606. ISBN 0-471-25090-2.
[18] Garcia-Viloca, M; Gao, J; Karplus, M; Truhlar, DG (2004). "How enzymes work: analysis by modern rate theory and computer
simulations". Science 303 (5655): 186–95. doi:10.1126/science.1088172. PMID 14716003.
[19] Olsson, MH; Siegbahn, PE; Warshel, A (2004). "Simulations of the large kinetic isotope effect and the temperature dependence of the
hydrogen atom transfer in lipoxygenase". Journal of the American Chemical Society 126 (9): 2820–8. doi:10.1021/ja037233l.
PMID 14995199.
[20] Masgrau, L; Roujeinikova, A; Johannissen, LO; Hothi, P; Basran, J; Ranaghan, KE; Mulholland, AJ; Sutcliffe, MJ et al. (2006). "Atomic
description of an enzyme reaction dominated by proton tunneling". Science 312 (5771): 237–41. doi:10.1126/science.1126002.
PMID 16614214.
[21] Hwang, J.-K.; Warshel, A.. "How important are quantum mechanical nuclear motions in enzyme catalysis". J. Am. Chem. Soc 1996 (118):
11745–11751.
[22] Ball, P. (2004). "Enzymes: By chance, or by design?". Nature 431 (7007): 396. Bibcode 2004Natur.431..396B. doi:10.1038/431396a.
[23] Olsson, M.H.M.; Parson, W.W.; Warshel, A.. "Dynamical Contributions to Enzyme Catalysis: Critical Tests of A Popular Hypothesis".
Chem. Rev. 2006 (105): 1737–1756.
[24] Volkenshtein M.V., Dogonadze R.R., Madumarov A.K., Urushadze Z.D., Kharkats Yu.I. Theory of Enzyme Catalysis.- Molekuliarnaya
Biologia, Moscow, 6, 1972, 431-439
[25] Volkenshtein M.V., Dogonadze R.R., Madumarov A.K., Urushadze Z.D., Kharkats Yu.I. Electronic and Conformational Interactions in
Enzyme Catalysis. In: E.L. Andronikashvili (Ed.), Konformatsionnie Izmenenia Biopolimerov v Rastvorakh, Publishing House "Nauka",
Moscow, 1973, 153-157
[26] http:/ / enzyme. expasy. org/ EC/ 5. 3. 1. 1
[27] http:/ / enzyme. expasy. org/ EC/ 3. 4. 21. 4
[28] http:/ / enzyme. expasy. org/ EC/ 4. 1. 2. 13

Further reading
• Alan Fersht, Structure and Mechanism in Protein Science : A Guide to Enzyme Catalysis and Protein Folding. W.
H. Freeman, 1998. ISBN 0-7167-3268-8
• Dedicated issue of Philosophical Transactions B on Quantum catalysis in enzymes freely available. (http://
publishing.royalsociety.org/quantum-catalysis)
 148

Enzyme kinetics

Enzyme kinetics
Enzyme kinetics is the study of the chemical
reactions that are catalysed by enzymes. In
enzyme kinetics, the reaction rate is measured and
the effects of varying the conditions of the
reaction investigated. Studying an enzyme's
kinetics in this way can reveal the catalytic
mechanism of this enzyme, its role in
metabolism, how its activity is controlled, and
how a drug or an agonist might inhibit the
enzyme.

Enzymes are usually protein molecules that

manipulate other molecules — the enzymes'
substrates. These target molecules bind to an
enzyme's active site and are transformed into
products through a series of steps known as the
enzymatic mechanism. These mechanisms can be
divided into single-substrate and
multiple-substrate mechanisms. Kinetic studies
on enzymes that only bind one substrate, such as
triosephosphate isomerase, aim to measure the
affinity with which the enzyme binds this
substrate and the turnover rate.
Dihydrofolate reductase from E. coli with its two substrates, dihydrofolate
When enzymes bind multiple substrates, such as (right) and NADPH (left), bound in the active site. The protein is shown as a
dihydrofolate reductase (shown right), enzyme ribbon diagram, with alpha helices in red, beta sheets in yellow and loops in
[1]
kinetics can also show the sequence in which blue. Generated from 7DFR .

these substrates bind and the sequence in which

products are released. An example of enzymes that bind a single substrate and release multiple products are
proteases, which cleave one protein substrate into two polypeptide products. Others join two substrates together,
such as DNA polymerase linking a nucleotide to DNA. Although these mechanisms are often a complex series of
steps, there is typically one rate-determining step that determines the overall kinetics. This rate-determining step
may be a chemical reaction or a conformational change of the enzyme or substrates, such as those involved in the
release of product(s) from the enzyme.

Knowledge of the enzyme's structure is helpful in interpreting kinetic data. For example, the structure can suggest
how substrates and products bind during catalysis; what changes occur during the reaction; and even the role of
particular amino acid residues in the mechanism. Some enzymes change shape significantly during the mechanism;
in such cases, it is helpful to determine the enzyme structure with and without bound substrate analogues that do not
undergo the enzymatic reaction.
Enzyme kinetics 149

Not all biological catalysts are protein enzymes; RNA-based catalysts such as ribozymes and ribosomes are essential
to many cellular functions, such as RNA splicing and translation. The main difference between ribozymes and
enzymes is that RNA catalysts are composed of nucleotides, whereas enzymes are composed of amino acids.
Ribozymes also perform a more limited set of reactions, although their reaction mechanisms and kinetics can be
analysed and classified by the same methods.

General principles
The reaction catalysed by an enzyme uses
exactly the same reactants and produces
exactly the same products as the uncatalysed
reaction. Like other catalysts, enzymes do
not alter the position of equilibrium between
substrates and products.[2] However, unlike
uncatalysed chemical reactions,
enzyme-catalysed reactions display
saturation kinetics. For a given enzyme
concentration and for relatively low
substrate concentrations, the reaction rate
As larger amounts of substrate are added to a reaction, the available enzyme
increases linearly with substrate binding sites become filled to the limit of . Beyond this limit the enzyme is
concentration; the enzyme molecules are saturated with substrate and the reaction rate ceases to increase.
largely free to catalyse the reaction, and
increasing substrate concentration means an increasing rate at which the enzyme and substrate molecules encounter
one another. However, at relatively high substrate concentrations, the reaction rate asymptotically approaches the
theoretical maximum; the enzyme active sites are almost all occupied and the reaction rate is determined by the
intrinsic turnover rate of the enzyme. The substrate concentration midway between these two limiting cases is
denoted by KM.

The two most important kinetic properties of an enzyme are how quickly the enzyme becomes saturated with a
particular substrate, and the maximum rate it can achieve. Knowing these properties suggests what an enzyme might
do in the cell and can show how the enzyme will respond to changes in these conditions.
Enzyme kinetics 150

Enzyme assays
Enzyme assays are laboratory procedures that measure
the rate of enzyme reactions. Because enzymes are not
consumed by the reactions they catalyse, enzyme
assays usually follow changes in the concentration of
either substrates or products to measure the rate of
reaction. There are many methods of measurement.
Spectrophotometric assays observe change in the
absorbance of light between products and reactants;
radiometric assays involve the incorporation or release
of radioactivity to measure the amount of product made
over time. Spectrophotometric assays are most
convenient since they allow the rate of the reaction to
Progress curve for an enzyme reaction. The slope in the initial rate be measured continuously. Although radiometric assays
period is the initial rate of reaction v. The Michaelis–Menten require the removal and counting of samples (i.e., they
equation describes how this slope varies with the concentration of are discontinuous assays) they are usually extremely
substrate.
sensitive and can measure very low levels of enzyme
activity.[3] An analogous approach is to use mass
spectrometry to monitor the incorporation or release of stable isotopes as substrate is converted into product.

The most sensitive enzyme assays use lasers focused through a microscope to observe changes in single enzyme
molecules as they catalyse their reactions. These measurements either use changes in the fluorescence of cofactors
during an enzyme's reaction mechanism, or of fluorescent dyes added onto specific sites of the protein to report
movements that occur during catalysis.[4] These studies are providing a new view of the kinetics and dynamics of
single enzymes, as opposed to traditional enzyme kinetics, which observes the average behaviour of populations of
millions of enzyme molecules.[5] [6]

An example progress curve for an enzyme assay is shown above. The enzyme produces product at an initial rate that
is approximately linear for a short period after the start of the reaction. As the reaction proceeds and substrate is
consumed, the rate continuously slows (so long as substrate is not still at saturating levels). To measure the initial
(and maximal) rate, enzyme assays are typically carried out while the reaction has progressed only a few percent
towards total completion. The length of the initial rate period depends on the assay conditions and can range from
milliseconds to hours. However, equipment for rapidly mixing liquids allows fast kinetic measurements on initial
rates of less than one second.[7] These very rapid assays are essential for measuring pre-steady-state kinetics, which
are discussed below.
Most enzyme kinetics studies concentrate on this initial, approximately linear part of enzyme reactions. However, it
is also possible to measure the complete reaction curve and fit this data to a non-linear rate equation. This way of
measuring enzyme reactions is called progress-curve analysis.[8] This approach is useful as an alternative to rapid
kinetics when the initial rate is too fast to measure accurately.

Single-substrate reactions
Enzymes with single-substrate mechanisms include isomerases such as triosephosphateisomerase or
bisphosphoglycerate mutase, intramolecular lyases such as adenylate cyclase and the hammerhead ribozyme, a RNA
lyase.[9] However, some enzymes that only have a single substrate do not fall into this category of mechanisms.
Catalase is an example of this, as the enzyme reacts with a first molecule of hydrogen peroxide substrate, becomes
oxidised and is then reduced by a second molecule of substrate. Although a single substrate is involved, the existence
of a modified enzyme intermediate means that the mechanism of catalase is actually a ping–pong mechanism, a type
Enzyme kinetics 151

of mechanism that is discussed in the Multi-substrate reactions section below.

Michaelis–Menten kinetics
As enzyme-catalysed reactions are
saturable, their rate of catalysis does not
show a linear response to increasing
substrate. If the initial rate of the reaction is
measured over a range of substrate
concentrations (denoted as [S]), the reaction
rate (v) increases as [S] increases, as shown
on the right. However, as [S] gets higher,
the enzyme becomes saturated with
substrate and the rate reaches Vmax, the
enzyme's maximum rate.

Saturation curve for an enzyme showing the relation between the concentration of
substrate and rate.

Single-substrate mechanism for an enzyme reaction. k1, k-1 and k2 are the rate
constants for the individual steps.

The Michaelis–Menten kinetic model of a single-substrate reaction is shown on the right. There is an initial
bimolecular reaction between the enzyme E and substrate S to form the enzyme–substrate complex ES. Although the
enzymatic mechanism for the unimolecular reaction can be quite complex, there is typically one
rate-determining enzymatic step that allows this reaction to be modelled as a single catalytic step with an apparent
unimolecular rate constant kcat. If the reaction path proceeds over one or several intermediates, kcat will be a function
of several elementary rate constants, whereas in the simplest case of a single elementary reaction (e.g. no
intermediates) it will be identical to the elementary unimolecular rate constant k2. The apparent unimolecular rate
constant kcat is also called turnover number and denotes the maximum number of enzymatic reactions catalysed per
second.
The Michaelis–Menten equation[10] describes how the (initial) reaction rate v0 depends on the position of the
substrate-binding equilibrium and the rate constant k2.

    (Michaelis–Menten equation)

with the constants

Enzyme kinetics 152

This Michaelis–Menten equation is the basis for most single-substrate enzyme kinetics. Two crucial assumptions
underlie this equation (apart from the general assumption about the mechanism only involving no intermediate or
product inhibition, and there is no allostericity or cooperativity). The first assumption is the so called
quasi-steady-state assumption (or pseudo-steady-state hypothesis), namely that the concentration of the
substrate-bound enzyme (and hence also the unbound enzyme) changes much more slowly than those of the product
and substrate and thus the change over time of the complex can be set to zero . The second
assumption is that the total enzyme concentration does not change over time, thus
. A complete derivation can be found here.
The Michaelis constant KM is experimentally defined as the concentration at which the rate of the enzyme reaction is
half Vmax, which can be verified by substituting [S] = Km into the Michaelis–Menten equation and can also be seen
graphically. If the rate-determining enzymatic step is slow compared to substrate dissociation ( ), the
Michaelis constant KM is roughly the dissociation constant KD of the ES complex.
If is small compared to then the term and also very little ES complex is
formed, thus . Therefore, the rate of product formation is

Thus the product formation rate depends on the enzyme concentration as well as on the substrate concentration, the
equation resembles a bimolecular reaction with a corresponding pseudo-second order rate constant . This
constant is a measure of catalytic efficiency. The most efficient enzymes reach a in the range of 108 -
1010 M−1 s−1. These enzymes are so efficient they effectively catalyse a reaction each time they encounter a
substrate molecule and have thus reached an upper theoretical limit for efficiency (diffusion limit); these enzymes
have often been termed perfect enzymes.[11]

Direct use of the Michaelis–Menten equation for time course kinetic analysis
Further information: Rate equation
The observed velocities predicted by the Michaelis–Menten equation can be used to directly model the time course
disappearance of substrate and the production of product through incorporation of the Michaelis–Menten equation
into the equation for first order chemical kinetics. This can only be achieved however if one recognises the problem
associated with the use of Euler's number in the description of first order chemical kinetics. i.e. e-k is a split constant
that introduces a systematic error into calculations and can be rewritten as a single constant which represents the
remaining substrate after each time period.[12]

In 1997, Santiago Schnell and Claudio Mendoza derived a closed form solution for the time course kinetics analysis
of the Michaelis-Menten mechanism.[13] The solution has the form:

where W[] is the Lambert-W function.[14] [15]

Enzyme kinetics 153

Linear plots of the Michaelis–Menten equation

Using an interactive
Michaelis–Menten kinetics tutorial at
the University of Virginia,[α] the
effects on the behaviour of an enzyme
of varying kinetic constants can be
explored.

The plot of v versus [S] above is not

linear; although initially linear at low
[S], it bends over to saturate at high
[S]. Before the modern era of nonlinear
curve-fitting on computers, this
nonlinearity could make it difficult to
estimate KM and Vmax accurately.
Therefore, several researchers Lineweaver–Burk or double-reciprocal plot of kinetic data, showing the significance of
developed linearisations of the the axis intercepts and gradient.

Michaelis–Menten equation, such as

the Lineweaver–Burk plot, the Eadie–Hofstee diagram and the Hanes–Woolf plot. All of these linear representations
can be useful for visualising data, but none should be used to determine kinetic parameters, as computer software is
readily available that allows for more accurate determination by nonlinear regression methods.[16]

The Lineweaver–Burk plot or double reciprocal plot is a common way of illustrating kinetic data. This is produced
by taking the reciprocal of both sides of the Michaelis–Menten equation. As shown on the right, this is a linear form
of the Michaelis–Menten equation and produces a straight line with the equation y = mx + c with a y-intercept
equivalent to 1/Vmax and an x-intercept of the graph representing -1/KM.

Naturally, no experimental values can be taken at negative 1/[S]; the lower limiting value 1/[S] = 0 (the y-intercept)
corresponds to an infinite substrate concentration, where 1/v=1/Vmax as shown at the right; thus, the x-intercept is an
extrapolation of the experimental data taken at positive concentrations. More generally, the Lineweaver–Burk plot
skews the importance of measurements taken at low substrate concentrations and, thus, can yield inaccurate
estimates of Vmax and KM.[17] A more accurate linear plotting method is the Eadie-Hofstee plot. In this case, v is
plotted against v/[S]. In the third common linear representation, the Hanes-Woolf plot, [S]/v is plotted against [S]. In
general, data normalisation can help diminish the amount of experimental work and can increase the reliability of the
output, and is suitable for both graphical and numerical analysis.[18]

Practical significance of kinetic constants

The study of enzyme kinetics is important for two basic reasons. Firstly, it helps explain how enzymes work, and
secondly, it helps predict how enzymes behave in living organisms. The kinetic constants defined above, KM and
Vmax, are critical to attempts to understand how enzymes work together to control metabolism.
Making these predictions is not trivial, even for simple systems. For example, oxaloacetate is formed by malate
dehydrogenase within the mitochondrion. Oxaloacetate can then be consumed by citrate synthase,
phosphoenolpyruvate carboxykinase or aspartate aminotransferase, feeding into the citric acid cycle,
gluconeogenesis or aspartic acid biosynthesis, respectively. Being able to predict how much oxaloacetate goes into
which pathway requires knowledge of the concentration of oxaloacetate as well as the concentration and kinetics of
each of these enzymes. This aim of predicting the behaviour of metabolic pathways reaches its most complex
Enzyme kinetics 154

expression in the synthesis of huge amounts of kinetic and gene expression data into mathematical models of entire
organisms. Alternatively, one useful simplification of the metabolic modelling problem is to ignore the underlying
enzyme kinetics and only rely on information about the reaction network's stoichiometry, a technique called flux
balance analysis.[19] [20]

Michaelis–Menten kinetics with intermediate

One could also consider the less simple case

where a complex with the enzyme and an intermediate exists and the intermediate is converted into product in a
second step. In this case we have a very similar equation[21]

but the constants are different

We see that for the limiting case , thus when the last step from EI to E + P is much faster than the
previous step, we get again the original equation. Mathematically we have then and .

Multi-substrate reactions
Multi-substrate reactions follow complex rate equations that describe how the substrates bind and in what sequence.
The analysis of these reactions is much simpler if the concentration of substrate A is kept constant and substrate B
varied. Under these conditions, the enzyme behaves just like a single-substrate enzyme and a plot of v by [S] gives
apparent KM and Vmax constants for substrate B. If a set of these measurements is performed at different fixed
concentrations of A, these data can be used to work out what the mechanism of the reaction is. For an enzyme that
takes two substrates A and B and turns them into two products P and Q, there are two types of mechanism: ternary
complex and ping–pong.

Ternary-complex mechanisms
In these enzymes, both substrates bind to
the enzyme at the same time to produce an
EAB ternary complex. The order of
binding can either be random (in a
random mechanism) or substrates have to
bind in a particular sequence (in an
ordered mechanism). When a set of v by
[S] curves (fixed A, varying B) from an
enzyme with a ternary-complex
mechanism are plotted in a
Random-order ternary-complex mechanism for an enzyme reaction. The reaction path
Lineweaver–Burk plot, the set of lines is shown as a line and enzyme intermediates containing substrates A and B or
produced will intersect. products P and Q are written below the line.
Enzyme kinetics 155

Enzymes with ternary-complex mechanisms include glutathione S-transferase,[22] dihydrofolate reductase[23] and
DNA polymerase.[24] The following links show short animations of the ternary-complex mechanisms of the enzymes
dihydrofolate reductase[β] and DNA polymerase[γ].

Ping–pong mechanisms
As shown on the right, enzymes with a
ping-pong mechanism can exist in two
states, E and a chemically modified form
of the enzyme E*; this modified enzyme
Ping–pong mechanism for an enzyme reaction. Intermediates contain substrates A
is known as an intermediate. In such and B or products P and Q.
mechanisms, substrate A binds, changes
the enzyme to E* by, for example, transferring a chemical group to the active site, and is then released. Only after
the first substrate is released can substrate B bind and react with the modified enzyme, regenerating the unmodified
E form. When a set of v by [S] curves (fixed A, varying B) from an enzyme with a ping–pong mechanism are plotted
in a Lineweaver–Burk plot, a set of parallel lines will be produced. This is called a secondary plot.

Enzymes with ping–pong mechanisms include some oxidoreductases such as thioredoxin peroxidase,[25] transferases
such as acylneuraminate cytydilyltransferase[26] and serine proteases such as trypsin and chymotrypsin.[27] Serine
proteases are a very common and diverse family of enzymes, including digestive enzymes (trypsin, chymotrypsin,
and elastase), several enzymes of the blood clotting cascade and many others. In these serine proteases, the E*
intermediate is an acyl-enzyme species formed by the attack of an active site serine residue on a peptide bond in a
protein substrate. A short animation showing the mechanism of chymotrypsin is linked here.[δ]

Non-Michaelis–Menten kinetics
Some enzymes produce a sigmoid v by [S]
plot, which often indicates cooperative
binding of substrate to the active site. This
means that the binding of one substrate
molecule affects the binding of subsequent
substrate molecules. This behavior is most
common in multimeric enzymes with
several interacting active sites.[28] Here, the
mechanism of cooperation is similar to that
of hemoglobin, with binding of substrate to
one active site altering the affinity of the
other active sites for substrate molecules.
Positive cooperativity occurs when binding
of the first substrate molecule increases the
affinity of the other active sites for substrate.
Saturation curve for an enzyme reaction showing sigmoid kinetics.
Negative cooperativity occurs when binding
of the first substrate decreases the affinity of
the enzyme for other substrate molecules.

Allosteric enzymes include mammalian tyrosyl tRNA-synthetase, which shows negative cooperativity,[29] and
bacterial aspartate transcarbamoylase[30] and phosphofructokinase,[31] which show positive cooperativity.
Cooperativity is surprisingly common and can help regulate the responses of enzymes to changes in the
concentrations of their substrates. Positive cooperativity makes enzymes much more sensitive to [S] and their
Enzyme kinetics 156

activities can show large changes over a narrow range of substrate concentration. Conversely, negative cooperativity
makes enzymes insensitive to small changes in [S].
The Hill equation (biochemistry)[32] is often used to describe the degree of cooperativity quantitatively in
non-Michaelis–Menten kinetics. The derived Hill coefficient n measures how much the binding of substrate to one
active site affects the binding of substrate to the other active sites. A Hill coefficient of <1 indicates negative
cooperativity and a coefficient of >1 indicates positive cooperativity.

Pre-steady-state kinetics
In the first moment after an enzyme is
mixed with substrate, no product has been
formed and no intermediates exist. The
study of the next few milliseconds of the
reaction is called Pre-steady-state kinetics
also referred to as Burst kinetics.
Pre-steady-state kinetics is therefore
concerned with the formation and
consumption of enzyme–substrate
intermediates (such as ES or E*) until their
steady-state concentrations are reached.

This approach was first applied to the

hydrolysis reaction catalysed by
[33] Pre-steady state progress curve, showing the burst phase of an enzyme reaction.
chymotrypsin. Often, the detection of an
intermediate is a vital piece of evidence in
investigations of what mechanism an enzyme follows. For example, in the ping–pong mechanisms that are shown
above, rapid kinetic measurements can follow the release of product P and measure the formation of the modified
enzyme intermediate E*.[34] In the case of chymotrypsin, this intermediate is formed by an attack on the substrate by
the nucleophilic serine in the active site and the formation of the acyl-enzyme intermediate.

In the figure to the right, the enzyme produces E* rapidly in the first few seconds of the reaction. The rate then slows
as steady state is reached. This rapid burst phase of the reaction measures a single turnover of the enzyme.
Consequently, the amount of product released in this burst, shown as the intercept on the y-axis of the graph, also
gives the amount of functional enzyme which is present in the assay.[35]

Chemical mechanism
An important goal of measuring enzyme kinetics is to determine the chemical mechanism of an enzyme reaction, i.e.,
the sequence of chemical steps that transform substrate into product. The kinetic approaches discussed above will
show at what rates intermediates are formed and inter-converted, but they cannot identify exactly what these
intermediates are.
Kinetic measurements taken under various solution conditions or on slightly modified enzymes or substrates often
shed light on this chemical mechanism, as they reveal the rate-determining step or intermediates in the reaction. For
example, the breaking of a covalent bond to a hydrogen atom is a common rate-determining step. Which of the
possible hydrogen transfers is rate determining can be shown by measuring the kinetic effects of substituting each
hydrogen by deuterium, its stable isotope. The rate will change when the critical hydrogen is replaced, due to a
primary kinetic isotope effect, which occurs because bonds to deuterium are harder to break than bonds to
hydrogen.[36] It is also possible to measure similar effects with other isotope substitutions, such as 13C/12C and
18 16
O/ O, but these effects are more subtle.[37]
Enzyme kinetics 157

Isotopes can also be used to reveal the fate of various parts of the substrate molecules in the final products. For
example, it is sometimes difficult to discern the origin of an oxygen atom in the final product; since it may have
come from water or from part of the substrate. This may be determined by systematically substituting oxygen's stable
isotope 18O into the various molecules that participate in the reaction and checking for the isotope in the product.[38]
The chemical mechanism can also be elucidated by examining the kinetics and isotope effects under different pH
conditions,[39] by altering the metal ions or other bound cofactors,[40] by site-directed mutagenesis of conserved
amino acid residues, or by studying the behaviour of the enzyme in the presence of analogues of the substrate(s).[41]

Enzyme inhibition and activation

Enzyme inhibitors are molecules that reduce
or abolish enzyme activity, while enzyme
activators are molecules that increase the
catalytic rate of enzymes. These interactions
can be either reversible (i.e., removal of the
inhibitor restores enzyme activity) or
irreversible (i.e., the inhibitor permanently
inactivates the enzyme).

Reversible inhibitors Kinetic scheme for reversible enzyme inhibitors.

Traditionally reversible enzyme inhibitors

have been classified as competitive, uncompetitive, or non-competitive, according to their effects on Km and Vmax.
These different effects result from the inhibitor binding to the enzyme E, to the enzyme–substrate complex ES, or to
both, respectively. The particular type of an inhibitor can be discerned by studying the enzyme kinetics as a function
of the inhibitor concentration. The three types of inhibition produce Lineweaver–Burke and Eadie–Hofstee plots[17]
that vary in distinctive ways with inhibitor concentration. For a straightforward qualitative explanation, see[42]

Non-linear regression fits of the enzyme kinetics data to rate equations[43] can yield accurate estimates of
dissociation constants and yield important information relating to the mechanism of action.

Adding zero to the bottom ([I]-[I])

Dividing by [I]+Ki
Enzyme kinetics 158

This notation demonstrates that similar to the Michaelis–Menten equation,where the rate of reaction depends on the
percent of the enzyme population interacting with substrate
fraction of the enzyme population bound by substrate

fraction of the enzyme population bound by inhibitor

the effect of the inhibitor is a result of the percent of the enzyme population interacting with inhibitor. The only
problem with this equation in its present form is that it assumes absolute inhibition of the enzyme with inhibitor
binding, when in fact there can be a wide range of affects anywhere from 100% inhibition of substrate turn over to
just >0%. To account for this the equation can be easily modified to allow for different degrees of inhibition by
including a delta Vmax term.

or

This term can then define the residual enzymatic activity present when the inhibitor is interacting with individual
enzymes in the population. However the inclusion of this term has the added value of allowing for the possibility of
activation if the secondary Vmax term turns out to be higher than the initial term. To account for the possibly of
activation as well the notation can then be rewritten replacing the inhibitor "I" with a modifier term denoted here as
"X".

While this terminology results in a simplified way of dealing with kinetic effects relating to the maximum velocity of
the Michaelis–Menten equation, it highlights potential problems with the term used to describe effects relating to the
Km. The Km relating to the affinity of the enzyme for the substrate should in most cases relate to potential changes in
the binding site of the enzyme which would directly result from enzyme inhibitor interactions. As such a term similar
to the one proposed above to modulate Vmax should be appropriate in most situations.:[44]
Enzyme kinetics 159

Irreversible inhibitors
Enzyme inhibitors can also irreversibly inactivate enzymes, usually by covalently modifying active site residues.
These reactions, which may be called suicide substrates, follow exponential decay functions and are usually
saturable. Below saturation, they follow first order kinetics with respect to inhibitor.

Mechanisms of catalysis
The favoured model for the
enzyme–substrate interaction is the induced
fit model.[45] This model proposes that the
initial interaction between enzyme and
substrate is relatively weak, but that these
weak interactions rapidly induce
conformational changes in the enzyme that
strengthen binding. These conformational
changes also bring catalytic residues in the
active site close to the chemical bonds in the
substrate that will be altered in the
reaction.[46] Conformational changes can be
measured using circular dichroism or dual
polarisation interferometry. After binding
takes place, one or more mechanisms of
The energy variation as a function of reaction coordinate shows the stabilisation of
catalysis lower the energy of the reaction's
the transition state by an enzyme.
transition state by providing an alternative
chemical pathway for the reaction.
Mechanisms of catalysis include catalysis by bond strain; by proximity and orientation; by active-site proton donors
or acceptors; covalent catalysis and quantum tunnelling.[34] [47]

Enzyme kinetics cannot prove which modes of catalysis are used by an enzyme. However, some kinetic data can
suggest possibilities to be examined by other techniques. For example, a ping–pong mechanism with burst-phase
pre-steady-state kinetics would suggest covalent catalysis might be important in this enzyme's mechanism.
Alternatively, the observation of a strong pH effect on Vmax but not Km might indicate that a residue in the active site
needs to be in a particular ionisation state for catalysis to occur.

Footnotes
α.  Link: Interactive Michaelis–Menten kinetics tutorial (Java required) [48]
β.  Link: dihydrofolate reductase mechanism (Gif) [49]
γ.  Link: DNA polymerase mechanism (Gif) [50]
δ.  Link: Chymotrypsin mechanism (Flash required) [51]

References
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Enzyme kinetics 160

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acylneuraminate cytidylyltransferase from Pasteurella haemolytica A2" (http:/ / www. biochemj. org/ bj/ 358/ 0585/ bj3580585. htm).
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Transcarbamoylase versus Yeast Chorismate Mutase" (http:/ / mmbr. asm. org/ cgi/ content/ full/ 65/ 3/ 404). Microbiol. Mol. Biol. Rev. 65
(3): 404–21, table of contents. doi:10.1128/MMBR.65.3.404-421.2001. PMC 99034. PMID 11528003. .
Enzyme kinetics 161

[31] Schirmer T, Evans PR (January 1990). "Structural basis of the allosteric behaviour of phosphofructokinase". Nature 343 (6254): 140–5.
doi:10.1038/343140a0. PMID 2136935.
[32] Hill, A. V. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J. Physiol. (Lond.), 1910 40,
iv-vii.
[33] Hartley BS, Kilby BA (February 1954). "The reaction of p-nitrophenyl esters with chymotrypsin and insulin". Biochem. J. 56 (2): 288–97.
PMC 1269615. PMID 13140189.
[34] Fersht, Alan (1999). Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding. San Francisco: W.H.
Freeman. ISBN 0-7167-3268-8.
[35] Bender ML, Begué-Cantón ML, Blakeley RL, et al. (December 1966). "The determination of the concentration of hydrolytic enzyme
solutions: alpha-chymotrypsin, trypsin, papain, elastase, subtilisin, and acetylcholinesterase". J. Am. Chem. Soc. 88 (24): 5890–913.
doi:10.1021/ja00976a034. PMID 5980876.
[36] Cleland WW (January 2005). "The use of isotope effects to determine enzyme mechanisms" (http:/ / www. sciencedirect. com/
science?_ob=ArticleURL& _udi=B6WB5-4DD8DXJ-8& _coverDate=01/ 01/ 2005& _alid=466049795& _rdoc=1& _fmt=& _orig=search&
_qd=1& _cdi=6701& _sort=d& view=c& _acct=C000050221& _version=1& _urlVersion=0& _userid=10&
md5=cf322c4a1c7db6b9f89551a8469a1a2d). Arch. Biochem. Biophys. 433 (1): 2–12. doi:10.1016/j.abb.2004.08.027. PMID 15581561. .
[37] Northrop D (1981). "The expression of isotope effects on enzyme-catalyzed reactions". Annu. Rev. Biochem. 50: 103–31.
doi:10.1146/annurev.bi.50.070181.000535. PMID 7023356.
[38] Baillie T, Rettenmeier A (1986). "Drug biotransformation: mechanistic studies with stable isotopes". Journal of clinical pharmacology 26
(6): 448–51. PMID 3734135.
[39] Cleland WW (1982). "Use of isotope effects to elucidate enzyme mechanisms". CRC Crit. Rev. Biochem. 13 (4): 385–428.
doi:10.3109/10409238209108715. PMID 6759038.
[40] Christianson DW, Cox JD (1999). "Catalysis by metal-activated hydroxide in zinc and manganese metalloenzymes". Annu. Rev. Biochem.
68: 33–57. doi:10.1146/annurev.biochem.68.1.33. PMID 10872443.
[41] Kraut D, Carroll K, Herschlag D (2003). "Challenges in enzyme mechanism and energetics". Annu. Rev. Biochem. 72: 517–71.
doi:10.1146/annurev.biochem.72.121801.161617. PMID 12704087.
[42] Waldrop GL (January 2009). "A qualitative approach to enzyme inhibition". Biochemistry and Molecular Biology Education 37 (1): 11–15.
doi:10.1002/bmb.20243. PMID 21567682.
[43] Leatherbarrow RJ (December 1990). "Using linear and non-linear regression to fit biochemical data". Trends Biochem. Sci. 15 (12): 455–8.
doi:10.1016/0968-0004(90)90295-M. PMID 2077683.
[44] Walsh R, Martin E, Darvesh S. A versatile equation to describe reversible enzyme inhibition and activation kinetics: modeling
beta-galactosidase and butyrylcholinesterase. Biochim Biophys Acta. 2007 1770:733-46.
[45] Koshland DE (February 1958). "Application of a Theory of Enzyme Specificity to Protein Synthesis". Proc. Natl. Acad. Sci. U.S.A. 44 (2):
98–104. doi:10.1073/pnas.44.2.98. PMC 335371. PMID 16590179.
[46] Hammes G (2002). "Multiple conformational changes in enzyme catalysis". Biochemistry 41 (26): 8221–8. doi:10.1021/bi0260839.
PMID 12081470.
[47] Sutcliffe M, Scrutton N (2002). "A new conceptual framework for enzyme catalysis. Hydrogen tunnelling coupled to enzyme dynamics in
flavoprotein and quinoprotein enzymes" (http:/ / content. febsjournal. org/ cgi/ content/ full/ 269/ 13/ 3096). Eur. J. Biochem. 269 (13):
3096–102. doi:10.1046/j.1432-1033.2002.03020.x. PMID 12084049. .
[48] http:/ / cti. itc. virginia. edu/ ~cmg/ Demo/ scriptFrame. html
[49] http:/ / chem-faculty. ucsd. edu/ kraut/ dhfr. html
[50] http:/ / chem-faculty. ucsd. edu/ kraut/ dNTP. html
[51] http:/ / courses. cm. utexas. edu/ jrobertus/ ch339k/ overheads-2/ 06_21_chymotrypsin. html

Further reading
Introductory
• Cornish-Bowden, Athel (2004). Fundamentals of enzyme kinetics (3rd ed.). London: Portland Press.
ISBN 1-85578-158-1.
• Stevens, Lewis; Price, Nicholas C. (1999). Fundamentals of enzymology: the cell and molecular biology of
catalytic proteins. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-850229-X.
• Bugg, Tim (2004). Introduction to Enzyme and Coenzyme Chemistry. Cambridge, MA: Blackwell Publishers.
ISBN 1-4051-1452-5.
Advanced
• Segel, Irwin H. (1993). Enzyme kinetics: behavior and analysis of rapid equilibrium and steady state enzyme
systems (New ed.). New York: Wiley. ISBN 0-471-30309-7.
Enzyme kinetics 162

• Fersht, Alan (1999). Structure and mechanism in protein science: a guide to enzyme catalysis and protein folding.
San Francisco: W.H. Freeman. ISBN 0-7167-3268-8.
• Santiago Schnell, Philip K. Maini (2004). "A century of enzyme kinetics: Reliability of the KM and vmax
estimates" (http://www.informatics.indiana.edu/schnell/papers/ctb8_169.pdf). Comments on Theoretical
Biology 8 (2–3): 169–87. doi:10.1080/08948550302453.
• Walsh, Christopher (1979). Enzymatic reaction mechanisms. San Francisco: W. H. Freeman.
ISBN 0-7167-0070-0.
• Cleland, William Wallace; Cook, Paul (2007). Enzyme kinetics and mechanism. New York: Garland Science.
ISBN 0-8153-4140-7.

External links
• Animation of an enzyme assay (http://www.kscience.co.uk/animations/model.swf) — Shows effects of
manipulating assay conditions
• MACiE (http://www.ebi.ac.uk/thornton-srv/databases/MACiE/) — A database of enzyme reaction
mechanisms
• ENZYME (http://us.expasy.org/enzyme/) — Expasy enzyme nomenclature database
• ENZO (http://enzo.cmm.ki.si) — Web application for easy construction and quick testing of kinetic models of
enzyme catalyzed reactions.
• ExCatDB (http://mbs.cbrc.jp/EzCatDB/) — A database of enzyme catalytic mechanisms
• BRENDA (http://www.brenda-enzymes.info/) — Comprehensive enzyme database, giving substrates,
inhibitors and reaction diagrams
• SABIO-RK (http://sabio.villa-bosch.de/SABIORK/) — A database of reaction kinetics
• Joseph Kraut's Research Group, University of California San Diego (http://chem-faculty.ucsd.edu/kraut/dhfr.
html) — Animations of several enzyme reaction mechanisms
• Symbolism and Terminology in Enzyme Kinetics (http://www.chem.qmul.ac.uk/iubmb/kinetics/) — A
comprehensive explanation of concepts and terminology in enzyme kinetics
• An introduction to enzyme kinetics (http://orion1.paisley.ac.uk/kinetics/contents.html) — An accessible set
of on-line tutorials on enzyme kinetics
• Enzyme kinetics animated tutorial (http://www.wiley.com/college/pratt/0471393878/student/animations/
enzyme_kinetics/index.html) — An animated tutorial with audio
 163

Lipids and membranes

Lipid
Lipids constitute a broad group of
naturally occurring molecules that
include fats, waxes, sterols, fat-soluble
vitamins (such as vitamins A, D, E,
and K), monoglycerides, diglycerides,
triglycerides, phospholipids, and
others. The main biological functions
of lipids include energy storage, as
structural components of cell
membranes, and as important signaling
molecules.[4]

Lipids may be broadly defined as

hydrophobic or amphiphilic small
molecules; the amphiphilic nature of
some lipids allows them to form
structures such as vesicles, liposomes,
or membranes in an aqueous
environment. Biological lipids
originate entirely or in part from two
distinct types of biochemical subunits [1] [2]
Structures of some common lipids. At the top are oleic acid and cholesterol. The
or "building-blocks": ketoacyl and middle structure is a triglyceride composed of oleoyl, stearoyl, and palmitoyl chains
isoprene groups.[4] Using this attached to a glycerol backbone. At the bottom is the common phospholipid,
[3]
approach, lipids may be divided into phosphatidylcholine.

eight categories: fatty acyls,

glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of
ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).[4]

Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides.
Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, monoglycerides, and
phospholipids), as well as other sterol-containing metabolites such as cholesterol.[5] Although humans and other
mammals use various biosynthetic pathways to both break down and synthesize lipids, some essential lipids cannot
be made this way and must be obtained from the diet.

Categories of lipids
Lipid 164

Fatty acyls
Fatty acyls, a generic term for describing fatty acids, their conjugates, and derivatives, are a diverse group of
molecules synthesized by chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA
groups in a process called fatty acid synthesis.[6] [7] They are made of a hydrocarbon chain that terminates with a
carboxylic acid group; this arrangement confers the molecule with a polar, hydrophilic end, and a nonpolar,
hydrophobic end that is insoluble in water. The fatty acid structure is one of the most fundamental categories of
biological lipids, and is commonly used as a building-block of more structurally complex lipids. The carbon chain,
typically between four and 24 carbons long,[8] may be saturated or unsaturated, and may be attached to functional
groups containing oxygen, halogens, nitrogen, and sulfur. Where a double bond exists, there is the possibility of
either a cis or a trans geometric isomerism, which significantly affects the molecule's molecular configuration.
Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more double bonds there
are in a chain. This in turn plays an important role in the structure and function of cell membranes.[9] Most naturally
occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially
hydrogenated fats and oils.[10]
Examples of biologically important fatty acids are the eicosanoids, derived primarily from arachidonic acid and
eicosapentaenoic acid, which include prostaglandins, leukotrienes, and thromboxanes. Other major lipid classes in
the fatty acid category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates
such as wax esters, fatty acid thioester coenzyme A derivatives, fatty acid thioester ACP derivatives and fatty acid
carnitines. The fatty amides include N-acyl ethanolamines, such as the cannabinoid neurotransmitter anandamide.[11]

Glycerolipids
Glycerolipids are composed mainly of mono-, di-, and tri-substituted glycerols,[12] the most well-known being the
fatty acid triesters of glycerol (triacylglycerols), also known as triglycerides. In these compounds, the three hydroxyl
groups of glycerol are each esterified, usually by different fatty acids. Because they function as a food store, these
lipids comprise the bulk of storage fat in animal tissues. The hydrolysis of the ester bonds of triacylglycerols and the
release of glycerol and fatty acids from adipose tissue is called fat mobilization.[13]
Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence
of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category
are the digalactosyldiacylglycerols found in plant membranes[14] and seminolipid from mammalian sperm cells.[15]

Glycerophospholipids
Glycerophospholipids, also referred to as phospholipids, are ubiquitous in nature and are key components of the lipid
bilayer of cells, as well as being involved in metabolism and cell signaling. Neural tissue (including the brain)
contains relatively high amounts of glycerophospholipids, and alterations in their composition has been implicated in
various neurological disorders.[16] Glycerophospholipids may be subdivided into distinct classes, based on the nature
of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria, or the sn-1
position in the case of archaebacteria.[17]
Examples of glycerophospholipids found in biological membranes are
phosphatidylcholine (also known as PC, GPCho or lecithin),
phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (PS
or GPSer). In addition to serving as a primary component of cellular
membranes and binding sites for intra- and intercellular proteins, some
Phosphatidylethanolamine glycerophospholipids in eukaryotic cells, such as phosphatidylinositols
and phosphatidic acids are either precursors of or, themselves,
Lipid 165

membrane-derived second messengers.[18] Typically, one or both of these hydroxyl groups are acylated with
long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as
well as dialkylether variants in archaebacteria.[19]

Sphingolipids
Sphingolipids are a complex family of compounds[20] that share a common structural feature, a sphingoid base
backbone that is synthesized de novo from the amino acid serine and a long-chain fatty acyl CoA, then converted
into ceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of
mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of
sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or
mono-unsaturated with chain lengths from 16 to 26 carbon atoms.[21]
The major phosphosphingolipids of mammals are sphingomyelins
(ceramide phosphocholines),[22] whereas insects contain mainly
ceramide phosphoethanolamines[23] and fungi have phytoceramide
phosphoinositols and mannose-containing headgroups.[24] The
Sphingomyelin
glycosphingolipids are a diverse family of molecules composed of one
or more sugar residues linked via a glycosidic bond to the sphingoid
base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.

Sterol lipids
Sterol lipids, such as cholesterol and its derivatives, are an important component of membrane lipids,[25] along with
the glycerophospholipids and sphingomyelins. The steroids, all derived from the same fused four-ring core structure,
have different biological roles as hormones and signaling molecules. The eighteen-carbon (C18) steroids include the
estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21
subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids.[26] The secosteroids,
comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure.[27] Other
examples of sterols are the bile acids and their conjugates,[28] which in mammals are oxidized derivatives of
cholesterol and are synthesized in the liver. The plant equivalents are the phytosterols, such as β-sitosterol,
stigmasterol, and brassicasterol; the latter compound is also used as a biomarker for algal growth.[29] The
predominant sterol in fungal cell membranes is ergosterol.[30]

Prenol lipids
Prenol lipids are synthesized from the 5 carbon precursors isopentenyl diphosphate and dimethylallyl diphosphate
that are produced mainly via the mevalonic acid (MVA) pathway.[31] The simple isoprenoids (linear alcohols,
diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to number of these
terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids are important
simple isoprenoids that function as antioxidants and as precursors of vitamin A.[32] Another biologically important
class of molecules is exemplified by the quinones and hydroquinones, which contain an isoprenoid tail attached to a
quinonoid core of non-isoprenoid origin.[33] Vitamin E and vitamin K, as well as the ubiquinones, are examples of
this class. Prokaryotes synthesize polyprenols (called bactoprenols) in which the terminal isoprenoid unit attached to
oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the terminal isoprenoid is reduced.[34]
Lipid 166

Saccharolipids
Saccharolipids describe compounds in
which fatty acids are linked directly to a
sugar backbone, forming structures that are
compatible with membrane bilayers. In the
saccharolipids, a monosaccharide substitutes
for the glycerol backbone present in
glycerolipids and glycerophospholipids. The
most familiar saccharolipids are the acylated
glucosamine precursors of the Lipid A
component of the lipopolysaccharides in
Gram-negative bacteria. Typical lipid A
molecules are disaccharides of glucosamine,
which are derivatized with as many as seven
fatty-acyl chains. The minimal
lipopolysaccharide required for growth in E.
coli is Kdo2-Lipid A, a hexa-acylated
[35]
disaccharide of glucosamine that is Structure of the saccharolipid Kdo2-Lipid A. Glucosamine residues in blue,
glycosylated with two Kdo residues in red, acyl chains in black and phosphate groups in green.

3-deoxy-D-manno-octulosonic acid (Kdo)

residues.[35]

Polyketides
Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as
iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise a
large number of secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources,
and have great structural diversity.[36] [37] Many polyketides are cyclic molecules whose backbones are often further
modified by glycosylation, methylation, hydroxylation, oxidation, and/or other processes. Many commonly used
anti-microbial, anti-parasitic, and anti-cancer agents are polyketides or polyketide derivatives, such as
erythromycins, tetracyclines, avermectins, and antitumor epothilones.[38]

Biological functions

Membranes
Eukaryotic cells are compartmentalized into membrane-bound organelles that carry out different biological
functions. The glycerophospholipids are the main structural component of biological membranes, such as the cellular
plasma membrane and the intracellular membranes of organelles; in animal cells the plasma membrane physically
separates the intracellular components from the extracellular environment. The glycerophospholipids are
amphipathic molecules (containing both hydrophobic and hydrophilic regions) that contain a glycerol core linked to
two fatty acid-derived "tails" by ester linkages and to one "head" group by a phosphate ester linkage. While
glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such
as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological
membranes.[39] In plants and algae, the galactosyldiacylglycerols,[40] and sulfoquinovosyldiacylglycerol,[14] which
lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the
most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.
Lipid 167

Bilayers have been found to exhibit high levels of birefringence, which can be used to probe the degree of order (or
disruption) within the bilayer using techniques such as dual polarization interferometry
A biological membrane is a form of lipid bilayer. The
formation of lipid bilayers is an energetically preferred
process when the glycerophospholipids described
above are in an aqueous environment.[41] In an aqueous
system, the polar heads of lipids align towards the
polar, aqueous environment, while the hydrophobic
tails minimize their contact with water and tend to
cluster together, forming a vesicle; depending on the
concentration of the lipid, this biophysical interaction
may result in the formation of micelles, liposomes, or
lipid bilayers. Other aggregations are also observed and
form part of the polymorphism of amphiphile (lipid)
behavior. Phase behavior is an area of study within
biophysics and is the subject of current academic
research.[42] [43] Micelles and bilayers form in the polar
medium by a process known as the hydrophobic
effect.[44] When dissolving a lipophilic or amphiphilic
substance in a polar environment, the polar molecules
(i.e., water in an aqueous solution) become more
ordered around the dissolved lipophilic substance, since Self-organization of phospholipids: a spherical liposome, a micelle,
and a lipid bilayer.
the polar molecules cannot form hydrogen bonds to the
lipophilic areas of the amphiphile. So in an aqueous
environment, the water molecules form an ordered "clathrate" cage around the dissolved lipophilic molecule.[45]

Energy storage
Triacylglycerols, stored in adipose tissue, are a major form of energy storage in animals. The adipocyte, or fat cell, is
designed for continuous synthesis and breakdown of triacylglycerols, with breakdown controlled mainly by the
activation of hormone-sensitive enzyme lipase.[46] The complete oxidation of fatty acids provides high caloric
content, about 9 kcal/g, compared with 4 kcal/g for the breakdown of carbohydrates and proteins. Migratory birds
that must fly long distances without eating use stored energy of triacylglycerols to fuel their flights.[47]

Signaling
In recent years, evidence has emerged showing that lipid signaling is a vital part of the cell signaling.[48] Lipid
signaling may occur via activation of G protein-coupled or nuclear receptors, and members of several different lipid
categories have been identified as signaling molecules and cellular messengers.[49] These include
sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in
regulating calcium mobilization,[50] cell growth, and apoptosis;[51] diacylglycerol (DAG) and the
phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C;[52] the
prostaglandins, which are one type of fatty-acid derived eicosanoid involved in inflammation and immunity;[53] the
steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as
reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are liver X
receptor agonists.[54]
Lipid 168

Other functions
The "fat-soluble" vitamins (A, D, E and K) – which are isoprene-based lipids – are essential nutrients stored in the
liver and fatty tissues, with a diverse range of functions. Acyl-carnitines are involved in the transport and metabolism
of fatty acids in and out of mitochondria, where they undergo beta oxidation.[55] Polyprenols and their
phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides across
membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic
glycosylation reactions, in extracellular polysaccharide biosynthesis (for instance, peptidoglycan polymerization in
bacteria), and in eukaryotic protein N-glycosylation.[56] [57] Cardiolipins are a subclass of glycerophospholipids
containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial
membrane.[58] [59] [60] They are believed to activate enzymes involved with oxidative phosphorylation.[61] Lipids
also form the basis of steroid hormones. [62]

Metabolism
The major dietary lipids for humans and other animals are animal and plant triglycerides, sterols, and membrane
phospholipids. The process of lipid metabolism synthesizes and degrades the lipid stores and produces the structural
and functional lipids characteristic of individual tissues.

Biosynthesis
In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to
triacylglycerol. This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the
production of triacylglycerol, a process called lipogenesis.[63] Fatty acids are made by fatty acid synthases that
polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions
that add the acetyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an
alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty
acid synthase reactions are carried out by a single multifunctional protein,[64] while in plant plastids and bacteria
separate enzymes perform each step in the pathway.[65] [66] The fatty acids may be subsequently converted to
triacylglycerols that are packaged in lipoproteins and secreted from the liver.
The synthesis of unsaturated fatty acids involves a desaturation reaction, whereby a double bond is introduced into
the fatty acyl chain. For example, in humans, the desaturation of stearic acid by stearoyl-CoA desaturase-1 produces
oleic acid. The doubly unsaturated fatty acid linoleic acid as well as the triply unsaturated α-linolenic acid cannot be
synthesized in mammalian tissues, and are therefore essential fatty acids and must be obtained from the diet.[67]
Triacylglycerol synthesis takes place in the endoplasmic reticulum by metabolic pathways in which acyl groups in
fatty acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.[68]
Terpenes and isoprenoids, including the carotenoids, are made by the assembly and modification of isoprene units
donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[69] These
precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these
compounds from acetyl-CoA,[70] while in plants and bacteria the non-mevalonate pathway uses pyruvate and
glyceraldehyde 3-phosphate as substrates.[69] [71] One important reaction that uses these activated isoprene donors is
steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed
into a set of rings to make lanosterol.[72] Lanosterol can then be converted into other steroids such as cholesterol and
ergosterol.[72] [73]
Lipid 169

Degradation
Beta oxidation is the metabolic process by which fatty acids are broken down in the mitochondria and/or in
peroxisomes to generate acetyl-CoA. For the most part, fatty acids are oxidized by a mechanism that is similar to,
but not identical with, a reversal of the process of fatty acid synthesis. That is, two-carbon fragments are removed
sequentially from the carboxyl end of the acid after steps of dehydrogenation, hydration, and oxidation to form a
beta-keto acid, which is split by thiolysis. The acetyl-CoA is then ultimately converted into ATP, CO2, and H2O
using the citric acid cycle and the electron transport chain.
Hence the Krebs Cycle can start at acetyl-CoA when fat is being broken down for energy if there is little or no
glucose available.
The energy yield of the complete oxidation of the fatty acid palmitate is 106 ATP.[74] Unsaturated and odd-chain
fatty acids require additional enzymatic steps for degradation.

Nutrition and health

Most of the lipid found in food is in the form of triacylglycerols, cholesterol, and phospholipids. A minimum amount
of dietary fat is necessary to facilitate absorption of fat-soluble vitamins (A, D, E, and K) and carotenoids.[75]
Humans and other mammals have a dietary requirement for certain essential fatty acids, such as linoleic acid (an
omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple
precursors in the diet.[67] Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number
and position of the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils).
Alpha-linolenic acid is found in the green leaves of plants, and in selected seeds, nuts, and legumes (in particular
flax, rapeseed, walnut, and soy).[76] Fish oils are particularly rich in the longer-chain omega-3 fatty acids
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).[77] A large number of studies have shown positive
health benefits associated with consumption of omega-3 fatty acids on infant development, cancer, cardiovascular
diseases, and various mental illnesses, such as depression, attention-deficit hyperactivity disorder, and dementia.[78]
[79]
In contrast, it is now well-established that consumption of trans fats, such as those present in partially
hydrogenated vegetable oils, are a risk factor for cardiovascular disease.[80] [81] [82]
A few studies have suggested that total dietary fat intake is linked to an increased risk of obesity[83] [84] and
diabetes.[85] [86] However, a number of very large studies, including the Women's Health Initiative Dietary
Modification Trial, an eight year study of 49,000 women, the Nurses' Health Study and the Health Professionals
Follow-up Study, revealed no such links.[87] [88] [89] None of these studies suggested any connection between
percentage of calories from fat and risk of cancer, heart disease, or weight gain. The Nutrition Source, a website
maintained by the Department of Nutrition at the Harvard School of Public Health, summarizes the current evidence
on the impact of dietary fat: "Detailed research—much of it done at Harvard—shows that the total amount of fat in
the diet isn't really linked with weight or disease."[90]
Lipid 170

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[76] Russo GL (2009). "Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention"
(http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0006-2952(08)00777-6). Biochemical Pharmacology 77 (6): 937–46.
doi:10.1016/j.bcp.2008.10.020. PMID 19022225. .
[77] Bhagavan, p. 388.
[78] Riediger ND, Othman RA, Suh M, Moghadasian MH (2009). "A systemic review of the roles of n-3 fatty acids in health and disease".
Journal of the American Dietetic Association 109 (4): 668–79. doi:10.1016/j.jada.2008.12.022. PMID 19328262.
[79] Galli C, Risé P (2009). "Fish consumption, omega 3 fatty acids and cardiovascular disease. The science and the clinical trials". Nutrition and
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[80] Micha R, Mozaffarian D (2008). "Trans fatty acids: effects on cardiometabolic health and implications for policy". Prostaglandins,
Leukotrienes, and Essential Fatty Acids 79 (3–5): 147–52. doi:10.1016/j.plefa.2008.09.008. PMC 2639783. PMID 18996687.
[81] Dalainas I, Ioannou HP (2008). "The role of trans fatty acids in atherosclerosis, cardiovascular disease and infant development".
International Angiology: a Journal of the International Union of Angiology 27 (2): 146–56. PMID 18427401.
[82] Mozaffarian D, Willett WC (2007). "Trans fatty acids and cardiovascular risk: a unique cardiometabolic imprint?". Current Atherosclerosis
Reports 9 (6): 486–93. doi:10.1007/s11883-007-0065-9. PMID 18377789.
[83] Astrup A, Dyerberg J, Selleck M, Stender S (2008). "Nutrition transition and its relationship to the development of obesity and related
chronic diseases". Obesity Review 9 Suppl 1: 48–52. doi:10.1111/j.1467-789X.2007.00438.x. PMID 18307699.
[84] Astrup A (2005). "The role of dietary fat in obesity". Seminars in Vascular Medicine 5 (1): 40–47. doi:10.1055/s-2005-871740.
PMID 15968579.
[85] Ma Y. et al (2006). "Low-carbohydrate and high-fat intake among adult patients with poorly controlled type 2 diabetes mellitus". Nutrition
22 (11-12): 1129–1136. doi:10.1016/j.nut.2006.08.006. PMC 2039705. PMID 17027229.
[86] Astrup A (2008). "Dietary management of obesity". JPEN Journal of Parenteral and Enteral Nutrition 32 (5): 575–77.
doi:10.1177/0148607108321707. PMID 18753397.
[87] Beresford SA, Johnson KC, Ritenbaugh C, et al. (2006). "Low-fat dietary pattern and risk of colorectal cancer: the Women's Health
Initiative Randomized Controlled Dietary Modification Trial". JAMA: the Journal of the American Medical Association 295 (6): 643–54.
doi:10.1001/jama.295.6.643. PMID 16467233.
[88] Howard BV, Manson JE, Stefanick ML, et al. (2006). "Low-fat dietary pattern and weight change over 7 years: the Women's Health
Initiative Dietary Modification Trial" (http:/ / jama. ama-assn. org/ cgi/ pmidlookup?view=long& pmid=16391215). JAMA: the Journal of the
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Lipid 173

Bibliography
• Bhagavan NV (2002). Medical Biochemistry (http://books.google.com/?id=vT9YttFTPi0C&
printsec=frontcover). San Diego: Harcourt/Academic Press. ISBN 0-12-095440-0.
• Devlin TM (1997). Textbook of Biochemistry: With Clinical Correlations (4th ed.). Chichester: John Wiley &
Sons. ISBN 0-471-17053-4.
• Stryer L, Berg JM, Tymoczko JL (2007). Biochemistry (6th ed.). San Francisco: W.H. Freeman.
ISBN 0-7167-8724-5.
• Van Holde KE, Mathews CK (1996). Biochemistry (2nd ed.). Menlo Park, Calif: Benjamin/Cummings Pub. Co.
ISBN 0-8053-3931-0.

External links
Introductory
• List of lipid-related web sites (http://www.cyberlipid.org/cyberlip/link0041.htm)
• Nature Lipidomics Gateway (http://www.lipidmaps.org/) - Round-up and summaries of recent lipid research
• Lipid Library (http://www.lipidlibrary.co.uk/) - General reference on lipid chemistry and biochemistry
• Cyberlipid.org (http://www.cyberlipid.org/) - Resources and history for lipids.
• Molecular Computer Simulations (http://www.fos.su.se/~sasha/Lipid_membranes.html) - Modeling of Lipid
Membranes
• Lipids, Membranes and Vesicle Trafficking (http://www.biochemweb.org/lipids_membranes.shtml) - The
Virtual Library of Biochemistry and Cell Biology
Nomenclature
• IUPAC nomenclature of lipids (http://www.chem.qmul.ac.uk/iupac/lipid/)
• IUPAC glossary entry for the lipid class of molecules (http://www.chem.qmul.ac.uk/iupac/class/lipid.html)
Databases
• LIPID MAPS (http://www.lipidmaps.org/data/databases.html) - Comprehensive lipid and lipid-associated
gene/protein databases.
• LipidBank (http://lipidbank.jp/) - Japanese database of lipids and related properties, spectral data and
references.
• LIPIDAT (http://www.lipidat.tcd.ie/) - Database composed mainly of phospholipids and associated
thermodynamic data.
General
• ApolloLipids (http://www.apollolipids.org/) - Provides dyslipidemia and cardiovascular disease prevention and
treatment information as well as continuing medical education programs
• National Lipid Association (http://www.lipid.org/) - Professional medical education organization for health
care professionals who seek to prevent morbidity and mortality stemming from dyslipidemias and other
cholesterol-related disorders.
Biological membrane 174

Biological membrane
A biological membrane or biomembrane is an enclosing or
separating membrane that acts as a selective barrier, within or
around a cell. It consists of a lipid bilayer with embedded proteins
that may constitute close to 50% of membrane content.[1] The
cellular membranes should not be confused with isolating tissues
formed by layers of cells, such as mucous and basement
membranes.

Function
Membranes in cells typically define enclosed spaces or
compartments in which cells may maintain a chemical or
biochemical environment that differs from the outside. For
example, the membrane around peroxisomes shields the rest of the
cell from peroxides, and the cell membrane separates a cell from
its surrounding medium. Most organelles are defined by such Cross section view of the structures that can be formed
membranes, and are called "membrane-bound" organelles. by phospholipids in aqueous solutions

Probably the most important feature of a biomembrane is that it is

a selectively permeable structure. This means that the size, charge, and other chemical properties of the atoms and
molecules attempting to cross it will determine whether they succeed in doing so. Selective permeability is essential
for effective separation of a cell or organelle from its surroundings. Biological membranes also have certain
mechanical or elastic properties.
Particles that are required for cellular function but are unable to diffuse freely across a membrane enter through a
membrane transport protein or are taken in by means of endocytosis.

Diversity of biological membranes

Many types of specialized plasma membranes can separate cell from external environment: apical, basolateral,
presynaptic and postsynaptic ones, membranes of flagella, cilia, microvillus, filopodia and lamellipodia, the
sarcolemma of muscle cells, as well as specialized myelin and dendritic spine membranes of neurons. Plasma
membranes can also form different types of "supramembrane" structures such as caveola, postsynaptic density,
podosome, invadopodium, desmosome, hemidesmosome, focal adhesion, and cell junctions. These types of
membranes differ in lipid and protein composition.
Distinct types of membranes also create intracellular organelles: endosome; smooth and rough endoplasmic
reticulum; sarcoplasmic reticulum; Golgi apparatus; lysosome; mitochondrion (inner and outer membranes); nucleus
(inner and outer membranes); peroxisome; vacuole; cytoplasmic granules; cell vesicles (phagosome, autophagosome,
clathrin-coated vesicles, COPI-coated and COPII-coated vesicles) and secretory vesicles (including synaptosome,
acrosomes, melanosomes, and chromaffin granules).
Different types of biological membranes have diverse lipid and protein compositions. The content of membranes
defines their physical and biological properties. Some components of membranes play a key role in medicine, such
as the efflux pumps that pump drugs out of a cell.
Biological membrane 175

References
[1] Mark L. Latash (2007). Neurophysiological basis of movement. Human Kinetics Publishers. ISBN 978-0-7360-6367-8.

• von Heijne G, Rees D (August 2008). "Membranes: reading between the lines" (http://linkinghub.elsevier.com/
retrieve/pii/S0959-440X(08)00091-2). Curr. Opin. Struct. Biol. 18 (4): 403–5. doi:10.1016/j.sbi.2008.06.003.
PMID 18634876.

External links
• MeSH Membranes (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Membranes)

Membrane protein
A membrane protein is a protein molecule that
is attached to, or associated with the membrane of
a cell or an organelle. More than half of all
proteins interact with membranes.

Function
Biological membranes consist of a phospholipid
bilayer and a variety of proteins that accomplish
vital biological functions.
• Structural proteins are attached to
microfilaments in the cytoskeleton which
ensures stability of the cell.
• Cell adhesion molecules allow cells to identify
each other and interact. Such proteins are
involved in immune response, for example.
• Membrane enzymes produce a variety of
substances essential for cell function.
• Membrane receptor proteins serve as
connection between the cell's internal and
external environments.
• Transport proteins play an important role in
the maintenance of concentrations of ions. Crystal structure of Potassium channel KvAP. Calculated hydrocarbon
These transport proteins come in two forms: boundaries of the lipid bilayer are indicated by red and blue dots.

carrier proteins and channel proteins.

• [ [membrane cells]] are the is a biological membrane that separates the interior of all cells from the outside
environment
Membrane protein 176

Main categories
Membrane proteins can be divided into several categories:[1]
• Integral membrane proteins which are permanently bound to the lipid bilayer
• Peripheral membrane proteins that are temporarily associated with lipid bilayer or with integral membrane
proteins
• Lipid-anchored proteins bound to lipid bilayer bound through lipidated amino acid residues
In addition, pore-forming toxins and many antibacterial peptides are water-soluble molecules, but undergo a
conformational transition upon association with lipid bilayer and become reversibly or irreversibly
membrane-associated.
A slightly different classification is to divide all membrane proteins to integral and amphitropic.[2] The amphitropic
are proteins that can exist in two alternative states: a water-soluble and a lipid bilayer-bound. The amphitropic
protein category includes water-soluble channel-forming polypeptide toxins, which associate irreversibly with
membranes, but excludes peripheral proteins that interact with other membrane proteins rather than with lipid
bilayer.

Integral membrane proteins

Integral membrane proteins are permanently attached to the membrane. They can be defined as those proteins which
require a detergent (such as SDS or Triton X-100) or some other apolar solvent to be displaced. They can be
classified according to their relationship with the bilayer:
• Integral polytopic proteins, also known as "transmembrane proteins," are proteins that are permanently attached to
the lipid membrane and span across the membrane (at least once). The transmembrane regions of the proteins are
either beta-barrels or alpha-helical. The alpha-helical domains are present in all types of biological membranes
including outer membranes. The beta-barrels were found only in outer membranes of Gram-negative bacteria,
lipid-rich cell walls of a few Gram-positive bacteria, and outer membranes of mitochondria and chloroplasts.
• Integral monotopic proteins are proteins that are permanently attached to the lipid membrane from only one side
and do not span across the membrane.

Peripheral membrane proteins

Peripheral membrane proteins are also known as extrinsic proteins, they do not interact with the hydrophobic core of
the lipid bilayer. Some peripheral membrane proteins are located at the outer part of the plasma membrane
(exoplasmic). They interact with the membrane indirectly by binding to the integral membrane proteins.
[3]

Peripheral membrane proteins are temporarily attached either to the lipid bilayer or to integral proteins by a
combination of hydrophobic, electrostatic, and other non-covalent interactions. Peripheral proteins dissociate
following treatment with a polar reagent, such as a solution with an elevated pH or high salt concentrations.
Integral and peripheral proteins may be post-translationally modified, with added fatty acid or prenyl chains, or GPI
(glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.
Membrane protein 177

Polypeptide toxins
Polypeptide toxins, such as colicins or hemolysins, and certain proteins involved in apoptosis, are sometimes
considered a separate category. These proteins are water-soluble but can aggregate and associate irreversibly with the
lipid bilayer and form alpha-helical or beta-barrel transmembrane channels.

Intracellular localization
Proteins are specifically targeted to many different types of biological membranes [4]

Membrane protein complexes

Membrane proteins commonly function as complexes. These complexes are vital to cellular function. Understanding
how these complexes are assembled, degraded, and their composition are crucial to understanding their function and
regulation. Reoccurring in recent literature are the ideas that: membrane protein complexes assemble in an orderly
fashion, chaperones aid assembly by preventing unfavorable interactions, and membrane proteins can be
interchanged in existing complexes. Membrane protein complexes assemble through the orderly assembly of
intermediates. For example, the simple membrane-embedded four subunit complex, cytochrome bo3 of Escherichia
coli, is assembled via two intermediate complexes. This suggests a linearly organized assembly pathway. Although
interactions between other subunits could lead to the formation of many intermediates, they do not occur. Ordered
assembly could be the cell's protection against harmful intermediates. Chaperones interact with membrane proteins
guiding their assembly. They aid in preventing the assembly of dead-end and toxic intermediates, as well as
unwanted aggregations. Via chaperones assembly can occur through inactive intermediates potentially preventing
damaging interactions they could cause. Membrane protein complexes are not fixed entities. Though a process called
dynamic exchange, membrane proteins are exchanged in and out of exsitisting protein complexes. This has its
implications as a repair mechanism and in regulation. [5]

Assembly of membrane protein

There are two different ways a membrane protein could undergoes during construction are Constitutive membrane
protein and non-constitutive membrane protein.

Constitutive membrane protein

The messengerRNA attaches to the translocon which is located to the cell membrane. The mRNA is translated into
the translocon transmembrane tunnel. After the synthesis of protein the mRNA is released which closes the
translocon and the protein is released in the bilayer membrane. When the protein is left in the membrane bilayer
more protein folding occurs creating its final 3D structure (White).

Non-constitutive membrane protein

Examples of non-constitutive membrane proteins are toxins and antimicrobialpeptides. These membrane proteins
inserts into specific target membranes by physicochemical processes. It inserts usually before, during, or after
oligomerization into the target membrane (White).[6]

Membrane protein structures

In membrane proteins the two known structural classes of membrane proteins are alpha-helical bundle and
beta-barrel porin. The portion of the membrane proteins that are attached to the lipid bilayer are consisting of
hydophobic amino acids only. This is done so that the peptide bonds' carbonyl and amine will react with each other
instead of the hydrophobic surrounding. The portion of the protein that is not touching the lipid bilayer and is
Membrane protein 178

protruding out of the cell membrane are usually hydrophilic amino acids.[7]
The structures of membrane proteins are stabilized by weak interactions and influenced by additional interactions
with the solubilizing environment. The influence of the environment on membrane protein structures is especially
significant. Despite the significant functional importance of membrane proteins, the structural biology has been
particularly challenging as shown by the low number of membrane protein structures determined. Integral membrane
proteins are present in a heterogeneous environment that poses major obstacles for existing structural methodologies.
Many of the successful membrane protein structures are characterized by X-ray crystallography and are very large
structures in which the interactions with the membrane mimetic environments can be anticipated to be small in
comparison to those within the protein structures. The small domains are particularly sensitive to the influence of
membrane mimetic environments, potentially leading to non-native structures. Fortunately, there are many sample
preparation conditions that can be chosen for crystallization and for solution NMR. All membrane protein structural
biology should be subjected to careful scrutiny; through a combination of structural methodologies it should be
possible to achieve an understanding of the native functional state for membrane protein structures.[8]

References
White, Stephen. “General Principle of Membrane Protein Folding and Stability.” Stephen White Laboratory
Homepage. 10 Nov. 2009. web.
[1] Gerald Karp (2009). Cell and Molecular Biology: Concepts and Experiments (http:/ / books. google. com/ books?id=arRGYE0GxRQC&
pg=PA128). John Wiley and Sons. pp. 128–. ISBN 9780470483374. . Retrieved 13 November 2010.
[2] Johnson JE, Cornell RB (1999). "Amphitropic proteins: regulation by reversible membrane interactions (review)". Mol. Membr. Biol. 16 (3):
217–235. doi:10.1080/096876899294544. PMID 10503244.
[3] Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.
[4] Classification of membrane proteins with known 3D structure to different membrane types (http:/ / opm. phar. umich. edu/ atlas. php)
[5] Daley, Daniel. 2008,"The Assembly of Membrane Proteins into Complexes", Current Opinion in Structural Biology, 18:420-424.
[6] White, Stephen. “General Principle of Membrane Protein Folding and Stability.” Stephen White Laboratory Homepage. 10 Nov. 2009. web.
[7] White, Stephen. “General Principle of Membrane Protein Folding and Stability.” Stephen White Laboratory Homepage. 10 Nov. 2009. web.
[8] Cross, Timothy, Mukesh Sharma, Myunggi Yi, Huan-Xiang Zhou (2010). "Influence of Solubilizing Environments on Membrane Protein
Structures"

External links
• TCDB (http://www.tcdb.org/) - Transporter Classification database
• Orientations of Proteins in Membranes (OPM) database (http://opm.phar.umich.edu/) 3D structures of integral
and peripheral membrane proteins arranged in the lipid bilayer
• The Protein Data Bank of Transmembrane Proteins (http://pdbtm.enzim.hu/) 3D models of all transmembrane
proteins currently in PDB. Approximate positions of membrane boundary planes were calculated for each PDB
entry.
• List of transmembrane proteins of known 3D structure (http://blanco.biomol.uci.edu/
Membrane_Proteins_xtal.html)
• TransportDB (http://www.membranetransport.org/) Genomics-oriented database of transporters from TIGR
• Membrane PDB (http://www.mpdb.tcd.ie/) Database of 3D structures of integral membrane proteins and
hydrophobic peptides with an emphasis on crystallization conditions
• Membrane targeting domains (MeTaDoR) (http://proteomics.bioengr.uic.edu/metador/MeTaDoR.html)
• Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php)
• MeSH Membrane+proteins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Membrane+
proteins)
• The Human Membrane Proteome (http://www.biomedcentral.com/1741-7007/7/50) - A comprehensive
article covering the transmembrane protein component of the human proteome
Cell membrane 179

Cell membrane
The cell membrane or plasma
membrane is a biological membrane that
separates the interior of all cells from the
outside environment.[1] The cell
membrane is selectively permeable to
ions and organic molecules and controls
the movement of substances in and out of
cells.[2] It basically protects the cell from
outside forces. It consists of the lipid
bilayer with embedded proteins. Cell
membranes are involved in a variety of
cellular processes such as cell adhesion,
ion conductivity and cell signaling and
serve as the attachment surface for
several extracellular structures, including
the cell wall, glycocalyx, and
intracellular cytoskeleton.

Function
The cell membrane surrounds the
cytoplasm of a cell and, in animal cells,
physically separates the intracellular Illustration of a Eukaryotic cell membrane
components from the extracellular
environment. Fungi, bacteria and plants also have the cell wall which provides a mechanical support for the cell and
precludes the passage of larger molecules. The cell membrane also plays a role in anchoring the cytoskeleton to
provide shape to the cell, and in attaching to the extracellular matrix and other cells to help group cells together to
form tissues.

The membrane is differentially permeable and able to regulate what enters and exits the cell, thus facilitating the
transport of materials needed for survival. The movement of substances across the membrane can be either passive,
occurring without the input of cellular energy, or active, requiring the cell to expend energy in transporting it. The
membrane also maintains the cell potential. The cell membrane thus works as a selective filter that allows only
certain things to come inside or go outside the cell. To do so, the membrane employs a number of transport
mechanisms:
1. Diffusion : Some substances (small molecules, ions) such as carbon dioxide (CO2), oxygen (O2), and water, can
move across the plasma membrane by diffusion, which is a passive transport process.
2. Osmosis : Because the membrane acts as a barrier for certain molecules and ions, they can occur in different
concentrations on the two sides of the membrane. Such a concentration difference across a semipermeable membrane
can set up a osmotic flow for the solvent, in this case water. Water can thus be transported across the membrane by
osmosis.
3. Mediated Transport : Nutrients such as sugars and materials of growth such as amino acid must enter the cell, and
the waste of metabolism must leave. Such molecules are moved across the membrane by special proteins called
transport proteins or permeases. Permeases form a small passageway through the membrane, enabling the solute
Cell membrane 180

molecule to cross the phospholipid bilayer. Permeases are usually quite specific, recognizing and transporting only a
limited group of chemical substances, often even only a single substance.
4. Endocytosis : Endocytosis is the process in which cells absorb molecules by engulfing them. The plasma
membrane creates a small deformation inward, called an invagination, in which the substance to be transported is
captured. The deformation then pinches off from the membrane on the inside of the cell, creating a vesicle
containing the captured substance. Endocytosis is a pathway for internalizing solid particles (cell eating or
phagocytosis), small molecules and ions (cell drinking or pinocytosis), and macromolecules. Endocytosis requires
energy and is thus a form of active transport.
5. Exocytosis : Just as material can be brought into the cell by invagination and formation of a vesicle, the membrane
of a vesicle can be fused with the plasma membrane, extruding its contents to the surrounding medium. This is the
process of exocytosis. Exocytosis occurs in various cells to remove undigested residues of substances brought in by
endocytosis, to secrete substances such as hormones and enzymes, and to transport a substance completely across a
cellular barrier. In the process of exocytosis, the undigested waste-containing food vacuole or the secretory vesicle
budded from Golgi apparatus, is first moved by cytoskeleton from the interior of the cell to the surface. The vesicle
membrane comes in contact with the plasma membrane. The lipid molecules of the two bilayers rearrange
themselves and the two membranes are, thus, fused. A passage is formed in the fused membrane and the vesicles
discharges its contents outside the cell.

Prokaryotes
Gram-negative bacteria have a plasma membrane and an outer membrane separated by a periplasmic space. Other
prokaryotic species have only a plasma membrane. Prokaryotic cells are also surrounded by a cell wall composed of
peptidoglycan (amino acid and sugar). Some eukaryotic cells also have cells walls, but none that are made of
peptidoglycan.

Structure

Fluid mosaic model

According to the fluid mosaic model of S.J. Singer and G.L. Nicolson (1972), biological membranes can be
considered as a two-dimensional liquid in which all lipid and protein molecules diffuse more or less easily.[3]
Although the lipid bilayers that form the basis of the membranes do indeed form two-dimensional liquids by
themselves, the plasma membrane also contains a large quantity of proteins, which provide more structure. Examples
of such structures are protein-protein complexes, pickets and fences formed by the actin-based cytoskeleton, and
potentially lipid rafts.
Cell membrane 181

Lipid bilayer
Lipid bilayers go through a self assembly process in the formation
of membranes. The cell membrane consists primarily of a thin
layer of amphipathic phospholipids which spontaneously arrange
so that the hydrophobic "tail" regions are shielded from the
surrounding polar fluid, causing the more hydrophilic "head"
regions to associate with the cytosolic and extracellular faces of
the resulting bilayer. This forms a continuous, spherical lipid
bilayer. Forces such as Van der Waal, electrostatic, hyrdogen Diagram of the arrangement of amphipathic lipid
bonds, and noncovalent interactions, are all forces that contribute molecules to form a lipid bilayer. The yellow polar
head groups separate the grey hydrophobic tails from
to the formation of the lipid bilayer. Overall, hydrophobic
the aqueous cytosolic and extracellular environments.
interactions are the major driving force in the formation of lipid
bilayers.

Lipid bilayers have very low permeability for ions and most polar molecules.The arrangement of hydrophilic heads
and hydrophobic tails of the lipid bilayer prevent polar solutes (e.g. amino acids, nucleic acids, carbohydrates,
proteins, and ions) from diffusing across the membrane, but generally allows for the passive diffusion of
hydrophobic molecules. This affords the cell the ability to control the movement of these substances via
transmembrane protein complexes such as pores and gates.
Flippases and scramblases concentrate phosphatidyl serine, which carries a negative charge, on the inner membrane.
Along with NANA, this creates an extra barrier to charged moieties moving through the membrane.
Membranes serve diverse functions in eukaryotic and prokaryotic cells. One important role is to regulate the
movement of materials into and out of cells. The phospholipid bilayer structure (fluid mosaic model) with specific
membrane proteins accounts for the selective permeability of the membrane and passive and active transport
mechanisms. In addition, membranes in prokaryotes and in the mitochondria and chloroplasts of eukaryotes facilitate
the synthesis of ATP through chemiosmosis.

Membrane polarity
The apical membrane of a polarized cell is
the surface of the plasma membrane that
faces the lumen. This is particularly evident
in epithelial and endothelial cells, but also
describes other polarized cells, such as
neurons.

The basolateral membrane of a polarized

cell is the surface of the plasma membrane
that forms its basal and lateral surfaces. It
faces towards the interstitium, and away
from the lumen.
"Basolateral membrane" is a compound
phrase referring to the terms basal (base)
membrane and lateral (side) membrane, Alpha intercalated cell
which, especially in epithelial cells, are
identical in composition and activity. Proteins (such as ion channels and pumps) are free to move from the basal to
the lateral surface of the cell or vice versa in accordance with the fluid mosaic model.
Cell membrane 182

Tight junctions that join epithelial cells near their apical surface prevent the migration of proteins from the
basolateral membrane to the apical membrane. The basal and lateral surfaces thus remain roughly equivalent to one
another, yet distinct from the apical surface.

Integral membrane proteins

The cell membrane contains many integral membrane proteins, which pepper the entire surface. These structures,
which can be visualized by electron microscopy or fluorescence microscopy, can be found on the inside of the
membrane, the outside, or may span the entire membrane. These may include integrins, cadherins, desmosomes,
clathrin-coated pits, caveolaes, and different structures involved in cell adhesion. Integral proteins are the most
abundant type of protein to span the lipid bilayer. They interact widely with hydrocarbon chains of membrane lipids
and can be released by agents that compete for the same nonpolar interactions.

Peripheral membrane proteins

Peripheral proteins are proteins that are bounded to the membrane by electrostatic interactions and hydrogen bonding
with the hydrophilic phospholipid heads. Many of these proteins can be found bounded to the surfaces of integral
proteins on either the cytoplasimic side of the cell or the extracellular side of the membrane. Some are anchored to
the bilayer through covalent bond with a fatty acid.

Membrane skeleton
The cytoskeleton is found underlying the cell membrane in the cytoplasm and provides a scaffolding for membrane
proteins to anchor to, as well as forming organelles that extend from the cell. Indeed, cytoskeletal elements interact
extensively and intimately with the cell membrane.[4] Anchoring proteins restricts them to a particular cell surface —
for example, the apical surface of epithelial cells that line the vertebrate gut — and limits how far they may diffuse
within the bilayer. The cytoskeleton is able to form appendage-like organelles, such as cilia, which are
microtubule-based extensions covered by the cell membrane, and filopodia, which are actin-based extensions. These
extensions are ensheathed in membrane and project from the surface of the cell in order to sense the external
environment and/or make contact with the substrate or other cells. The apical surfaces of epithelial cells are dense
with actin-based finger-like projections known as microvilli, which increase cell surface area and thereby increase
the absorption rate of nutrients. Localized decoupling of the cytoskeleton and cell membrane results in formation of
a bleb.

Composition
Cell membranes contain a variety of biological molecules, notably lipids and proteins. Material is incorporated into
the membrane, or deleted from it, by a variety of mechanisms:
• Fusion of intracellular vesicles with the membrane (exocytosis) not only excretes the contents of the vesicle but
also incorporates the vesicle membrane's components into the cell membrane. The membrane may form blebs
around extracellular material that pinch off to become vesicles (endocytosis).
• If a membrane is continuous with a tubular structure made of membrane material, then material from the tube can
be drawn into the membrane continuously.
• Although the concentration of membrane components in the aqueous phase is low (stable membrane components
have low solubility in water), there is an exchange of molecules between the lipid and aqueous phases.
Cell membrane 183

Lipids
The cell membrane consists of three
classes of amphipathic lipids:
phospholipids, glycolipids, and
cholesterols. The amount of each depends
upon the type of cell, but in the majority
of cases phospholipids are the most
abundant.[5] In RBC studies, 30% of the
plasma membrane is lipid.

The fatty chains in phospholipids and

glycolipids usually contain an even
number of carbon atoms, typically
between 16 and 20. The 16- and
18-carbon fatty acids are the most
common. Fatty acids may be saturated or
unsaturated, with the configuration of the
double bonds nearly always cis. The
length and the degree of unsaturation of
fatty acid chains have a profound effect
on membrane fluidity[6] as unsaturated
lipids create a kink, preventing the fatty
Examples of the major membrane phospholipids and glycolipids: phosphatidylcholine
acids from packing together as tightly,
(PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns),
thus decreasing the melting temperature phosphatidylserine (PtdSer).
(increasing the fluidity) of the membrane.
The ability of some organisms to regulate the fluidity of their cell membranes by altering lipid composition is called
homeoviscous adaptation.

The entire membrane is held together via non-covalent interaction of hydrophobic tails, however the structure is
quite fluid and not fixed rigidly in place. Under physiological conditions phospholipid molecules in the cell
membrane are in the liquid crystalline state. It means the lipid molecules are free to diffuse and exhibit rapid lateral
diffusion along the layer in which they are present. However, the exchange of phospholipid molecules between
intracellular and extracellular leaflets of the bilayer is a very slow process. Lipid rafts and caveolae are examples of
cholesterol-enriched microdomains in the cell membrane.

In animal cells cholesterol is normally found dispersed in varying degrees throughout cell membranes, in the
irregular spaces between the hydrophobic tails of the membrane lipids, where it confers a stiffening and
strengthening effect on the membrane.[2]

Phospholipids forming lipid vesicles

Lipid vesicles or lisosomes are circular pockets that are enclosed by a lipid bilayer. These structures are used in
laboratories to study the effects of chemicals in cells by delivering these chemicals directly to the cell, as well as
getting more insight into cell membrane permeability. Lipid vesicles and liposomes are formed by first suspending a
lipid in an aqueous solution then agitating the mixture through sonication, resulting in a vesicle. By measuring the
rate of efflux from that of the inside of the vesicle to the ambient solution, allows researcher to better understand
membrane permeability. Vesicles can be formed with molecules and ions inside the vesicle by forming the vesicle
with the desired molecule or ion present in the solution. Proteins can also be embedded into the membrane through
solubilizing the desired proteins in the presence of detergents and attaching them to the phospholipids in which the
Cell membrane 184

liposome is formed. These provide researchers with a tool to examine various membrane protein functions.

Carbohydrates
Plasma membranes also contain carbohydrates, predominantly glycoproteins, but with some glycolipids
(cerebrosides and gangliosides). For the most part, no glycosylation occurs on membranes within the cell; rather
generally glycosylation occurs on the extracellular surface of the plasma membrane.
The glycocalyx is an important feature in all cells, especially epithelia with microvilli. Recent data suggest the
glycocalyx participates in cell adhesion, lymphocyte homing, and many others.
The penultimate sugar is galactose and the terminal sugar is sialic acid, as the sugar backbone is modified in the
golgi apparatus. Sialic acid carries a negative charge, providing an external barrier to charged particles.

Proteins
Proteins within the membrane are key to the functioning of the overall membrane. These proteins mainly transport
chemicals and information across the membrane. Every membrane has a varying degree of protein content. Proteins
can be in the form of peripheral or integral.

Type Description Examples

Integral proteins Span the membrane and have a hydrophilic cytosolic domain, which interacts with internal Ion channels, proton
or molecules, a hydrophobic membrane-spanning domain that anchors it within the cell pumps, G
transmembrane membrane, and a hydrophilic extracellular domain that interacts with external molecules. The protein-coupled
proteins hydrophobic domain consists of one, multiple, or a combination of α-helices and β sheet receptor
protein motifs.

Lipid anchored Covalently bound to single or multiple lipid molecules; hydrophobically insert into the cell G proteins
proteins membrane and anchor the protein. The protein itself is not in contact with the membrane.

Peripheral Attached to integral membrane proteins, or associated with peripheral regions of the lipid Some enzymes, some
proteins bilayer. These proteins tend to have only temporary interactions with biological membranes, hormones
and, once reacted the molecule, dissociates to carry on its work in the cytoplasm.

The cell membrane plays host to a large amount of protein that is responsible for its various activities. The amount of
protein differs between species and according to function, however the typical amount in a cell membrane is 50%.[6]
These proteins are undoubtedly important to a cell: Approximately a third of the genes in yeast code specifically for
them, and this number is even higher in multicellular organisms.[5]
The cell membrane, being exposed to the outside environment, is an important site of cell-cell communication. As
such, a large variety of protein receptors and identification proteins, such as antigens, are present on the surface of
the membrane. Functions of membrane proteins can also include cell-cell contact, surface recognition, cytoskeleton
contact, signaling, enzymatic activity, or transporting substances across the membrane.
Most membrane proteins must be inserted in some way into the membrane. For this to occur, an N-terminus "signal
sequence" of amino acids directs proteins to the endoplasmic reticulum, which inserts the proteins into a lipid
bilayer. Once inserted, the proteins are then transported to their final destination in vesicles, where the vesicle fuses
with the target membrane.
Cell membrane 185

Variation
The cell membrane has different lipid and protein compositions in distinct types of cells and may have therefore
specific names for certain cell types:
• Sarcolemma in myocytes
• Oolemma in oocytes
• Historically, the plasma membrane was also referred to as the plasmalemma.

Permeability
The permeability of a membrane is the ease with which molecules pass through it. These molecules are known as
permeant molecules. Permeability depends mainly on the electric charge of the molecule and to a lesser extent the
molar mass of the molecule. Due to the cell membrane's hydrophobic nature, electrically neutral and small molecules
pass through the membrane easier than charged, large ones.
The inability of charged molecules to pass through the cell membrane results in pH parturition of substances
throughout the fluid compartments of the body.

References
[1] Kimball's Biology Pages (http:/ / users. rcn. com/ jkimball. ma. ultranet/ BiologyPages/ C/ CellMembranes. html), Cell Membranes
[2] Alberts B, Johnson A, Lewis J, et al. (2002). Molecular Biology of the Cell (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mboc4.
section. 1864) (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1. .
[3] Singer SJ, Nicolson GL (Feb 1972). "The fluid mosaic model of the structure of cell membranes" (http:/ / www. sciencemag. org/ cgi/
content/ abstract/ 175/ 4023/ 720). Science 175 (4023): 720–31. doi:10.1126/science.175.4023.720. PMID 4333397. .
[4] Doherty GJ and McMahon HT (2008). "Mediation, Modulation and Consequences of Membrane-Cytoskeleton Interactions" (http:/ /
arjournals. annualreviews. org/ doi/ abs/ 10. 1146/ annurev. biophys. 37. 032807. 125912). Annual Review of Biophysics 37: 65–95.
doi:10.1146/annurev.biophys.37.032807.125912. PMID 18573073. .
[5] Lodish H, Berk A, Zipursky LS, et al. (2004). Molecular Cell Biology (4th ed.). New York: Scientific American Books. ISBN 0716731363.
[6] Jesse Gray, Shana Groeschler, Tony Le, Zara Gonzalez (2002). "Membrane Structure" (http:/ / www. bio. davidson. edu/ people/
macampbell/ 111/ memb-swf/ membranes. swf) (SWF). Davidson College. . Retrieved 2007-01-11.

External links
• Lipids, Membranes and Vesicle Trafficking - The Virtual Library of Biochemistry and Cell Biology (http://
www.biochemweb.org/lipids_membranes.shtml)
• Cell membrane protein extraction protocol (http://www.westernblotting.org/protocol membrane extraction.
htm)
• Membrane homeostasis, tension regulation, mechanosensitive membrane exchange and membrane traffic (http://
www.phys.unsw.edu.au/~jw/tension.html)
• 3D structures of proteins associated with plasma membrane of eukaryotic cells (http://opm.phar.umich.edu/
localization.php?localization=Eukaryotic plasma membrane)
• Lipid composition and proteins of some eukariotic membranes (http://opm.phar.umich.edu/atlas.
php?membrane=Eukaryotic plasma membrane)
• (http://www.etap.org/demo/biology1/instruction3tutor.html)
 186

Carbohydrate structure

Carbohydrate
A carbohydrate
(pronounced /kɑrbɵˈhaɪdreɪt/) is an organic
compound with the empirical formula
Cm(H2O)n (where m could be different
from n); that is, consists only of carbon,
hydrogen, and oxygen, with a
hydrogen:oxygen atom ratio of 2:1 (as in
water). However, there are exceptions to
this. One common example would be Lactose is a disaccharide found in milk. It consists of a molecule of D-galactose and a
deoxyribose, a component of DNA, which molecule of D-glucose bonded by beta-1-4 glycosidic linkage. It has a formula of
has the empirical formula C5H10O4. C12H22O11.

Carbohydrates can be viewed as hydrates

of carbon, hence their name. Structurally however, it is more accurate to view them as polyhydroxy aldehydes and
ketones.

The term is most common in biochemistry, where it is a synonym of saccharide. The carbohydrates (saccharides)
are divided into four chemical groupings: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. In
general, the monosaccharides and disaccharides, which are smaller (lower molecular weight) carbohydrates, are
commonly referred to as sugars.[1] The word saccharide comes from the Greek word σάκχαρον (sákkharon),
meaning "sugar". While the scientific nomenclature of carbohydrates is complex, the names of the monosaccharides
and disaccharides very often end in the suffix -ose. For example, blood sugar is the monosaccharide glucose, table
sugar is the disaccharide sucrose, and milk sugar is the disaccharide lactose (see illustration).

Carbohydrates perform numerous roles in living things. Polysaccharides serve for the storage of energy (e.g., starch
and glycogen), and as structural components (e.g., cellulose in plants and chitin in arthropods). The 5-carbon
monosaccharide ribose is an important component of coenzymes (e.g., ATP, FAD, and NAD) and the backbone of
the genetic molecule known as RNA. The related deoxyribose is a component of DNA. Saccharides and their
derivatives include many other important biomolecules that play key roles in the immune system, fertilization,
preventing pathogenesis, blood clotting, and development.[2]
In food science and in many informal contexts, the term carbohydrate often means any food that is particularly rich
in the complex carbohydrate starch (such as cereals, bread, and pasta) or simple carbohydrates, such as sugar (found
in candy, jams, and desserts).
Carbohydrate 187

Structure
Formerly the name "carbohydrate" was used in chemistry for any compound with the formula Cm (H2O) n. Following
this definition, some chemists considered formaldehyde (CH2O) to be the simplest carbohydrate, [3] while others
claimed that title for glycolaldehyde.[4] Today the term is generally understood in the biochemistry sense, which
excludes compounds with only one or two carbons.
Natural saccharides are generally built of simple carbohydrates called monosaccharides with general formula
(CH2O)n where n is three or more. A typical monosaccharide has the structure H-(CHOH)x(C=O)-(CHOH)y-H, that
is, an aldehyde or ketone with many hydroxyl groups added, usually one on each carbon atom that is not part of the
aldehyde or ketone functional group. Examples of monosaccharides are glucose, fructose, and glyceraldehydes.
However, some biological substances commonly called "monosaccharides" do not conform to this formula (e.g.,
uronic acids and deoxy-sugars such as fucose), and there are many chemicals that do conform to this formula but are
not considered to be monosaccharides (e.g., formaldehyde CH2O and inositol (CH2O)6).[5]
The open-chain form of a monosaccharide often coexists with a closed ring form where the aldehyde/ketone
carbonyl group carbon (C=O) and hydroxyl group (-OH) react forming a hemiacetal with a new C-O-C bridge.
Monosaccharides can be linked together into what are called polysaccharides (or oligosaccharides) in a large variety
of ways. Many carbohydrates contain one or more modified monosaccharide units that have had one or more groups
replaced or removed. For example, deoxyribose, a component of DNA, is a modified version of ribose; chitin is
composed of repeating units of N-acetyl glucosamine, a nitrogen-containing form of glucose.

Monosaccharides
Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed
to smaller carbohydrates. They are aldehydes or ketones with two or more
hydroxyl groups. The general chemical formula of an unmodified monosaccharide
is (C•H2O) n, literally a "carbon hydrate." Monosaccharides are important fuel
molecules as well as building blocks for nucleic acids. The smallest
monosaccharides, for which n = 3, are dihydroxyacetone and D- and
L-glyceraldehydes.

Classification of monosaccharides

D-glucose is an aldohexose with the

formula (C·H2O)6. The red atoms
The α and β anomers of glucose. Note the position of the hydroxyl group (red or highlight the aldehyde group, and
green) on the anomeric carbon relative to the CH2OH group bound to carbon 5: the blue atoms highlight the
they are either on the opposite sides (α), or the same side (β). asymmetric center furthest from the
aldehyde; because this -OH is on
Monosaccharides are classified according to three different characteristics: the the right of the Fischer projection,
placement of its carbonyl group, the number of carbon atoms it contains, and its this is a D sugar.
chiral handedness. If the carbonyl group is an aldehyde, the monosaccharide is an
aldose; if the carbonyl group is a ketone, the monosaccharide is a ketose. Monosaccharides with three carbon atoms
are called trioses, those with four are called tetroses, five are called pentoses, six are hexoses, and so on.[6] These two
systems of classification are often combined. For example, glucose is an aldohexose (a six-carbon aldehyde), ribose
is an aldopentose (a five-carbon aldehyde), and fructose is a ketohexose (a six-carbon ketone).
Carbohydrate 188

Each carbon atom bearing a hydroxyl group (-OH), with the exception of the first and last carbons, are asymmetric,
making them stereo centers with two possible configurations each (R or S). Because of this asymmetry, a number of
isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula
(C·H2O) 6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of 24 = 16 possible
stereoisomers. In the case of glyceraldehydes, an aldotriose, there is one pair of possible stereoisomers, which are
enantiomers and epimers. 1, 3-dihydroxyacetone, the ketose corresponding to the aldose glyceraldehydes, is a
symmetric molecule with no stereo centers). The assignment of D or L is made according to the orientation of the
asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the
right the molecule is a D sugar, otherwise it is an L sugar. The "D-" and "L-" prefixes should not be confused with
"d-" or "l-", which indicate the direction that the sugar rotates plane polarized light. This usage of "d-" and "l-" is no
longer followed in carbohydrate chemistry.[7]

Ring-straight chain isomerism

The aldehyde or ketone group of a straight-chain monosaccharide
will react reversibly with a hydroxyl group on a different carbon
atom to form a hemiacetal or hemiketal, forming a heterocyclic
ring with an oxygen bridge between two carbon atoms. Rings with
five and six atoms are called furanose and pyranose forms,
respectively, and exist in equilibrium with the straight-chain
form.[8]

During the conversion from straight-chain form to the cyclic form,

the carbon atom containing the carbonyl oxygen, called the
anomeric carbon, becomes a stereogenic center with two possible
Glucose can exist in both a straight-chain and ring
configurations: The oxygen atom may take a position either above
form.
or below the plane of the ring. The resulting possible pair of
stereoisomers is called anomers. In the α anomer, the -OH
substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the CH2OH side branch. The
alternative form, in which the CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane
of the ring, is called the β anomer. You can remember that the β anomer is cis by the mnemonic, "It's always better
to βe up". Because the ring and straight-chain forms readily interconvert, both anomers exist in equilibrium.[8] In a
Fischer Projection, the α anomer is represented with the anomeric hydroxyl group trans to the CH2OH and cis in the
β anomer.
Carbohydrate 189

Use in living organisms

Monosaccharides are the major source of fuel for metabolism, being used both as an energy source (glucose being
the most important in nature) and in biosynthesis. When monosaccharides are not immediately needed by many cells
they are often converted to more space efficient forms, often polysaccharides. In many animals, including humans,
this storage form is glycogen, especially in liver and muscle cells. In plants, starch is used for the same purpose.

Disaccharides
Two joined monosaccharides are called a disaccharide
and these are the simplest polysaccharides. Examples
include sucrose and lactose. They are composed of two
monosaccharide units bound together by a covalent
bond known as a glycosidic linkage formed via a
dehydration reaction, resulting in the loss of a hydrogen
atom from one monosaccharide and a hydroxyl group
from the other. The formula of unmodified
Sucrose, also known as table sugar, is a common disaccharide. It is
disaccharides is C12H22O11. Although there are composed of two monosaccharides: D-glucose (left) and D-fructose
numerous kinds of disaccharides, a handful of (right).
disaccharides are particularly notable.

Sucrose, pictured to the right, is the most abundant disaccharide, and the main form in which carbohydrates are
transported in plants. It is composed of one D-glucose molecule and one D-fructose molecule. The systematic name
for sucrose, O-α-D-glucopyranosyl-(1→2)-D-fructofuranoside, indicates four things:
• Its monosaccharides: glucose and fructose
• Their ring types: glucose is a pyranose, and fructose is a furanose
• How they are linked together: the oxygen on carbon number 1 (C1) of α-D-glucose is linked to the C2 of
D-fructose.
• The -oside suffix indicates that the anomeric carbon of both monosaccharides participates in the glycosidic bond.
Lactose, a disaccharide composed of one D-galactose molecule and one D-glucose molecule, occurs naturally in
mammalian milk. The systematic name for lactose is O-β-D-galactopyranosyl-(1→4)-D-glucopyranose. Other
notable disaccharides include maltose (two D-glucoses linked α-1,4) and cellulobiose (two D-glucoses linked β-1,4).
disaccharides can be classified into two types.They are reducing and non-reducing disaccahrides if the functional
group is present in bonding with another sugar unit it is called a reducing disaccharide or biose.
Carbohydrate 190

Oligosaccharides and polysaccharides

Oligosaccharides and polysaccharides
are composed of longer chains of
monosaccharide units bound together
by glycosidic bonds. The distinction
between the two is based upon the
number of monosaccharide units
present in the chain. Oligosaccharides
typically contain between three and ten
monosaccharide units, and
polysaccharides contain greater than
ten monosaccharide units. Definitions Amylose is a linear polymer of glucose mainly linked with α(1→4) bonds. It can be made
of several thousands of glucose units. It is one of the two components of starch, the other
of how large a carbohydrate must be to
being amylopectin.
fall into each category vary according
to personal opinion. Examples of
oligosaccharides include the disaccharides mentioned above, the trisaccharide raffinose and the tetrasaccharide
stachyose.

Oligosaccharides are found as a common form of protein posttranslational modification. Such posttranslational
modifications include the Lewis and ABO oligosaccharides responsible for blood group classifications and so of
tissue incompatibilities, the alpha-Gal epitope responsible for hyperacute rejection in xenotransplantation, and
O-GlcNAc modifications.
Polysaccharides represent an important class of biological polymers. Their function in living organisms is usually
either structure- or storage-related. Starch (a polymer of glucose) is used as a storage polysaccharide in plants, being
found in the form of both amylose and the branched amylopectin. In animals, the structurally similar glucose
polymer is the more densely branched glycogen, sometimes called 'animal starch'. Glycogen's properties allow it to
be metabolized more quickly, which suits the active lives of moving animals.
Cellulose and chitin are examples of structural polysaccharides. Cellulose is used in the cell walls of plants and other
organisms, and is claimed to be the most abundant organic molecule on earth.[9] It has many uses such as a
significant role in the paper and textile industries, and is used as a feedstock for the production of rayon (via the
viscose process), cellulose acetate, celluloid, and nitrocellulose. Chitin has a similar structure, but has
nitrogen-containing side branches, increasing its strength. It is found in arthropod exoskeletons and in the cell walls
of some fungi. It also has multiple uses, including surgical threads.
Other polysaccharides include callose or laminarin, chrysolaminarin, xylan, arabinoxylan, mannan, fucoidan and
galactomannan.
Carbohydrate 191

Nutrition
Foods high in carbohydrate include fruits, sweets, soft drinks, breads,
pastas, beans, potatoes, bran, rice, and cereals. Carbohydrates are a
common source of energy in living organisms; however, no
carbohydrate is an essential nutrient in humans.[10]
Carbohydrates are not necessary building blocks of other molecules,
and the body can obtain all its energy from protein and fats.[11] [12] The
brain fats contain 37.8 kilojoules (9 kilocalories) per gram. In the case
of protein, this is somewhat misleading as only some amino acids are
usable for fuel.
Organisms typically cannot metabolize all types of carbohydrate to
yield energy. Glucose is a nearly universal and accessible source of
calories. Many organisms also have the ability to metabolize other
monosaccharides and Disaccharides, though glucose is preferred. In
Escherichia coli, for example, the lac operon will express enzymes for
the digestion of lactose when it is present, but if both lactose and
glucose are present the lac operon is repressed, resulting in the glucose Grain products: rich sources of carbohydrates

being used first (see: Diauxie). Polysaccharides are also common

sources of energy. Many organisms can easily break down starches into glucose, however, most organisms cannot
metabolize cellulose or other polysaccharides like chitin and arabinoxylans. These carbohydrates types can be
metabolized by some bacteria and protists. Ruminants and termites, for example, use microorganisms to process
cellulose. Even though these complex carbohydrates are not very digestible, they may comprise important dietary
elements for humans. Called dietary fiber, these carbohydrates enhance digestion among other benefits.

Based on the effects on risk of heart disease and obesity, the Institute of Medicine recommends that American and
Canadian adults get between 45–65% of dietary energy from carbohydrates.[13] The Food and Agriculture
Organization and World Health Organization jointly recommend that national dietary guidelines set a goal of
55–75% of total energy from carbohydrates, but only 10% directly from sugars (their term for simple
carbohydrates).[14]

Classification
Historically nutritionists have classified carbohydrates as either simple or complex, however, the exact delineation of
these categories is ambiguous. Today, simple carbohydrate typically refers to monosaccharides and disaccharides
and complex carbohydrate means polysaccharides (and oligosaccharides). However, the term complex carbohydrate
was first used in slightly different context in the U.S. Senate Select Committee on Nutrition and Human Needs
publication Dietary Goals for the United States (1977). In this work, complex carbohydrate were defined as "fruit,
vegetables and whole-grains".[15] Some nutritionists use complex carbohydrate to refer to any sort of digestible
saccharide present in a whole food, where fiber, vitamins and minerals are also found (as opposed to processed
carbohydrates, which provide calories but few other nutrients).
Some simple carbohydrates (e.g. fructose) are digested very slowly, while some complex carbohydrates (starches),
especially if processed, raise blood sugar rapidly. The speed of digestion is determined by a variety of factors
including which other nutrients are consumed with the carbohydrate, how the food is prepared, individual differences
in metabolism, and the chemistry of the carbohydrate. The USDA's Dietary Guidelines for Americans 2005
dispensed with the simple/complex distinction, instead recommending fiber-rich foods and whole grains.[16]
The glycemic index (GI) and glycemic load concepts have been developed to characterize food behavior during
human digestion. They rank carbohydrate-rich foods based on the rapidity and magnitude of their effect on blood
Carbohydrate 192

glucose levels. Glycemic index is a measure of how quickly food glucose is absorbed, while glycemic load is a
measure of the total absorbable glucose in foods. The insulin index is a similar, more recent classification method
that ranks foods based on their effects on blood insulin levels, which are caused by glucose (or starch) and some
amino acids in food.

Carbohydrate chemistry
Carbohydrate chemistry is a large and economically important branch of organic chemistry. Some of the main
organic reactions that involve carbohydrates are:
• Carbohydrate acetalisation
• Cyanohydrin reaction
• Lobry-de Bruyn-van Ekenstein transformation
• Amadori rearrangement
• Nef reaction
• Wohl degradation
• Koenigs–Knorr reaction

References
[1] Flitsch, SL & Ulijn, RV (2003). "Sugars tied to the spot." Nature 421: 219–220 (http:/ / www. nature. com/ nature/ journal/ v421/ n6920/ pdf/
421219a. pdf).
[2] Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993).
Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. pp. 52–59. ISBN 0-13-981176-1.
[3] John Merle Coulter, Charler Reid Barnes, Henry Chandler Cowles (1930), A Textbook of Botany for Colleges and Universities (http:/ /
books. google. com. br/ books?id=WyZnVpCiTHIC& pg=PA375& dq=simplest+ carbohydrate)"
[4] Carl A. Burtis, Edward R. Ashwood, Norbert W. Tietz (2000), Tietz fundamentals of clinical chemistry (http:/ / books. google. com/
books?id=l5hqAAAAMAAJ& q=simplest+ carbohydrate)
[5] Matthews, C. E.; K. E. Van Holde; K. G. Ahern (1999) Biochemistry. 3rd edition. Benjamin Cummings. ISBN 0-8053-3066-6
[6] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[7] Pigman, Ward; Horton, D. (1972). "Chapter 1: Stereochemistry of the Monosaccharides". In Pigman and Horton. The Carbohydrates:
Chemistry and Biochemistry Vol 1A (2nd ed.). San Diego: Academic Press. pp. 1–67.
[8] Pigman, Ward; Anet, E.F.L.J. (1972). "Chapter 4: Mutarotations and Actions of Acids and Bases". In Pigman and Horton. The
Carbohydrates: Chemistry and Biochemistry Vol 1A (2nd ed.). San Diego: Academic Press. pp. 165–194.
[9] N.A.Campbell (1996) Biology (4th edition). Benjamin Cummings NY. p.23 ISBN 0-8053-1957-3
[10] http:/ / www. ajcn. org/ content/ 75/ 5/ 951. 2. full
[11] Is dietary carbohydrate essential for human nutrition? - Westman 75 (5): 951 - American Journal of Clinical Nutrition (http:/ / www. ajcn.
org/ cgi/ content/ full/ 75/ 5/ 951-a)
[12] A High-Protein, High-Fat, Carbohydrate-Free Diet Reduces Energy Intake, Hepatic Lipogenesis, and Adiposity in Rats - Pichon et al. 136
(5): 1256 - Journal of Nutrition (http:/ / jn. nutrition. org/ cgi/ reprint/ 136/ 5/ 1256?ijkey=ebf0450b5cf21e8d83dd43f62b5559254694f65f)
[13] Food and Nutrition Board (2002/2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein,
and Amino Acids (http:/ / newton. nap. edu/ books/ 0309085373/ html). Washington, D.C.: The National Academies Press. Page 769 (http:/ /
newton. nap. edu/ books/ 0309085373/ html/ 769. html). ISBN 0-309-08537-3.
[14] Joint WHO/FAO expert consultation (2003). Diet, Nutrition and the Prevention of Chronic Diseases (http:/ / www. who. int/ hpr/ NPH/
docs/ who_fao_expert_report. pdf) (PDF). Geneva: World Health Organization. Pages 55–56. ISBN 92-4-120916-X.
[15] Joint WHO/FAO expert consultation (1998), Carbohydrates in human nutrition, chapter 1 (http:/ / www. fao. org/ docrep/ W8079E/
w8079e07. htm). ISBN 92-5-104114-8.
[16] DHHS and USDA, Dietary Guidelines for Americans 2005, Chapter 7 Carbohydrates (http:/ / www. health. gov/ dietaryguidelines/ dga2005/
document/ html/ chapter7. htm)
Carbohydrate 193

External links
• Carbohydrates, including interactive models and animations (http://www2.ufp.pt/~pedros/bq/carb_en.htm)
(Requires MDL Chime (http://www.mdl.com/products/framework/chime/))
• IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN): Carbohydrate Nomenclature (http://
www.chem.qmw.ac.uk/iupac/2carb/)
• Carbohydrates detailed (http://www.cem.msu.edu/~reusch/VirtualText/carbhyd.htm)
• Complex And Simple Carbohydrates (http://evilcyber.com/nutrition/complex-and-simple-carbohydrates/)
Explanation of the differences
• Carbohydrates and Glycosylation - The Virtual Library of Biochemistry and Cell Biology (http://www.
biochemweb.org/carbohydrates.shtml)
• Functional Glycomics Gateway (http://www.functionalglycomics.org/), a collaboration between the
Consortium for Functional Glycomics and Nature Publishing Group
• Wine Carbohydrates (http://www.wineclubwizard.com/wine-carbohydrates.html)

Polysaccharide
Polysaccharides are long carbohydrate molecules, of
repeated monomer units joined together by glycosidic
bonds. They range in structure from linear to highly
branched. Polysaccharides are often quite
heterogeneous, containing slight modifications of the
repeating unit. Depending on the structure, these
macromolecules can have distinct properties from their 3D structure of cellulose, a beta-glucan polysaccharide.
monosaccharide building blocks. They may be
amorphous or even insoluble in water.[1] [2]

When all the monosaccharides in a polysaccharide are the same type, the polysaccharide is called a
homopolysaccharide or homoglycan, but when more than one type of monosaccharide is present they are called
heteropolysaccharides or heteroglycans. [3] [4]
Examples include storage polysaccharides such as starch and glycogen, and structural polysaccharides such as
cellulose and chitin.
Polysaccharides have a general formula of Cx(H2O)y where x is usually a large number between 200 and 2500.
Considering that the repeating units in the polymer backbone are often six-carbon monosaccharides, the general
formula can also be represented as (C6H10O5)n where 40≤n≤3000.
Polysaccharide 194

Structure
Natural saccharides are generally built of simple carbohydrates called monosaccharides with general formula
(CH2O)n where n is three or more. A typical monosaccharide has the structure H-(CHOH)x(C=O)-(CHOH)y-H, that
is, an aldehyde or ketone with many hydroxyl groups added, usually one on each carbon atom that is not part of the
aldehyde or ketone functional group. Examples of monosaccharides are glucose, fructose, and glyceraldehyde[5]
Polysaccharides are composed of long
chains of monosaccharide units bound
together by glycosidic bonds.
Polysaccharides contain more than ten
monosaccharide units. Definitions of
how large a carbohydrate must be to
fall into the categories polysaccharides
or oligosaccharides vary according to
personal opinion.

Polysaccharides is an important class

Amylose is a linear polymer of glucose mainly linked with α(1→4) bonds. It can be made
of biological polymers. Their function of several thousands of glucose units. It is one of the two components of starch, the other
in living organisms is usually either being amylopectin.
structure- or storage-related. Starch (a
polymer of glucose) is used as a storage polysaccharide in plants, being found in the form of both amylose and the
branched amylopectin. In animals, the structurally similar glucose polymer is the more densely branched glycogen,
sometimes called 'animal starch'. Glycogen's properties allow it to be metabolized more quickly, which suits the
active lives of moving animals.

Cellulose and chitin are examples of structural polysaccharides. Cellulose is used in the cell walls of plants and other
organisms, and is claimed to be the most abundant organic molecule on earth.[6] It has many uses such as a
significant role in the paper and textile industries, and is used as a feedstock for the production of rayon (via the
viscose process), cellulose acetate, celluloid, and nitrocellulose. Chitin has a similar structure, but has
nitrogen-containing side branches, increasing its strength. It is found in arthropod exoskeletons and in the cell walls
of some fungi. It also has multiple uses, including surgical threads.

Polysaccharides also include callose or laminarin, chrysolaminarin, xylan, arabinoxylan, mannan, fucoidan and
galactomannan.

Function

Nutrition
Polysaccharides are common sources of energy. Many organisms can easily break down starches into glucose,
however, most organisms cannot metabolize cellulose or other polysaccharides like chitin and arabinoxylans. These
carbohydrates types can be metabolized by some bacteria and protists. Ruminants and termites, for example, use
microorganisms to process cellulose.
Even though these complex carbohydrates are not very digestible, they may comprise important dietary elements for
humans. Called dietary fiber, these carbohydrates enhance digestion among other benefits. The main action of
dietary fiber is to change the nature of the contents of the gastrointestinal tract, and to change how other nutrients
and chemicals are absorbed.[7] [8] Soluble fiber binds to bile acids in the small intestine, making them less likely to
enter the body; this in turn lowers cholesterol levels in the blood.[9] Soluble fiber also attenuates the absorption of
sugar, reduces sugar response after eating, normalizes blood lipid levels and, once fermented in the colon, produces
short-chain fatty acids as byproducts with wide-ranging physiological activities (discussion below). Although
Polysaccharide 195

insoluble fiber is associated with reduced diabetes risk, the mechanism by which this occurs is unknown.[10]
Not yet formally proposed as an essential macronutrient, dietary fiber is nevertheless regarded as important for the
diet, with regulatory authorities in many developed countries recommending increases in fiber intake.[7] [8] [11] [12]

Storage polysaccharides

Starches
Starches are glucose polymers in which glucopyranose units are bonded by alpha-linkages. It is made up of a
mixture of Amylose (15–20%) and Amylopectin (80–85%). Amylose consists of a linear chain of several hundred
glucose molecules and Amylopectin is a branched molecule made of several thousand glucose units (every chain of
24–30 glucose units is one unit of Amylopectin). Starches are insoluble in water. They can be digested by
hydrolysis, catalyzed by enzymes called amylases, which can break the alpha-linkages (glycosidic bonds). Humans
and other animals have amylases, so they can digest starches. Potato, rice, wheat, and maize are major sources of
starch in the human diet. The formations of starches are the ways that plants store glucose.

Glycogen
Glycogen serves as the secondary long-term
energy storage in animal and fungal cells,
with the primary energy stores being held in
adipose tissue. Glycogen is made primarily
by the liver and the muscles, but can also be
made by glycogenesis within the brain and
stomach.[14]

Glycogen is the analogue of starch, a

glucose polymer in plants, and is sometimes
referred to as animal starch, having a
similar structure to amylopectin but more
extensively branched and compact than
starch. Glycogen is a polymer of α(1→4)
glycosidic bonds linked, with
α(1→6)-linked branches. Glycogen is found
in the form of granules in the
cytosol/cytoplasm in many cell types, and
plays an important role in the glucose cycle.
Glycogen forms an energy reserve that can Schematic 2-D cross-sectional view of glycogen. A core protein of glycogenin is
surrounded by branches of glucose units. The entire globular granule may contain
be quickly mobilized to meet a sudden need [13]
approximately 30,000 glucose units.
for glucose, but one that is less compact
than the energy reserves of triglycerides
(lipids).

In the liver hepatocytes, glycogen can compose up to eight percent of the fresh weight (100–120 g in an adult) soon
after a meal.[15] Only the glycogen stored in the
Polysaccharide 196

liver can be made accessible to other organs.

In the muscles, glycogen is found in a low
concentration (one to two percent of the
muscle mass). However, the amount of
glycogen stored in the body—especially
within the muscles, liver, and red blood
cells[16] [17] [18] —mostly depends on
physical training, basal metabolic rate, and
eating habits such as intermittent fasting.
Small amounts of glycogen are found in the
kidneys, and even smaller amounts in
certain glial cells in the brain and white
blood cells. The uterus also stores glycogen
during pregnancy to nourish the embryo.[19]

Glycogen is composed of a branched chain

of glucose residues. It is stored in liver and
muscles.
• It is an energy reserve for animals.
A view of the atomic structure of a single branched strand of glucose units in a
• It is the chief form of carbohydrate stored
glycogen molecule.
in animal body.
• It is insoluble in water. It turns red when mixed with iodine.
• It also yields glucose on hydrolysis.

Structural polysaccharides

Arabinoxylans
Arabinoxylans are found in both the primary and secondary cell walls of plants and are the copolymers of two
pentose sugars: arabinose and xylose.

Cellulose
The structural component of plants are formed primarily from cellulose. Wood is largely cellulose and lignin, while
paper and cotton are nearly pure cellulose. Cellulose is a polymer made with repeated glucose units bonded together
by beta-linkages. Humans and many other animals lack an enzyme to break the beta-linkages, so they do not digest
cellulose. Certain animals such as termites can digest cellulose, because bacteria possessing the enzyme are present
in their gut. Cellulose is insoluble in water. It does not change color when mixed with iodine. On hydrolysis, it yields
glucose. It is the most abundant carbohydrate in nature.

Chitin
Chitin is one of many naturally occurring polymers. It forms a structural component of many animals, such as
exoskeletons. Over time it is bio-degradable in the natural environment. Its breakdown may be catalyzed by enzymes
called chitinases, secreted by microorganisms such as bacteria and fungi, and produced by some plants. Some of
these microorganisms have receptors to simple sugars from the decomposition of chitin. If chitin is detected, they
then produce enzymes to digest it by cleaving the glycosidic bonds in order to convert it to simple sugars and
ammonia.
Polysaccharide 197

Chemically, chitin is closely related to chitosan (a more water-soluble derivative of chitin). It is also closely related
to cellulose in that it is a long unbranched chain of glucose derivatives. Both materials contribute structure and
strength, protecting the organism.

Pectins
Pectins are a family of complex polysaccharides that contain 1,4-linked α-D-galactosyluronic acid residues. They are
present in most primary cell walls and in the non-woody parts of terrestrial plants.

Acidic polysaccharides
Acidic polysaccharides are polysaccharides that contain carboxyl groups, phosphate groups and/or sulfuric ester
groups.

Bacterial polysaccharides
Bacterial polysaccharides represent a diverse range of macromolecules that include peptidoglycan,
lipopolysaccharides, capsules and exopolysaccharides; compounds whose functions range from structural cell-wall
components (e.g., peptidoglycan), and important virulence factors (e.g., Poly-N-acetylglucosamine in S. aureus), to
permitting the bacterium to survive in harsh environments (e.g., Pseudomonas aeruginosa in the human lung).[20]
Polysaccharide biosynthesis is a tightly regulated, energy-intensive process and understanding the subtle interplay
between the regulation and energy conservation, polymer modification and synthesis, and the external ecological
functions is a huge area of research. The potential benefits are enormous and should enable for example the
development of novel antibacterial strategies (e.g., new antibiotics and vaccines) and the commercial exploitation to
develop novel applications.[21] [22]

Bacterial capsular polysaccharides

Pathogenic bacteria commonly produce a thick, mucous-like, layer of polysaccharide. This "capsule" cloaks
antigenic proteins on the bacterial surface that would otherwise provoke an immune response and thereby lead to the
destruction of the bacteria. Capsular polysaccharides are water soluble, commonly acidic, and have molecular
weights on the order of 100-1000 kDa. They are linear and consist of regularly repeating subunits of one to six
monosaccharides. There is enormous structural diversity; nearly two hundred different polysaccharides are produced
by E. coli alone. Mixtures of capsular polysaccharides, either conjugated or native are used as vaccines.
Bacteria and many other microbes, including fungi and algae, often secrete polysaccharides as an evolutionary
adaptation to help them adhere to surfaces and to prevent them from drying out. Humans have developed some of
these polysaccharides into useful products, including xanthan gum, dextran, welan gum, gellan gum, diutan gum and
pullulan.
Most of these polysaccharides exhibit interesting and very useful visco-elastic properties when dissolved in water at
very low levels.[23] This gives many foods and various liquid consumer products, like lotions, cleaners and paints,
for example, a viscous appearance when stationary, but fluidity when the slightest shear is applied, such as when
wiped, poured or brushed. This property is referred to as pseudoplasticity, or shear thinning.
Polysaccharide 198

Viscosity of Welan gum [24]

Shear Rate (rpm) Viscosity (cP)

0.3 23330

0.5 16000

1 11000

2 5500

4 3250

5 2900

10 1700

20 900

50 520

100 310

Aqueous solutions of the polysaccharide alone have a curious behavior when stirred. After stopping, the swirl
continues due to momentum, then stops, and then reverses direction briefly. This recoil demonstrates the elastic
effect of the polysaccharide chains previously streched in solution, returning to their relaxed state.
Cell-surface polysaccharides play diverse roles in bacterial ecology and physiology. They serve as a barrier between
the cell wall and the environment, mediate host-pathogen interactions, and form structural components of biofilms.
These polysaccharides are synthesized from nucleotide-activated precursors (called nucleotide sugars) and, in most
cases, all the enzymes necessary for biosynthesis, assembly and transport of the completed polymer are encoded by
genes organized in dedicated clusters within the genome of the organism. Lipopolysaccharide is one of the most
important cell-surface polysaccharides, as it plays a key structural role in outer membrane integrity, as well as being
an important mediator of host-pathogen interactions.
The enzymes that make the A-band (homopolymeric) and B-band (heteropolymeric) O-antigens have been identified
and the metabolic pathways defined.[25] The exopolysaccharide alginate is a linear copolymer of β-1,4-linked
D-mannuronic acid and L-guluronic acid residues, and is responsible for the mucoid phenotype of late-stage cystic
fibrosis disease. The pel and psl loci are two recently discovered gene clusters that also encode exopolysaccharides
found to be important for biofilm formation. Rhamnolipid is a biosurfactant whose production is tightly regulated at
the transcriptional level, but the precise role that it plays in disease is not well understood at present. Protein
glycosylation, particularly of pilin and flagellin, is a recent focus of research by several groups and it has been shown
to be important for adhesion and invasion during bacterial infection.[26]

References
[1] Varki A, Cummings R, Esko J, Freeze H, Stanley P, Bertozzi C, Hart G, Etzler M (2008). Essentials of glycobiology (http:/ / www. ncbi. nlm.
nih. gov/ bookshelf/ br. fcgi?book=glyco2). Cold Spring Harbor Laboratory Press; 2nd edition. ISBN 0-87969-770-9. .
[2] Varki A, Cummings R, Esko J, Jessica Freeze, Hart G, Marth J (1999). Essentials of glycobiology (http:/ / www. ncbi. nlm. nih. gov/ books/
bv. fcgi?rid=glyco. TOC& depth=2). Cold Spring Harbor Laboratory Press. ISBN 0-87969-560-9. .
[3] IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) " homopolysaccharide
(homoglycan) (http:/ / goldbook. iupac. org/ H02856. html)".
[4] IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "
heteropolysaccharide (heteroglycan) (http:/ / goldbook. iupac. org/ H02812. html)".
[5] Matthews, C. E.; K. E. Van Holde; K. G. Ahern (1999) Biochemistry. 3rd edition. Benjamin Cummings. ISBN 0-8053-3066-6
[6] N.A.Campbell (1996) Biology (4th edition). Benjamin Cummings NY. p.23 ISBN 0-8053-1957-3
[7] "Dietary Reference Intakes for Energy, Carbohydrate, fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005),
Chapter 7: Dietary, Functional and Total fiber." (http:/ / www. nal. usda. gov/ fnic/ DRI/ / DRI_Energy/ 339-421. pdf). US Department of
Agriculture, National Agricultural Library and National Academy of Sciences, Institute of Medicine, Food and Nutrition Board. .
Polysaccharide 199

[8] Eastwood M, Kritchevsky D (2005). "Dietary fiber: how did we get where we are?". Annu Rev Nutr 25: 1–8.
doi:10.1146/annurev.nutr.25.121304.131658. PMID 16011456.
[9] Anderson JW, Baird P, Davis RH et al. (2009). "Health benefits of dietary fiber". Nutr Rev 67 (4): 188–205.
doi:10.1111/j.1753-4887.2009.00189.x. PMID 19335713.
[10] Weickert MO, Pfeiffer AF (2008). "Metabolic effects of dietary fiber consumption and prevention of diabetes". J Nutr 138 (3): 439–42.
PMID 18287346.
[11] "Dietary reference values for carbohydrates and dietary fiber" (http:/ / www. efsa. europa. eu/ EFSA/ DocumentSet/
nda_op_drv_carbohydrates_draft_en_released for consultation,0. pdf?ssbinary=true). European Food Safety Authority. .
[12] Jones PJ, Varady KA (2008). "Are functional foods redefining nutritional requirements?" (http:/ / article. pubs. nrc-cnrc. gc. ca/ ppv/
RPViewDoc?issn=1715-5312& volume=33& issue=1& startPage=118) (PDF). Appl Physiol Nutr Metab 33 (1): 118–23.
doi:10.1139/H07-134. PMID 18347661. .
[13] Page 12 in: (http:/ / books. google. dk/ books?id=SRptlOx7yj4C& printsec=frontcover& hl=en) Exercise physiology: energy, nutrition, and
human performance By William D. McArdle, Frank I. Katch, Victor L. Katch Edition: 6, illustrated Published by Lippincott Williams &
Wilkins, 2006 ISBN 0781749905, 9780781749909, 1068 pages
[14] Anatomy and Physiology. Saladin, Kenneth S. McGraw-Hill, 2007.
[15] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[16] Moses SW, Bashan N, Gutman A (December 1972). "Glycogen metabolism in the normal red blood cell" (http:/ / www. bloodjournal. org/
cgi/ pmidlookup?view=long& pmid=5083874). Blood 40 (6): 836–43. PMID 5083874. .
[17] http:/ / jeb. biologists. org/ cgi/ reprint/ 129/ 1/ 141. pdf
[18] Miwa I, Suzuki S (November 2002). "An improved quantitative assay of glycogen in erythrocytes". Annals of Clinical Biochemistry 39 (Pt
6): 612–3. doi:10.1258/000456302760413432. PMID 12564847.
[19] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[20] Sutherland, I. W. (2002). Vandamme, E. J., Ed.. ed. Polysaccharides from Microorganisms, Plants and Animals, in: Biopolymers, Volume
5, Polysaccharides I: Polysaccharides from Prokaryotes. Weiheim Wiley VCH. pp. 1–19. ISBN 978-3-527-30226-0.
[21] Ullrich M (editor) (2009). Bacterial Polysaccharides: Current Innovations and Future Trends. Caister Academic Press.
ISBN 978-1-904455-45-5.
[22] Rehm BHA (editor). (2009). Microbial Production of Biopolymers and Polymer Precursors: Applications and Perspectives. Caister
Academic Press. ISBN 978-1-904455-36-3.
[23] Viscosity of Welan Gum vs. Concentration in Water. http:/ / www. xydatasource. com/ xy-showdatasetpage. php?datasetcode=345115&
dsid=80
[24] http:/ / www. xydatasource. com/ xy-showdatasetpage. php?datasetcode=45615& dsid=76& searchtext=polysaccharide
[25] Guo H, Yi W, Song JK, Wang PG (2008). "Current understanding on biosynthesis of microbial polysaccharides". Curr Top Med Chem 8
(2): 141–51. doi:10.2174/156802608783378873. PMID 18289083.
[26] Cornelis P (editor). (2008). Pseudomonas: Genomics and Molecular Biology (http:/ / www. horizonpress. com/ pseudo) (1st ed.). Caister
Academic Press. ISBN 978-1-904455-19-6. . .

External links
• Polysaccharide Structure (http://employees.csbsju.edu/hjakubowski/classes/ch331/cho/complexoligosacch.
htm)
• Applications and commercial sources of polysaccharides (http://www.polysaccharidecenter.com)
• European Polysaccharide Network of Excellence (http://www.epnoe.eu)
 200

Intermediary metabolism
 201

Metabolism

Overview of metabolism
Metabolism (from Greek: μεταβολή
"metabolē", "change" or Greek: μεταβολισμός
metabolismos, "outthrow") is the set of chemical
reactions that happen in the cells of living
organisms to sustain life. These processes allow
organisms to grow and reproduce, maintain their
structures, and respond to their environments.
Metabolism is usually divided into two
categories. Catabolism breaks down organic
matter, for example to harvest energy in cellular
respiration. Anabolism uses energy to construct
components of cells such as proteins and nucleic
acids. Structure of adenosine triphosphate, a central intermediate in energy
metabolism
The chemical reactions of metabolism are
organized into metabolic pathways, in which one
chemical is transformed through a series of steps into another chemical, by a sequence of enzymes. Enzymes are
crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not
occur by themselves, by coupling them to spontaneous reactions that release energy. As enzymes act as catalysts
they allow these reactions to proceed quickly and efficiently. Enzymes also allow the regulation of metabolic
pathways in response to changes in the cell's environment or signals from other cells.

The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous.
For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The speed
of metabolism, the metabolic rate, influences how much food an organism will require, and also affects how it is able
to obtain that food.
A striking feature of metabolism is the similarity of the basic metabolic pathways and components between even
vastly different species.[2] For example, the set of carboxylic acids that are best known as the intermediates in the
citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacteria
Escherichia coli and huge multicellular organisms like elephants.[3] These striking similarities in metabolic pathways
are likely due to their early appearance in evolutionary history, and being retained because of their efficacy.[4] [5]
Overview of metabolism 202

Key biochemicals
Further information: Biomolecule, cell (biology) and biochemistry
Most of the structures that make up animals, plants and
microbes are made from three basic classes of
molecule: amino acids, carbohydrates and lipids (often
called fats). As these molecules are vital for life,
metabolic reactions either focus on making these
molecules during the construction of cells and tissues,
or breaking them down and using them as a source of
energy, in the digestion and use of food. Many
important biochemicals can be joined together to make
polymers such as DNA and proteins. These
macromolecules are essential.

Structure of a triacylglycerol lipid

Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms

Amino acids Amino acids Proteins (also called polypeptides) Fibrous proteins and globular proteins

Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose

Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins

Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are
the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical
functions, such as the proteins that form the cytoskeleton, a system of scaffolding that maintains the cell shape.[6]
Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes,
and the cell cycle.[7]

Lipids
Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes
such as the cell membrane, or as a source of energy.[7] Lipids are usually defined as hydrophobic or amphipathic
biological molecules that will dissolve in organic solvents such as benzene or chloroform.[8] The fats are a large
group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a
triacylglyceride.[9] Several variations on this basic structure exist, including alternate backbones such as sphingosine
in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are
another major class of lipids that are made in cells.[10]
Overview of metabolism 203

Carbohydrates
Carbohydrates are aldehydes or ketones with many
hydroxyl groups that can exist as straight chains or
rings. Carbohydrates are the most abundant biological
molecules, and fill numerous roles, such as the storage
and transport of energy (starch, glycogen) and structural
components (cellulose in plants, chitin in animals).[7]
The basic carbohydrate units are called
monosaccharides and include galactose, fructose, and
most importantly glucose. Monosaccharides can be
linked together to form polysaccharides in almost
limitless ways.[11]

Nucleotides Glucose can exist in both a straight-chain and ring form.

The two nucleic acids, DNA and RNA are polymers of

nucleotides, each nucleotide comprising a phosphate group, a ribose sugar group, and a nitrogenous base. Nucleic
acids are critical for the storage and use of genetic information, through the processes of transcription and protein
biosynthesis.[7] This information is protected by DNA repair mechanisms and propagated through DNA replication.
Many viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template
from its viral RNA genome.[12] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it
can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These
bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as
coenzymes in metabolic group transfer reactions.[13]

Coenzymes
Further information: Coenzyme
Metabolism involves a vast array of
chemical reactions, but most fall under a
few basic types of reactions that involve the
transfer of functional groups.[14] This
common chemistry allows cells to use a
small set of metabolic intermediates to carry
chemical groups between different Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to
[13] the sulfur atom at the extreme left.
reactions. These group-transfer
intermediates are called coenzymes. Each
class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes
that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made,
consumed and then recycled.[15]

One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is
used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells,
but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[15] ATP acts as a
bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions
consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.
Overview of metabolism 204

A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition,
most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated
or are coupled to nucleotides when they are used in cells.[16] Nicotinamide adenine dinucleotide (NADH), a
derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate
types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of
the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[17]
Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH
form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.

Minerals and cofactors

Further information: Metal Ions in Life
Sciences, Metal metabolism, and
bioinorganic chemistry
Inorganic elements play critical roles in
metabolism; some are abundant (e.g. sodium
and potassium) while others function at
minute concentrations. About 99% of a
mammal's mass is made up of the elements
carbon, nitrogen, calcium, sodium, chlorine,
potassium, hydrogen, phosphorus, oxygen
and sulfur.[18] Organic compounds (proteins,
lipids and carbohydrates) contain the
majority of the carbon and nitrogen; most of
the oxygen and hydrogen is present as
water.[18]

The abundant inorganic elements act as

Structure of hemoglobin. The protein subunits are in red and blue, and the ionic electrolytes. The most important ions
[1]
iron-containing heme groups in green. From PDB 1GZX . are sodium, potassium, calcium,
magnesium, chloride, phosphate and the
organic ion bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure
and pH.[19] Ions are also critical for nerve and muscle function, as action potentials in these tissues are produced by
the exchange of electrolytes between the extracellular fluid and the cytosol.[20] Electrolytes enter and leave cells
through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the
movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.[21]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant.[22] [23]
These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and
oxygen-carrier proteins such as hemoglobin.[24] Metal cofactors are bound tightly to specific sites in proteins;
although enzyme cofactors can be modified during catalysis, they always return to their original state by the end of
the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage
proteins such as ferritin or metallothionein when not being used.[25] [26]
Overview of metabolism 205

Catabolism
Further information: Catabolism
Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and
oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by
anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism and organisms can
be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table
below. Organic molecules are used as a source of energy by organotrophs, while lithotrophs use inorganic substrates
and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on
redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules,
water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate.[27] In
animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon
dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do
not release energy, but are used as a way of storing energy absorbed from sunlight.[7]

Classification of organisms based on their metabolism

Energy source sunlight photo- -troph

Preformed molecules chemo-

Electron donor organic compound organo-

inorganic compound litho-

Carbon source organic compound hetero-

inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large
organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside
cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl
coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water
and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by
reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.

Digestion
Further information: Digestion and gastrointestinal tract
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into
their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these
polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside
hydrolases that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings,[28] [29] while animals only secrete these enzymes
from specialized cells in their guts.[30] The amino acids or sugars released by these extracellular enzymes are then
pumped into cells by specific active transport proteins.[31] [32]
Overview of metabolism 206

Energy from organic compounds

Further information: Cellular respiration,
fermentation, carbohydrate catabolism, fat
catabolism and protein catabolism
Carbohydrate catabolism is the breakdown
of carbohydrates into smaller units.
Carbohydrates are usually taken into cells
once they have been digested into
monosaccharides.[33] Once inside, the major
route of breakdown is glycolysis, where
sugars such as glucose and fructose are
converted into pyruvate and some ATP is
generated.[34] Pyruvate is an intermediate in
several metabolic pathways, but the majority
is converted to acetyl-CoA and fed into the
citric acid cycle. Although some more ATP
A simplified outline of the catabolism of proteins, carbohydrates and fats is generated in the citric acid cycle, the most
important product is NADH, which is made
from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic
conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for
re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces
the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.

Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids
are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids
release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their
structures.
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as
a source of energy.[35] The oxidation pathway starts with the removal of the amino group by a transaminase. The
amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of
these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms
α-ketoglutarate.[36] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis
(discussed below).[37]

Energy transformations

Oxidative phosphorylation
Further information: Oxidative phosphorylation, chemiosmosis and mitochondrion
In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the protagon acid cycle
are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of
proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are
found in the cell's inner membrane.[38] These proteins use the energy released from passing electrons from reduced
molecules like NADH onto oxygen to pump protons across a membrane.[39]
Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and
generates an electrochemical gradient.[40] This force drives protons back into the mitochondrion through the base of
Overview of metabolism 207

an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the
synthase domain to change shape and phosphorylate adenosine diphosphate – turning it into ATP.[15]

Energy from inorganic compounds

Further information: Microbial metabolism and nitrogen cycle
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of
inorganic compounds. These organisms can use hydrogen,[41] reduced sulfur compounds (such as sulfide, hydrogen
sulfide and thiosulfate),[1] ferrous iron (FeII)[42] or ammonia[43] as sources of reducing power and they gain energy
from the oxidation of these compounds with electron acceptors such as oxygen or nitrite.[44] These microbial
processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and
are critical for soil fertility.[45] [46]

Energy from light

Further information: Phototroph, photophosphorylation, chloroplast
The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists.
This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis,
which is discussed below. The energy capture and carbon fixation systems can however operate separately in
prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching
between carbon fixation and the fermentation of organic compounds.[47] [48]
In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves
energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.[15]
The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic
reaction centres or rhodopsins. Reaction centers are classed into two types depending on the type of photosynthetic
pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have
two.[49]
In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing
oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump
protons across the thylakoid membrane in the chloroplast.[7] These protons move back through the membrane as they
drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to
reduce the coenzyme NADP+, for use in the Calvin cycle which is discussed below, or recycled for further ATP
generation.[50]

Anabolism
Further information: Anabolism
Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to
synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed
step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of
precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into
reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as
proteins, polysaccharides, lipids and nucleic acids.
Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as
plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple
molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex
substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be
further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from
Overview of metabolism 208

light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.

Carbon fixation
Further information: Photosynthesis, carbon fixation and chemosynthesis
Photosynthesis is the synthesis of carbohydrates from sunlight and
carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic
photosynthesis splits water, with oxygen produced as a waste product.
This process uses the ATP and NADPH produced by the
photosynthetic reaction centres, as described above, to convert CO2
into glycerate 3-phosphate, which can then be converted into glucose.
This carbon-fixation reaction is carried out by the enzyme RuBisCO as
part of the Calvin – Benson cycle.[51] Three types of photosynthesis
occur in plants, C3 carbon fixation, C4 carbon fixation and CAM
Plant cells (bounded by purple walls) filled with
photosynthesis. These differ by the route that carbon dioxide takes to
chloroplasts (green), which are the site of
the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and photosynthesis
CAM photosynthesis incorporate the CO2 into other compounds first,
as adaptations to deal with intense sunlight and dry conditions.[52]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be
fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[53] or the carboxylation of acetyl-CoA.[54] [55]
Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic
compounds to drive the reaction.[56]

Carbohydrates and glycans

Further information: Gluconeogenesis, glyoxylate cycle, glycogenesis and glycosylation
In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then
used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate,
glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to
glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[34] However, this
pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is
important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways
from running simultaneously in a futile cycle.[57] [58]
Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot
be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate; plants
do, but animals do not, have the necessary enzymatic machinery.[59] As a result, after long-term starvation,
vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot
metabolize fatty acids.[60] In other organisms such as plants and bacteria, this metabolic problem is solved using the
glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of
acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[59] [61]
Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a
reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group
on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the
polysaccharides produced can have straight or branched structures.[62] The polysaccharides produced can have
structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called
oligosaccharyltransferases.[63] [64]
Overview of metabolism 209

Fatty acids, isoprenoids and steroids

Further information: Fatty acid synthesis, steroid metabolism
Fatty acids are made by fatty acid
synthases that polymerize and then
reduce acetyl-CoA units. The acyl
chains in the fatty acids are extended
by a cycle of reactions that add the
actyl group, reduce it to an alcohol,
dehydrate it to an alkene group and
then reduce it again to an alkane group.
The enzymes of fatty acid biosynthesis
are divided into two groups, in animals
and fungi all these fatty acid synthase
reactions are carried out by a single
multifunctional type I protein,[65]
while in plant plastids and bacteria
separate type II enzymes perform each
step in the pathway.[66] [67]

Terpenes and isoprenoids are a large

class of lipids that include the
carotenoids and form the largest class
of plant natural products.[68] These
compounds are made by the assembly
and modification of isoprene units
Simplified version of the steroid synthesis pathway with the intermediates isopentenyl
donated from the reactive precursors
pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate
isopentenyl pyrophosphate and (GPP) and squalene shown. Some intermediates are omitted for clarity.
dimethylallyl pyrophosphate.[69] These
precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these
compounds from acetyl-CoA,[70] while in plants and bacteria the non-mevalonate pathway uses pyruvate and
glyceraldehyde 3-phosphate as substrates.[69] [71] One important reaction that uses these activated isoprene donors is
steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed
into a set of rings to make lanosterol.[72] Lanosterol can then be converted into other steroids such as cholesterol and
ergosterol.[72] [73]

Proteins
Further information: Protein biosynthesis, amino acid synthesis
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all
twenty, but mammals can synthesize only eleven nonessential amino acids.[7] Thus, nine essential amino acids must
be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the
pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the
formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.[74]
Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has
a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be
combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge
variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA
Overview of metabolism 210

molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried
out by an aminoacyl tRNA synthetase.[75] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the
amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[76]

Nucleotide synthesis and salvage

Further information: Nucleotide salvage, pyrimidine biosynthesis, and purine metabolism
Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of
metabolic energy.[77] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[77] [78]
Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the
precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine,
glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the
other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[79]

Xenobiotics and redox metabolism

Further information: Xenobiotic metabolism, drug metabolism, Alcohol metabolism and antioxidants
All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they
accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called
xenobiotics.[80] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of
xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[81]
UDP-glucuronosyltransferases,[82] and glutathione S-transferases.[83] This system of enzymes acts in three stages to
firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The
modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further
metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial
biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[84] Many of these microbial
reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these
organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even
persistent organic pollutants such as organochloride compounds.[85]
A related problem for aerobic organisms is oxidative stress.[86] Here, processes including oxidative phosphorylation
and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen
peroxide.[87] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes
such as catalases and peroxidases.[88] [89]

Thermodynamics of living organisms

Further information: Biological thermodynamics
Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second
law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase.
Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are
open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium,
but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the
entropy of their environments.[90] The metabolism of a cell achieves this by coupling the spontaneous processes of
catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by
creating disorder.[91]
Overview of metabolism 211

Regulation and control

Further information: Metabolic pathway, metabolic control analysis, hormone, regulatory enzymes, and cell
signaling
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely
regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[92] [93] Metabolic
regulation also allows organisms to respond to signals and interact actively with their environments.[94] Two closely
linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an
enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control
exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux
through the pathway).[95] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but
if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control
of the pathway.[96]
There are multiple levels of metabolic
regulation. In intrinsic regulation, the
metabolic pathway self-regulates to respond
to changes in the levels of substrates or
products; for example, a decrease in the
amount of product can increase the flux
through the pathway to compensate.[95] This
type of regulation often involves allosteric
regulation of the activities of multiple
enzymes in the pathway.[97] Extrinsic
control involves a cell in a multicellular
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor
organism changing its metabolism in
(1) which in turn starts many protein activation cascades (2). These include:
response to signals from other cells. These translocation of Glut-4 transporter to the plasma membrane and influx of glucose
signals are usually in the form of soluble (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
messengers such as hormones and growth
factors and are detected by specific receptors on the cell surface.[98] These signals are then transmitted inside the cell
by second messenger systems that often involved the phosphorylation of proteins.[99]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone
insulin.[100] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin
receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into
storage molecules such as fatty acids and glycogen.[101] The metabolism of glycogen is controlled by activity of
phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These
enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating
phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the
phosphorylation of these enzymes.[102]
Overview of metabolism 212

Evolution
Further information: Molecular evolution and phylogenetics
The central pathways of metabolism
described above, such as glycolysis
and the citric acid cycle, are present in
all three domains of living things and
were present in the last universal
ancestor.[3] [103] This universal
ancestral cell was prokaryotic and
probably a methanogen that had
extensive amino acid, nucleotide,
carbohydrate and lipid
[104] [105]
metabolism. The retention of
these ancient pathways during later
evolution may be the result of these
reactions being an optimal solution to
Evolutionary tree showing the common ancestry of organisms from all three domains of their particular metabolic problems,
life. Bacteria are colored blue, eukaryotes red, and archaea green. Relative positions of with pathways such as glycolysis and
some of the phyla included are shown around the tree.
the citric acid cycle producing their
end products highly efficiently and in a
[4] [5]
minimal number of steps. Mutation changes that affect non-coding DNA segments may merely affect the
metabolic efficiency of the individual for whom the mutation occurs.[106] The first pathways of enzyme-based
metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of
the ancient RNA world.[107]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These
include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of
entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction
pathway.[108] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes
in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step
fashion with novel functions being created from pre-existing steps in the pathway.[109] An alternative model comes
from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes
are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident
in the MANET database)[110] These recruitment processes result in an evolutionary enzymatic mosaic.[111] A third
possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and
perform similar functions on different molecules.[112]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For
example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids,
nucleotides and carbohydrates may instead be scavenged from the host.[113] Similar reduced metabolic capabilities
are seen in endosymbiotic organisms.[114]
Overview of metabolism 213

Investigation and manipulation

Further information: Protein methods, proteomics, metabolomics and metabolic network modelling
Classically, metabolism is studied by a
reductionist approach that focuses on a
single metabolic pathway. Particularly
valuable is the use of radioactive tracers at
the whole-organism, tissue and cellular
levels, which define the paths from
precursors to final products by identifying
radioactively labelled intermediates and
products.[115] The enzymes that catalyze
these chemical reactions can then be
purified and their kinetics and responses to
inhibitors investigated. A parallel approach
is to identify the small molecules in a cell or
tissue; the complete set of these molecules is
called the metabolome. Overall, these
studies give a good view of the structure and
function of simple metabolic pathways, but
are inadequate when applied to more
complex systems such as the metabolism of
a complete cell.[116]
Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and
metabolites are shown as red squares and the interactions between them as black
An idea of the complexity of the metabolic
lines.
networks in cells that contain thousands of
different enzymes is given by the figure
showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide
lists containing anything up to 45,000 genes.[117] However, it is now possible to use this genomic data to reconstruct
complete networks of biochemical reactions and produce more holistic mathematical models that may explain and
predict their behavior.[118] These models are especially powerful when used to integrate the pathway and metabolite
data obtained through classical methods with data on gene expression from proteomic and DNA microarray
studies.[119] Using these techniques, a model of human metabolism has now been produced, which will guide future
drug discovery and biochemical research.[120] These models are now being used in network analysis, to classify
human diseases into groups that share common proteins or metabolites.[121] [122]

Bacterial metabolic networks seem to be a striking example of bow-tie[123] [124] [125] organization, an architecture
able to input a wide range of nutrients and produce a large variety of products and complex macromolecules using a
relatively few intermediate common currencies.
A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants
or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such
as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[126] These genetic modifications
usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of
wastes.[127]
Overview of metabolism 214

History
Further information: History of biochemistry and history of molecular biology
The term metabolism is derived from the Greek Μεταβολισμός –
"Metabolismos" for "change", or "overthrow".[128] The history of the
scientific study of metabolism spans several centuries and has moved from
examining whole animals in early studies, to examining individual metabolic
reactions in modern biochemistry. The first controlled experiments in human
metabolism were published by Santorio Santorio in 1614 in his book Ars de
statica medicina.[129] He described how he weighed himself before and after
eating, sleep, working, sex, fasting, drinking, and excreting. He found that
most of the food he took in was lost through what he called "insensible
perspiration".

In these early studies, the mechanisms of these metabolic processes had not
been identified and a vital force was thought to animate living tissue.[130] In
the 19th century, when studying the fermentation of sugar to alcohol by yeast,
Louis Pasteur concluded that fermentation was catalyzed by substances
within the yeast cells he called "ferments". He wrote that "alcoholic Santorio Santorio in his steelyard
balance, from Ars de statica medicina,
fermentation is an act correlated with the life and organization of the yeast
first published 1614
cells, not with the death or putrefaction of the cells."[131] This discovery,
along with the publication by Friedrich Wöhler in 1828 of the chemical
synthesis of urea,[132] notable for being the first organic compound prepared from wholly inorganic precursors,
proved that the organic compounds and chemical reactions found in cells were no different in principle than any
other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of
the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of
biochemistry.[133] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the
most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of
metabolism.[134] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the
glyoxylate cycle.[135] [61] Modern biochemical research has been greatly aided by the development of new
techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron
microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis
of the many molecules and metabolic pathways in cells.

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Further reading
Introductory
• Rose, S. and Mileusnic, R., The Chemistry of Life. (Penguin Press Science, 1999), ISBN 0-14-027273-9
• Schneider, E. D. and Sagan, D., Into the Cool: Energy Flow, Thermodynamics, and Life. (University Of Chicago
Press, 2005), ISBN 0-226-73936-8
• Lane, N., Oxygen: The Molecule that Made the World. (Oxford University Press, USA, 2004), ISBN
0-19-860783-0
Advanced
• Price, N. and Stevens, L., Fundamentals of Enzymology: Cell and Molecular Biology of Catalytic Proteins.
(Oxford University Press, 1999), ISBN 0-19-850229-X
• Berg, J. Tymoczko, J. and Stryer, L., Biochemistry. (W. H. Freeman and Company, 2002), ISBN 0-7167-4955-6
• Cox, M. and Nelson, D. L., Lehninger Principles of Biochemistry. (Palgrave Macmillan, 2004), ISBN
0-7167-4339-6
Overview of metabolism 220

• Brock, T. D. Madigan, M. T. Martinko, J. and Parker J., Brock's Biology of Microorganisms. (Benjamin
Cummings, 2002), ISBN 0-13-066271-2
• Da Silva, J.J.R.F. and Williams, R. J. P., The Biological Chemistry of the Elements: The Inorganic Chemistry of
Life. (Clarendon Press, 1991), ISBN 0-19-855598-9
• Nicholls, D. G. and Ferguson, S. J., Bioenergetics. (Academic Press Inc., 2002), ISBN 0-12-518121-3

External links
biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i
 221

Carbohydrate metabolism

Glycolysis
Glycolysis (from glycose, an older
term[1] for glucose + -lysis
degradation) is the metabolic pathway
that converts glucose C6H12O6, into
pyruvate, CH3COCOO− + H+. The
free energy released in this process is
used to form the high-energy
compounds ATP (adenosine
triphosphate) and NADH (reduced
nicotinamide adenine dinucleotide).
Glycolysis overview
Glycolysis is a definite sequence of ten
reactions involving ten intermediate compounds (one of the steps involves two intermediates). The intermediates
provide entry points to glycolysis. For example, most monosaccharides, such as fructose, glucose, and galactose, can
be converted to one of these intermediates. The intermediates may also be directly useful. For example, the
intermediate dihydroxyacetone phosphate (DHAP) is a source of the glycerol that combines with fatty acids to form
fat.

It occurs, with variations, in nearly all organisms, both aerobic and anaerobic. The wide occurrence of glycolysis
indicates that it is one of the most ancient known metabolic pathways.[2] It occur in the cytosol of the cell.
The most common type of glycolysis is the Embden-Meyerhof-Parnas pathway (EMP pathway), which was first
discovered by Gustav Embden, Otto Meyerhof and Jakub Karol Parnas. Glycolysis also refers to other pathways,
such as the Entner–Doudoroff pathway and various heterofermentative and homofermentative pathways. However,
the discussion here will be limited to the Embden-Meyerhof pathway.
The entire glycolysis pathway can be separated into two phases[3] :
1. The Preparatory Phase - in which ATP is consumed and is hence also known as the investment phase
2. The Pay Off Phase - in which ATP is produced.

Overview
The overall reaction of glycolysis is:

D-[Glucose] [Pyruvate]

2
+ 2 [NAD]+ + 2 [ADP] + 2 [P]i + 2 [NADH] + 2 H+ + 2 [ATP] + 2 H2O

The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and
charges. Atom balance is maintained by the two phosphate (Pi) groups:[4]
• each exists in the form of a hydrogen phosphate anion (HPO42-), dissociating to contribute 2 H+ overall
Glycolysis 222

• each liberates an oxygen atom when it binds to an ADP (adenosine diphosphate) molecule, contributing 2 O
overall
Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxy groups
of ADP dissociate into -O- and H+, giving ADP3-, and this ion tends to exist in an ionic bond with Mg2+, giving
ADPMg-. ATP behaves identically except that it has four hydroxy groups, giving ATPMg2-. When these differences
along with the true charges on the two phosphate groups are considered together, the net charges of -4 on each side
are balanced.
For simple anaerobic fermentations,
the metabolism of one molecule of
glucose to two molecules of pyruvate
has a net yield of two molecules of
ATP. Most cells will then carry out
further reactions to 'repay' the used
NAD+ and produce a final product of
ethanol or lactic acid. Many bacteria
use inorganic compounds as hydrogen
acceptors to regenerate the NAD+.

Glycolysis Cells performing aerobic respiration

synthesize much more ATP, but not as
part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis. Eukaryotic aerobic
respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of
these are produced by a vastly different mechanism to the substrate-level phosphorylation in glycolysis.
The lower-energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater
flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of
anaerobically-oxidizable substrates, such as fatty acids, are found.

Elucidation of the pathway

In 1860, Louis Pasteur discovered that microorganisms are responsible for fermentation. In 1897, Eduard Buchner
found that extracts of certain cells can cause fermentation. In 1905, Arthur Harden and William Youngalong with
Nick Sheppard determined that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a
heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) are required
together for fermentation to proceed. The details of the pathway were eventually determined by 1940, with a major
input from Otto Meyerhof and some years later by Luis Leloir. The biggest difficulties in determining the intricacies
of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast
glycolytic reactions.
Glycolysis 223

Sequence of reactions

Preparatory phase
The first five steps are regarded as the preparatory (or investment) phase, since they consume energy to convert the
glucose into two three-carbon sugar phosphates[3] (G3P).

The first step in glycolysis is phosphorylation of glucose by a family of

D-Glucose (Glc) Hexokinase α-D-Glucose-6-phosphate
enzymes called hexokinases to form glucose 6-phosphate (G6P). This
(HK) (G6P)
reaction consumes ATP, but it acts to keep the glucose concentration low,
a transferase
promoting continuous transport of glucose into the cell through the plasma
membrane transporters. In addition, it blocks the glucose from leaking out -
the cell lacks transporters for G6P, and free diffusion out of the cell is ATP H+ +
prevented due to the charged nature of G6P. Glucose may alternatively be
ADP
from the phosphorolysis or hydrolysis of intracellular starch or glycogen.
In animals, an isozyme of hexokinase called glucokinase is also used in the
liver, which has a much lower affinity for glucose (Km in the vicinity of
normal glycemia), and differs in regulatory properties. The different
substrate affinity and alternate regulation of this enzyme are a reflection of
the role of the liver in maintaining blood sugar levels.
Cofactors: Mg2+

G6P is then rearranged into fructose 6-phosphate (F6P) by glucose

phosphate isomerase. Fructose can also enter the glycolytic α-D-Glucose Phosphoglucose β-D-Fructose 6-phosphate
pathway by phosphorylation at this point. 6-phosphate (G6P) isomerase (F6P)
an isomerase
The change in structure is an isomerization, in which the G6P has
been converted to F6P. The reaction requires an enzyme,
phosphohexose isomerase, to proceed. This reaction is freely
reversible under normal cell conditions. However, it is often driven
forward because of a low concentration of F6P, which is constantly
consumed during the next step of glycolysis. Under conditions of
high F6P concentration, this reaction readily runs in reverse. This
phenomenon can be explained through Le Chatelier's Principle.
Isomerization to a keto sugar is necessary for carbanion
stabilization in the fourth reaction step (below).
Glycolysis 224

The energy expenditure of another ATP in this step

β-D-Fructose 6-phosphate phosphofructokinase β-D-Fructose 1,6-bisphosphate
is justified in 2 ways: The glycolytic process (up to
(F6P) (PFK-1) (F1,6BP)
this step) is now irreversible, and the energy supplied
a transferase
destabilizes the molecule. Because the reaction
catalyzed by Phosphofructokinase 1 (PFK-1) is
ATP
coupled to the hydrolysis of ATP, an energetically H+ +
favorable step, it is, in essence, irreversible, and a ADP
different pathway must be used to do the reverse
conversion during gluconeogenesis. This makes the
reaction a key regulatory point (see below). This is
also the rate-limiting step.
Furthermore, the second phosphorylation event is
necessary to allow the formation of two charged
groups (rather than only one) in the subsequent step
of glycolysis, ensuring the prevention of free
diffusion of substrates out of the cell.
The same reaction can also be catalyzed by
pyrophosphate-dependent phosphofructokinase (PFP
or PPi-PFK), which is found in most plants, some
bacteria, archea, and protists, but not in animals. This
enzyme uses pyrophosphate (PPi) as a phosphate
donor instead of ATP. It is a reversible reaction,
[5]
increasing the flexibility of glycolytic metabolism.
A rarer ADP-dependent PFK enzyme variant has
[6]
been identified in archaean species.

Cofactors: Mg2+

Destabilizing the molecule in the previous

reaction allows the hexose ring to be split by β-D-Fructose 1,6-bisphosphate fructose D-glyceraldehyde Dihydroxyacetone
aldolase into two triose sugars, (F1,6BP) bisphosphate 3-phosphate phosphate (DHAP)
dihydroxyacetone phosphate, a ketone, and aldolase (GADP)
glyceraldehyde 3-phosphate, an aldehyde. (ALDO)
There are two classes of aldolases: class I a lyase
aldolases, present in animals and plants, and
+
class II aldolases, present in fungi and
bacteria; the two classes use different
mechanisms in cleaving the ketose ring.
Electrons delocalized in the carbon-carbon
bond cleavage associate with the alcohol
group. The resulting carbanion is stabilized
by the structure of the carbanion itself via
resonance charge distribution and by the
presence of a charged ion prosthetic group.
Glycolysis 225

Triosephosphate isomerase rapidly interconverts dihydroxyacetone

phosphate with glyceraldehyde 3-phosphate (GADP) that proceeds further Dihydroxyacetone triosephosphate D-glyceraldehyde
into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate (DHAP) isomerase (TPI) 3-phosphate (GADP)
phosphate down the same pathway as glyceraldehyde 3-phosphate, an isomerase
simplifying regulation.

Pay-off phase
The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules
ATP and NADH[3] . Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off
phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain
of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.

The triose sugars are dehydrogenated and inorganic phosphate is

glyceraldehyde glyceraldehyde D-1,3-bisphosphoglycerate
added to them, forming 1,3-bisphosphoglycerate.
3-phosphate phosphate (1,3BPG)
The hydrogen is used to reduce two molecules of NAD+, a hydrogen
(GADP) dehydrogenase
carrier, to give NADH + H+ for each triose.
(GAPDH)
Hydrogen atom balance and charge balance are both maintained an oxidoreductase
because the phosphate (Pi) group actually exists in the form of a
[4]
hydrogen phosphate anion (HPO42-), which dissociates to
contribute the extra H+ ion and gives a net charge of -3 on both
NAD+ + NADH +
sides.
Pi H+
Glycolysis 226

This step is the enzymatic transfer of a phosphate group from

1,3-bisphosphoglycerate phosphoglycerate 3-phosphoglycerate
1,3-bisphosphoglycerate to ADP by phosphoglycerate kinase, forming ATP
(1,3-BPG) kinase (PGK) (3-P-G)
and 3-phosphoglycerate. At this step, glycolysis has reached the break-even
a transferase
point: 2 molecules of ATP were consumed, and 2 new molecules have now
been synthesized. This step, one of the two substrate-level phosphorylation
steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP ATP
ADP), this reaction does not occur. Because ATP decays relatively quickly
when it is not metabolized, this is an important regulatory point in the
glycolytic pathway.
ADP actually exists as ADPMg-, and ATP as ATPMg2-, balancing the
charges at -5 both sides.
Cofactors: Mg2+

phosphoglycerate
kinase (PGK)

Phosphoglycerate mutase now forms

2-phosphoglycerate. 3-phosphoglycerate phosphoglycerate mutase 2-phosphoglycerate
(3PG) (PGM) (2PG)
a mutase

Enolase next forms phosphoenolpyruvate from 2-phosphoglycerate.

2-phosphoglycerate enolase phosphoenolpyruvate
Cofactors: 2 Mg2+: one "conformational" ion to coordinate with the (2PG) (ENO) (PEP)
carboxylate group of the substrate, and one "catalytic" ion that participates a lyase
in the dehydration.

H2O

enolase
(ENO)
Glycolysis 227

A final substrate-level phosphorylation now forms a molecule of pyruvate and a

phosphoenolpyruvate pyruvate kinase pyruvate
molecule of ATP by means of the enzyme pyruvate kinase. This serves as an
(PEP) (PK) (Pyr)
additional regulatory step, similar to the phosphoglycerate kinase step.
a transferase
Cofactors: Mg2+

ADP + ATP
H+

Regulation
Glycolysis is regulated by slowing down or speeding up certain steps in the glycolysis pathway. This is
accomplished by inhibiting or activating the enzymes that are involved. The steps that are regulated may be
determined by calculating the change in free energy, ΔG, for each step. If a step's products and reactants are in
equilibrium, then the step is assumed to not be regulated. Since the change in free energy is zero for a system at
equilibrium, any step with a free energy change near zero is not being regulated. If a step is being regulated, then
that step's enzyme is not converting reactants into products as fast as it could, resulting in a build-up of reactants,
which would be converted to products if the enzyme were operating faster. Since the reaction is thermodynamically
favorable, the change in free energy for the step will be negative. A step with a large negative change in free energy
is assumed to be regulated.

Free energy changes

Concentrations of metabolites in erythrocytes[7]

Compound Concentration / mM

glucose 5.0

glucose-6-phosphate 0.083

fructose-6-phosphate 0.014

fructose-1,6-bisphosphate 0.031

dihydroxyacetone phosphate 0.14

glyceraldehyde-3-phosphate 0.019

1,3-bisphosphoglycerate 0.001

2,3-bisphosphoglycerate 4.0

3-phosphoglycerate 0.12

2-phosphoglycerate 0.03

phosphoenolpyruvate 0.023

pyruvate 0.051

ATP 1.85

ADP 0.14

Pi 1.0
Glycolysis 228

The change in free energy for each step of glycolysis estimated from the
concentration of metabolites in an erythrocyte.

The change in free energy, ΔG, for each step in the glycolysis pathway can be calculated using ΔG = ΔG°' + RTln Q,
where Q is the reaction quotient. This requires knowing the concentrations of the metabolites. All of these values are
available for erythrocytes, with the exception of the concentrations of NAD+ and NADH. The ratio of NAD+ to
NADH in the cytoplasm is approximately 1000 in the step 6, something that makes the oxidation of
glyceraldehyde-3-phosphate more favourable.
Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change
can be calculated. (Neglecting this is very common - the delta G of ATP hydrolysis in cells is not the standard free
energy change of ATP hydrolysis quoted in textbooks).

Change in free energy for each step of glycolysis[8]

Step Reaction ΔG°' / (kJ/mol) ΔG / (kJ/mol)

1 -16.7 -34
glucose + ATP4- → glucose-6-phosphate2- + ADP3- + H+

2 1.67 -2.9
glucose-6-phosphate2- → fructose-6-phosphate2-

3 -14.2 -19
fructose-6-phosphate2- + ATP4- → fructose-1,6-bisphosphate4- + ADP3- + H+

4 fructose-1,6-bisphosphate4- → dihydroxyacetone phosphate2- + glyceraldehyde-3-phosphate2- 23.9 -0.23

5 7.56 2.4
dihydroxyacetone phosphate2- → glyceraldehyde-3-phosphate2-

6 6.30 -1.29
glyceraldehyde-3-phosphate2- + Pi2- + NAD+ → 1,3-bisphosphoglycerate4- + NADH + H+

7 -18.9 0.09
1,3-bisphosphoglycerate4- + ADP3- → 3-phosphoglycerate3- + ATP4-

8 4.4 0.83
3-phosphoglycerate3- → 2-phosphoglycerate3-

9 1.8 1.1
2-phosphoglycerate3- → phosphoenolpyruvate3- + H2O

10 -31.7 -23.0
phosphoenolpyruvate3- + ADP3- + H+ → pyruvate- + ATP4-

From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the
steps in glycolysis are in equilibrium for that cell type. Three of the steps — the ones with large negative free energy
changes — are not in equilibrium and are referred to as irreversible; such steps are often subject to regulation.
Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase
the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone
Glycolysis 229

phosphate by the enzyme triose phosphate isomerase, which is a catalytically perfect enzyme; its rate is so fast that
the reaction can be assumed to be in equilibrium. The fact that ΔG is not zero indicates that the actual concentrations
in the erythrocyte are not accurately known.

Biochemical logic
The existence of more than one point of regulation indicates that intermediates between those points enter and leave
the glycolysis pathway by other processes. For example, in the first regulated step, hexokinase converts glucose into
glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into
glucose storage molecules, such as glycogen or starch. The reverse reaction, breaking down, e.g., glycogen, produces
mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced
can enter glycolysis after the first control point.
In the second regulated step (the third step of glycolysis), phosphofructokinase converts fructose-6-phosphate into
fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone
phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into
glycerol-3-phosphate, which can be used to form triglycerides.[9] On the converse, triglycerides can be broken down
into fatty acids and glycerol; the latter, in turn, can be converted into dihydroxyacetone phosphate, which can enter
glycolysis after the second control point.

Regulation
The three regulated enzymes are hexokinase, phosphofructokinase, and pyruvate kinase.
The flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The
rate in liver is regulated to meet major cellular needs: (1) the production of ATP, (2) the provision of building blocks
for biosynthetic reactions, and (3) to lower blood glucose, one of the major functions of the liver. When blood sugar
falls, glycolysis is halted in the liver to allow the reverse process, gluconeogenesis. In glycolysis, the reactions
catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase are effectively irreversible in most organisms. In
metabolic pathways, such enzymes are potential sites of control, and all three enzymes serve this purpose in
glycolysis.

Hexokinase

In animals, regulation of blood glucose levels by the pancreas in

conjunction with the liver is a vital part of homeostasis. In liver cells,
extra G6P (glucose-6-phosphate) may be converted to G1P for
conversion to glycogen, or it is alternatively converted by glycolysis to
acetyl-CoA and then citrate. Excess citrate is exported to the cytosol,
where ATP citrate lyase will regenerate acetyl-CoA and OAA. The
acetyl-CoA is then used for fatty acid synthesis and cholesterol
synthesis, two important ways of utilizing excess glucose when its [10]
Yeast hexokinase B. PDB 1IG8 .
concentration is high in blood. Liver contains both hexokinase and
glucokinase; the latter catalyses the phosphorylation of glucose to G6P
and is not inhibited by G6P. Thus, it allows glucose to be converted into glycogen, fatty acids, and cholesterol even
when hexokinase activity is low.[11] This is important when blood glucose levels are high. During hypoglycemia, the
glycogen can be converted back to G6P and then converted to glucose by the liver-specific enzyme glucose
6-phosphatase. This reverse reaction is an important role of liver cells to maintain blood sugars levels during fasting.
This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions.
Glycolysis 230

Phosphofructokinase

Phosphofructokinase is an important control point in the glycolytic

pathway, since it is one of the irreversible steps and has key allosteric
effectors, AMP and fructose 2,6-bisphosphate (F2,6BP).
Fructose 2,6-bisphosphate (F2,6BP) is a very potent activator of
phosphofructokinase (PFK-1), which is synthesised when F6P is
phosphorylated by a second phosphofructokinase (PFK2). In liver,
when blood sugar is low and glucagon elevates cAMP, PFK2 is
phosphorylated by protein kinase A. The phosphorylation inactivates
PFK2, and another domain on this protein becomes active as fructose
2,6-bisphosphatase, which converts F2,6BP back to F6P. Both
Bacillus stearothermophilus phosphofructokinase.
PDB 6PFK
[12]
.
glucagon and epinephrine cause high levels of cAMP in the liver. The
result of lower levels of liver fructose-2,6-bisphosphate is a decrease in
activity of phosphofructokinase and an increase in activity of fructose 1,6-bisphosphatase, so that gluconeogenesis
(in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since
the response of the liver to these hormones is to release glucose to the blood.

ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much
higher than those of AMP, typically 100-fold higher,[13] but the concentration of ATP does not change more than
about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP.[14] Thus,
the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in
energy charge in the cell.
Citrate inhibits phosphofructokinase when tested in vitro by enhancing the inhibitory effect of ATP. However, it is
doubtful that this is a meaningful effect in vivo, because citrate in the cytosol is utilized mainly for conversion to
acetyl-CoA for fatty acid and cholesterol synthesis.

Pyruvate kinase

This enzyme catalyzes the last step of glycolysis, in which pyruvate

and ATP are formed. Regulation of this enzyme is discussed in the
main topic, pyruvate kinase.

Post-glycolysis processes
The overall process of glycolysis is:
glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 pyruvate + 2 NADH + 2
H+ + 2 ATP + 2 H2O
If glycolysis were to continue indefinitely, all of the NAD+ would be
[15]
used up, and glycolysis would stop. To allow glycolysis to continue, Yeast pyruvate kinase. PDB 1A3W .

organisms must be able to oxidize NADH back to NAD+.

Fermentation
One method of doing this is to simply have the pyruvate do the oxidation; in this process, the pyruvate is converted
to lactate (the conjugate base of lactic acid) in a process called lactic acid fermentation:
pyruvate + NADH + H+ → lactate + NAD+
Glycolysis 231

This process occurs in the bacteria involved in making yogurt (the lactic acid causes the milk to curdle). This process
also occurs in animals under hypoxic (or partially-anaerobic) conditions, found, for example, in overworked muscles
that are starved of oxygen, or in infarcted heart muscle cells. In many tissues, this is a cellular last resort for energy;
most animal tissue cannot maintain anaerobic respiration for an extended length of time.
Some organisms, such as yeast, convert NADH back to NAD+ in a process called ethanol fermentation. In this
process, the pyruvate is converted first to acetaldehyde and carbon dioxide, then to ethanol.
Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen. This anaerobic fermentation
allows many single-cell organisms to use glycolysis as their only energy source.

Anaerobic respiration
In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate. However,
anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in cellular respiration:
nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and
elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium
compounds.

Aerobic respiration
In aerobic organisms, a complex mechanism has been developed to use the oxygen in air as the final electron
acceptor of respiration.
• First, pyruvate is converted to acetyl-CoA and CO2 within the mitochondria in a process called pyruvate
decarboxylation.
• Second, the acetyl-CoA enters the citric acid cycle, also known as Krebs Cycle, where it is fully oxidized to
carbon dioxide and water, producing yet more NADH.
• Third, the NADH is oxidized to NAD+ by the electron transport chain, using oxygen as the final electron
acceptor. This process creates a "hydrogen ion gradient" across the inner membrane of the mitochondria.
• Fourth, the proton gradient is used to produce a large amount of ATP in a process called oxidative
phosphorylation.

Intermediates for other pathways

This article concentrates on the catabolic role of glycolysis with regard to converting potential chemical energy to
usable chemical energy during the oxidation of glucose to pyruvate.many of the metabolites in the glycolytic
pathway are also used by anabolic pathways, and, as a consequence, flux through the pathway is critical to maintain
a supply of carbon skeletons for biosynthesis.
In addition, not all carbon entering the pathway leaves as pyruvate and may be extracted at earlier stages to provide
carbon compounds for other pathways.
These metabolic pathways are all strongly reliant on glycolysis as a source of metabolites:
• Gluconeogenesis
• Lipid metabolism
• Pentose phosphate pathway
• Citric acid cycle, which in turn leads to:
• Amino acid synthesis
• Nucleotide synthesis
• Tetrapyrrole synthesis
From an anabolic metabolism perspective, the NADH has a role to drive synthetic reactions, doing so by directly or
indirectly reducing the pool of NADP+ in the cell to NADPH, which is another important reducing agent for
Glycolysis 232

biosynthetic pathways in a cell.

Glycolysis in disease

Genetic diseases
Glycolytic mutations are generally rare due to importance of the metabolic pathway, this means that the majority of
occurring mutations result in an inability for the cell to respire, and therefore cause the death of the cell at an early
stage. However, some mutations are seen with one notable example being Pyruvate kinase deficiency, leading to
chronic hemolytic anemia.

Cancer
Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of
their normal tissues of origin. This phenomenon was first described in 1930 by Otto Warburg and is referred to as the
Warburg effect. The Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial
metabolism, rather than because of uncontrolled growth of cells. A number of theories have been advanced to
explain the Warburg effect.
This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is
utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of
2-18F-2-deoxyglucose (FDG) (a radioactive modified hexokinase substrate) with positron emission tomography
(PET).[16] [17]
There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus
starving cancerous cells in various new ways, including a ketogenic diet.

Alzheimer's disease
Disfunctioning glycolysis or glucose metabolism in fronto-temporo-parietal and cingulate cortices has been
associated with Alzheimer's disease,[18] probably due to the decreased amyloid β (1-42) (Aβ42) and increased tau,
phosphorylated tau in cerebrospinal fluid (CSF) [19]

Alternative nomenclature
Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them
are common to other pathways, such as the Calvin cycle.

This article Alternative names Alternative nomenclature

1 glucose Glc dextrose

3 fructose 6-phosphate F6P

4 fructose 1,6-bisphosphate F1,6BP fructose 1,6-diphosphate FBP, FDP, F1,6DP

5 dihydroxyacetone phosphate DHAP glycerone phosphate

6 glyceraldehyde 3-phosphate GADP 3-phosphoglyceraldehyde PGAL, G3P, GALP,GAP,TP

7 1,3-bisphosphoglycerate 1,3BPG glycerate PGAP, BPG, DPG

1,3-bisphosphate,
glycerate 1,3-diphosphate,
1,3-diphosphoglycerate

8 3-phosphoglycerate 3PG glycerate 3-phosphate PGA, GP

9 2-phosphoglycerate 2PG glycerate 2-phosphate

10 phosphoenolpyruvate PEP
Glycolysis 233

11 pyruvate Pyr pyruvic acid

References
[1] Webster's New International Dictionary of the English Language, 2nd ed. (1937) Merriam Company, Springfield, Mass.
[2] Romano AH, Conway T. (1996) Evolution of carbohydrate metabolic pathways. Res Microbiol. 147(6-7):448-55 PMID 9084754
[3] Glycolysis - Animation and Notes (http:/ / pharmaxchange. info/ press/ 2011/ 09/ glycolysis-animation-and-notes/ )
[4] Lane, A. N.; Fan, T. W. -M.; Higashi, R. M. (2009). "Metabolic acidosis and the importance of balanced equations". Metabolomics 5 (2):
163–165. doi:10.1007/s11306-008-0142-2.
[5] Reeves, R. E.; South D. J., Blytt H. J. and Warren L. G. (1974). "Pyrophosphate: D-fructose 6-phosphate 1-phosphotransferase. A new
enzyme with the glycolytic function 6-phosphate 1-phosphotransferase". J Biol Chem 249 (24): 7737–7741. PMID 4372217.
[6] Selig, M.; Xavier K. B., Santos H. and Schönheit P. (1997). "Comparative analysis of Embden-Meyerhof and Entner-Doudoroff glycolytic
pathways in hyperthermophilic archaea and the bacterium Thermotoga". Arch Microbiol 167 (4): 217–232. PMID 9075622.
[7] Garrett, R.; Grisham, C. M. (2005). Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. p. 584. ISBN 0-534-49011-6.
[8] Garrett, R.; Grisham, C. M. (2005). Biochemistry (3rd ed.). Belmont, CA: Thomson Brooks/Cole. pp. 582–583. ISBN 0-534-49011-6.
[9] Berg, J. M.; Tymoczko, J. L.; Stryer, L. (2007). Biochemistry (6th ed.). New York: Freeman. p. 622. ISBN 0-534-49011-6.
[10] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1IG8
[11] Voet D., and Voet J. G. (2004). Biochemistry 3rd Edition (New York, John Wiley & Sons, Inc.)
[12] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=6PFK
[13] Beis I., and Newsholme E. A. (1975). The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting
muscles from vertebrates and invertebrates. Biochem J 152, 23-32.
[14] Voet D., and Voet J. G. (2004). Biochemistry 3rd Edition (New York, John Wiley & Sons, Inc.).
[15] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1A3W
[16] "PET Scan: PET Scan Info Reveals ..." (http:/ / www. petscaninfo. com/ ). . Retrieved December 5, 2005.
[17] "4320139 549..559" (http:/ / biogenomica. com/ PDFs/ PauwelsPETandHexokinase. pdf). . Retrieved December 5, 2005.
[18] Hunt, A . et al.; Schonknecht, P; Henze, M; Seidl, U; Haberkorn, U; Schroder, J (2007). "Reduced cerebral glucose metabolism in patients at
risk for Alzheimer's disease". Psychiatry Research: Neuroimaging 155 (2): 147–154. doi:10.1016/j.pscychresns.2006.12.003.
PMID 17524628.
[19] Hunt, A . et al.; Van Der Flier, WM; Blankenstein, MA; Bouwman, FH; Van Kamp, GJ; Barkhof, F; Scheltens, P (2008). "CSF and MRI
markers independently contribute to the diagnosis of Alzheimer's disease". Neurobiology of Aging 29 (5): 669–675.
doi:10.1016/j.neurobiolaging.2006.11.018. PMID 17208336.

External links
• A Detailed Glycolysis Animation provided by [[IUBMB (http://www.iubmb-nicholson.org/swf/glycolysis.
swf)]] ( Adobe Flash (http://get.adobe.com/flashplayer/) Required)
• The Glycolytic enzymes in Glycolysis (http://nist.rcsb.org/pdb/molecules/pdb50_1.html) at Protein Data
Bank
• Glycolytic cycle with animations (http://www.wdv.com/CellWorld/Biochemistry/Glycolytic) at wdv.com
• Metabolism, Cellular Respiration and Photosynthesis - The Virtual Library of Biochemistry and Cell Biology
(http://www.biochemweb.org/metabolism.shtml) at biochemweb.org
• notes on glycolysis (http://www.rahulgladwin.com/blog/2007/01/notes-on-glycolysis.html) at
rahulgladwin.com
• The chemical logic behind glycolysis (http://www2.ufp.pt/~pedros/bq/glycolysis.htm) at ufp.pt
• Expasy biochemical pathways poster (http://www.expasy.org/tools/pathways/boehringer_legends.html) at
ExPASy
• Mnemonic at medicalmnemonics.com 317 5468 (http://www.medicalmnemonics.com/cgi-bin/lookup.
cfm?id1=317&id2=5468&id3=&id4=)
Gluconeogenesis 234

Gluconeogenesis
Gluconeogenesis (abbreviated GNG) is a metabolic pathway that results
in the generation of glucose from non-carbohydrate carbon substrates
such as lactate, glycerol, and glucogenic amino acids.
It is one of the two main mechanisms humans and many other animals
use to keep blood glucose levels from dropping too low (hypoglycemia).
The other means of maintaining blood glucose levels is through the
degradation of glycogen (glycogenolysis).[1]
Gluconeogenesis is a ubiquitous process, present in plants, animals,
fungi, bacteria, and other microorganisms.[2] In animals, gluconeogenesis
takes place mainly in the liver and, to a lesser extent, in the cortex of
kidneys. This process occurs during periods of fasting, starvation,
low-carbohydrate diets, or intense exercise and is highly endergonic. For
example, the pathway leading from pyruvate to glucose-6-phosphate
requires 4 molecules of ATP and 2 molecules of GTP. Gluconeogenesis
is often associated with ketosis. Gluconeogenesis is also a target of
therapy for type II diabetes, such as metformin, which inhibits glucose
formation and stimulates glucose uptake by cells.[3]

Entering the pathway

Lactate is transported back to the liver where it is converted into
pyruvate by the Cori cycle using the enzyme lactate dehydrogenase.
Pyruvate, the first designated substrate of the gluconeogenic pathway, Gluconeogenesis pathway with key molecules

can then be used to generate glucose.[4] and enzymes. Many steps are the opposite of
those found in the glycolysis.

All citric acid cycle intermediates, through

conversion to oxaloacetate, amino acids
other than lysine or leucine, and glycerol
can also function as substrates for
gluconeogenesis.[4] Transamination or
deamination of amino acids facilitates
entering of their carbon skeleton into the
cycle directly (as pyruvate or oxaloacetate),
or indirectly via the citric acid cycle.

Whether fatty acids can be converted into

glucose in animals has been a longstanding
question in biochemistry.[6] It is known that
odd-chain fatty acids can be oxidized to
yield propionyl CoA, a precursor for
succinyl CoA, which can be converted to
Catabolism of proteinogenic amino acids. Amino acids are classified according the
[5]
abilities of their products to enter gluconeogenesis: Glucogenic amino acids
have this abilityKetogenic amino acids do not. These products may still be used for
ketogenesis or lipid synthesis.Some amino acids are catabolized into both
glucogenic and ketogenic products.
Gluconeogenesis 235

pyruvate and enter into gluconeogenesis. In plants, specifically seedlings, the glyoxylate cycle can be used to convert
fatty acids (acetate) into the primary carbon source of the organism. The glyoxylate cycle produces four-carbon
dicarboxylic acids that can enter gluconeogenesis.[4]
In 1995, researchers identified the glyoxylate cycle in nematodes.[7] In addition, the glyoxylate enzymes malate
synthase and isocitrate lyase have been found in animal tissues.[8] Genes coding for malate synthase gene have been
identified in other [metazoans] including arthropods, echinoderms, and even some vertebrates. Mammals found to
possess these genes include monotremes (platypus) and marsupials (opossum) but not placental mammals. Genes for
isocitrate lyase are found only in nematodes, in which, it is apparent, they originated in horizontal gene transfer from
bacteria.
The existence of glyoxylate cycles in humans has not been established, and it is widely held that fatty acids cannot
be converted to glucose in humans directly. However, carbon-14 has been shown to end up in glucose when it is
supplied in fatty acids.[9] Despite these findings, it is considered unlikely that the 2-carbon acetyl-CoA derived from
the oxidation of fatty acids would produce a net yield of glucose via the citric acid cycle.[6]
Glycerol, which is a part of the triacylglycerol molecule, can be used in gluconeogenesis.

Location
In humans, gluconeogenesis is restricted to the liver and to a lesser extent the kidney.[10]
In all species, the formation of oxaloacetate from pyruvate and TCA cycle intermediates is restricted to the
mitochondrion, and the enzymes that convert PEP to glucose are found in the cytosol.[11] The location of the enzyme
that links these two parts of gluconeogenesis by converting oxaloacetate to PEP, PEP carboxykinase, is variable by
species: it can be found entirely within the mitochondria, entirely within the cytosol, or dispersed evenly between the
two, as it is in humans.[11] Transport of PEP across the mitochondrial membrane is accomplished by dedicated
transport proteins; however no such proteins exist for oxaloacetate.[11] Therefore species that lack
intra-mitochondrial PEP, oxaloacetate must be converted into malate or asparate, exported from the mitochondrion,
and converted back into oxaloacetate in order to allow gluconeogenesis to continue.[11]

Pathway
Gluconeogenesis is a pathway consisting of eleven enzyme-catalyzed reactions. The pathway can begin in the
mitochondria or cytoplasm, depending on the substrate being used. Many of the reactions are the reversible steps
found in glycolysis.
• Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate through carboxylation of
pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This
enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in the liver) and inhibited by high
levels of ADP.
• Oxaloacetate is reduced to malate using NADH, a step required for transport out of the mitochondria.
• Malate is oxidized to oxaloacetate using NAD+ in the cytoplasm, where the remaining steps of gluconeogenesis
occur.
• Oxaloacetate is decarboxylated and phosphorylated to produce phosphoenolpyruvate by phosphoenolpyruvate
carboxykinase. One molecule of GTP is hydrolyzed to GDP during this reaction.
• The next steps in the reaction are the same as reversed glycolysis. However, fructose-1,6-bisphosphatase converts
fructose-1,6-bisphosphate to fructose 6-phosphate, requiring one water molecule and releasing one phosphate.
This is also the rate-limiting step of gluconeogenesis.
• Glucose-6-phosphate is formed from fructose 6-phosphate by phosphoglucoisomerase. Glucose-6-phosphate can
be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse
in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which
Gluconeogenesis 236

intracellular glucose levels are controlled by cells.

• The final reaction of gluconeogenesis, the formation of glucose, occurs in the lumen of the endoplasmic
reticulum, where glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose. Glucose is
shuttled into the cytosol by glucose transporters located in the membrane of the endoplasmic reticulum.

Regulation
While most steps in gluconeogenesis are the reverse of those found in glycolysis, three regulated and strongly
exergonic reactions are replaced with more kinetically favorable reactions. Hexokinase/glucokinase,
phosphofructokinase, and pyruvate kinase enzymes of glycolysis are replaced with glucose-6-phosphatase,
fructose-1,6-bisphosphatase, and PEP carboxykinase. This system of reciprocal control allow glycolysis and
gluconeogenesis to inhibit each other and prevent the formation of a futile cycle.
The majority of the enzymes responsible for gluconeogenesis are found in the cytoplasm; the exceptions are
mitochondrial pyruvate carboxylase and, in animals, phosphoenolpyruvate carboxykinase. The latter exists as an
isozyme located in both the mitochondrion and the cytosol.[12] The rate of gluconeogenesis is ultimately controlled
by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal transduction by
cAMP and its phosphorylation.
Most factors that regulate the activity of the gluconeogenesis pathway do so by inhibiting the activity or expression
of key enzymes. However, both acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and
fructose-1,6-bisphosphatase, respectively). Due to the reciprocal control of the cycle, acetyl-CoA and citrate also
have inhibitory roles in the activity of pyruvate kinase.
Global control of gluconeogenesis is mediated by glucagon (released when blood glucose is low); it triggers
phosphorylation of enzymes and regulatory proteins by Protein Kinase A (a cyclic AMP regulated kinase) resulting
in inhibition of glycolysis and stimulation of gluconeogenesis, thus bringing blood glucose levels up.[13]

References
[1] Silva, Pedro. "The Chemical Logic Behind Gluconeogenesis" (http:/ / www2. ufp. pt/ ~pedros/ bq/ gng. htm). . Retrieved September 8, 2009.
[2] David L Nelson and Michael M Cox (2000). Lehninger Principles of Biochemistry. USA: Worth Publishers. pp. 724. ISBN 1-57259-153-6.
[3] Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G (2000).
"Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes". Diabetes 49 (12): 2063–9.
doi:10.2337/diabetes.49.12.2063. PMC 2995498. PMID 11118008. Free full text (http:/ / diabetes. diabetesjournals. org/ cgi/ reprint/ 49/ 12/
2063)PDF (82 KiB)
[4] Garrett, Reginald H.; Charles M. Grisham (2002). Principles of Biochemistry with a Human Focus. USA: Brooks/Cole, Thomson Learning.
pp. 578, 585. ISBN 0-03-097369-4.
[5] Chapter 20 (Amino Acid Degradation and Synthesis) in: Denise R., PhD. Ferrier. Lippincott's Illustrated Reviews: Biochemistry (Lippincott's
Illustrated Reviews). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2265-9.
[6] Figueiredo, Luis F., Stefan Schuster, Christoph Kaleta, David A. Fell (2009). "Can sugars be produced from fatty acids? A test case for
pathway analysis tools". Bioinformatics 25 (1): 152–158. doi:10.1093/bioinformatics/btn621. PMID 19117076.
[7] Liu, F., et al. (1995). "Bifunctional glyoxylate cycle protein of Caenorhabditis elegans: a developmentally regulated protein of intestine and
muscle". Developmental Biology 169 (2): 399–414. doi:10.1006/dbio.1995.1156. PMID 7781887.
[8] Fyodor A Kondrashov, Eugene V Koonin, Igor G Morgunov, Tatiana V Finogenova, Marie N Kondrashova (2006). "Evolution of glyoxylate
cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation". Biology Direct 1: 31.
doi:10.1186/1745-6150-1-31. PMC 1630690. PMID 17059607.
[9] Weinman, E.O., et al. (1957). "Conversion of fatty acids to carbohydrate: application of isotopes to this problem and role of the Krebs cycle
as a synthetic pathway". Physiol. Rev. 37 (2): 252–72. PMID 13441426.
[10] Widmaier, Eric (2006). Vander's Human Physiology. McGraw Hill. pp. 96. ISBN 0-07-282741-6.
[11] Voet, Donald; Judith Voet, Charlotte Pratt (2008). Fundamentals of Biochemistry. John Wiley & Sons Inc. p. 556. ISBN 978-0470-12930-2.
[12] Chakravarty, K., Cassuto, H., Resef, L., & Hanson, R.W. (2005) Factors that control the tissue-specific transcription of the gene for
phosphoenolpyruvate carboxykinase-C. Critical Reviews of Biochemistry and Molecular Biology, 40(3), 129-154.
[13] http:/ / rpi. edu/ dept/ bcbp/ molbiochem/ MBWeb/ mb1/ part2/ gluconeo. htm - Gluconeogenesis, by Diwan. Cites no sources.
Gluconeogenesis 237

External links
• Overview at indstate.edu (http://themedicalbiochemistrypage.org/gluconeogenesis.html)
• Interactive diagram at uakron.edu (http://ull.chemistry.uakron.edu/Pathways/gluconeogenesis/index.html#)
• The chemical logic behind gluconeogenesis (http://homepage.ufp.pt/pedros/bq/gng.htm)

Glycogen
Glycogen is a molecule that serves as the
secondary long-term energy storage in
animal and fungal cells, with the primary
energy stores being held in adipose tissue.
Glycogen is made primarily by the liver and
the muscles, but can also be made by
glycogenesis within the brain and
stomach.[2]

Glycogen is the analogue of starch, a

glucose polymer in plants, and is sometimes
referred to as animal starch, having a
similar structure to amylopectin but more
extensively branched and compact than
starch. Glycogen is a polymer of α(1→4)
glycosidic bonds linked, with
α(1→6)-linked branches. Glycogen is found
in the form of granules in the
cytosol/cytoplasm in many cell types, and
plays an important role in the glucose cycle. Schematic 2-D cross-sectional view of glycogen. A core protein of glycogenin is
surrounded by branches of glucose units. The entire globular granule may contain
Glycogen forms an energy reserve that can [1]
approximately 30,000 glucose units.
be quickly mobilized to meet a sudden need
for glucose, but one that is less compact
than the energy reserves of triglycerides (lipids).

In the liver hepatocytes, glycogen can compose up to eight percent of the fresh weight (100–120 g in an adult) soon
after a meal.[3] Only the glycogen stored in the liver can be made accessible to other organs. In the muscles,
glycogen is found in a low concentration (one to two percent of the muscle mass). However, the amount of glycogen
stored in the body—especially within the muscles, liver, and red blood cells[4] [5] [6] —mostly depends on physical
training, basal metabolic rate, and eating
Glycogen 238

habits such as intermittent fasting. Small

amounts of glycogen are found in the
kidneys, and even smaller amounts in
certain glial cells in the brain and white
blood cells. The uterus also stores glycogen
during pregnancy to nourish the embryo.[7]

Function and regulation of

liver glycogen
As a meal containing carbohydrates is eaten
and digested, blood glucose levels rise, and
the pancreas secretes insulin. Glucose from
the portal vein enters liver cells
(hepatocytes). Insulin acts on the
hepatocytes to stimulate the action of
several enzymes, including glycogen
synthase. Glucose molecules are added to
the chains of glycogen as long as both
A view of the atomic structure of a single branched strand of glucose units in a
insulin and glucose remain plentiful. In this glycogen molecule.
postprandial or "fed" state, the liver takes in
more glucose from the blood than it releases.

After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis
stops. When it is needed for energy, glycogen is broken down and converted again to glucose. Glycogen
phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver
glycogen will be the primary source of blood glucose to be used by the rest of the body for fuel.
Glucagon is another hormone produced by the pancreas, which in many respects serves as a counter-signal to insulin.
In response to insulin level below normal (when blood levels of glucose begin to fall below the normal range),
glucagon is secreted in increasing amounts to stimulate glycogenolysis and gluconeogenesis pathways.

In muscle and other cells

Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. Other
cells that contain small amounts use it locally as well. Muscle cells lack the enzyme glucose-6-phosphatase, which is
required to pass glucose into the blood, so the glycogen they store is destined for internal use and is not shared with
other cells. (This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into
glucose and send it through the blood stream as fuel for the brain or muscles). Glycogen is also a suitable storage
substance due to its insolubility in water, which means it does not affect the osmotistic levels and pressure of a cell.
Glycogen 239

Glycogen depletion and endurance exercise

Long-distance athletes such as marathon runners, cross-country skiers, and cyclists often experience glycogen
depletion, where almost all of the athlete's glycogen stores are depleted after long periods of exertion without enough
energy consumption. This phenomenon is referred to as "hitting the wall". In marathon runners, it normally happens
around the 20-mile (32 km) point of a marathon, depending on the size of the runner and the race course.
Glycogen depletion can be forestalled in four possible ways. First, during exercise carbohydrates with the highest
possible rate of conversion to blood glucose per time (high Glycemic Index) are ingested continuously. The best
possible outcome of this strategy replaces about 35% of glucose consumed at heart rates above about 80% of
maximum. Second, through training, the body can be conditioned to burn fat earlier, faster, and more efficiently,
sparing carbohydrate use from all sources. Third, by consuming foods low on the glycemic index for 12–18 hours
before the event, the liver and muscles will store the resulting slow but steady stream of glucose as glycogen, instead
of fat. This process is known as carbohydrate loading. .
When experiencing glycogen debt, athletes often experience extreme fatigue to the point that it is difficult to move.
As a reference, the very best professional cyclists in the world will usually finish a 4-5hr stage race right at the limit
of glycogen depletion using the first 3 strategies.
A study published in the Journal of Applied Physiology (online May 8, 2008) suggests that, when athletes ingest
both carbohydrate and caffeine following exhaustive exercise, their glycogen is replenished more rapidly.[8] [9]

Disorders of glycogen metabolism

The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of
abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal
glucose metabolism usually normalizes glycogen metabolism as well.
In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin level prevents the
glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of
hypoglycemia.
Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or
breakdown. These are collectively referred to as glycogen storage diseases.

Synthesis
Glycogen synthesis is, unlike its
breakdown, endergonic. This means
that glycogen synthesis requires the
input of energy. Energy for glycogen
synthesis comes from UTP, which
reacts with glucose-1-phosphate,
forming UDP-glucose, in a reaction
catalysed by UDP-glucose
pyrophosphorylase. Glycogen is
synthesized from monomers of Glycogen Structure Segment
UDP-glucose by the enzyme glycogen
synthase, which progressively lengthens the glycogen chain with (α1→4) bonded glucose. As glycogen synthase can
lengthen only an existing chain, the protein glycogenin is needed to initiate the synthesis of glycogen. The
glycogen-branching enzyme, amylo (α1→4) to (α1→6) transglycosylase, catalyzes the transfer of a terminal
Glycogen 240

fragment of 6-7 glucose residues from a nonreducing end to the C-6 hydroxyl group of a glucose residue deeper into
the interior of the glycogen molecule. The branching enzyme can act upon only a branch having at least 11 residues,
and the enzyme may transfer to the same glucose chain or adjacent glucose chains.

Breakdown
Glycogen is cleaved from the nonreducing ends of the chain by the enzyme glycogen phosphorylase to produce
monomers of glucose-1-phosphate, which is then converted to glucose 6-phosphate by phosphoglucomutase. A
special debranching enzyme is needed to remove the alpha(1-6) branches in branched glycogen and reshape the
chain into linear polymer. The G6P monomers produced have three possible fates:

• G6P can continue on the glycolysis pathway and be used as fuel.

• G6P can enter the pentose phosphate pathway via the enzyme Glucose-6-phosphate dehydrogenase to produce
NADPH and 5-carbon sugars.
• In the liver and kidney, G6P can be dephosphorylated back to Glucose by the enzyme Glucose 6-phosphatase.
This is the final step in the gluconeogenesis pathway.

References
[1] Page 12 in: (http:/ / books. google. dk/ books?id=SRptlOx7yj4C& printsec=frontcover& hl=en) Exercise physiology: energy, nutrition, and
human performance By William D. McArdle, Frank I. Katch, Victor L. Katch Edition: 6, illustrated Published by Lippincott Williams &
Wilkins, 2006 ISBN 0781749905, 9780781749909, 1068 pages
[2] Anatomy and Physiology. Saladin, Kenneth S. McGraw-Hill, 2007.
[3] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[4] Moses SW, Bashan N, Gutman A (December 1972). "Glycogen metabolism in the normal red blood cell" (http:/ / www. bloodjournal. org/
cgi/ pmidlookup?view=long& pmid=5083874). Blood 40 (6): 836–43. PMID 5083874. .
[5] http:/ / jeb. biologists. org/ cgi/ reprint/ 129/ 1/ 141. pdf
[6] Miwa I, Suzuki S (November 2002). "An improved quantitative assay of glycogen in erythrocytes". Annals of Clinical Biochemistry 39 (Pt 6):
612–3. doi:10.1258/000456302760413432. PMID 12564847.
[7] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[8] Pedersen DJ, Lessard SJ, Coffey VG, et al. (July 2008). "High rates of muscle glycogen resynthesis after exhaustive exercise when
carbohydrate is coingested with caffeine". Journal of Applied Physiology 105 (1): 7–13. doi:10.1152/japplphysiol.01121.2007.
PMID 18467543.
[9] Post-exercise Caffeine Helps Muscles Refuel (http:/ / newswise. com/ articles/ view/ 542216/ ) Newswise, Retrieved on July 6, 2008.
Glycogen 241

External links
• Glycogen detection using Periodic Acid Schiff Staining (http://www.histochem.net/protocol periodic acid
schiff.htm)
• Glycogen storage disease - McArdle's Disease Website (http://mcardlesdisease.org)
• MeSH Glycogen (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Glycogen)

Pentose phosphate pathway

The pentose phosphate pathway (also called the
phosphogluconate pathway and the hexose monophosphate
shunt) is a process that generates NADPH and pentoses
(5-carbon sugars). There are two distinct phases in the pathway.
The first is the oxidative phase, in which NADPH is generated,
and the second is the non-oxidative synthesis of 5-carbon
sugars. This pathway is an alternative to glycolysis. While it
does involve oxidation of glucose, its primary role is anabolic
rather than catabolic. For most organisms, it takes place in the
cytosol; in plants, most steps take place in plastids.[1]

Outcome
The primary results of the Pathway are:
• The generation of reducing equivalents, in the form of
NADPH, used in reductive biosynthesis reactions within
cells. (e.g. fatty acid synthesis)
• Production of ribose-5-phosphate (R5P), used in the
synthesis of nucleotides and nucleic acids.
• Production of erythrose-4-phosphate (E4P), used in the
synthesis of aromatic amino acids.
Aromatic amino acids, in turn, are precursors for many
biosynthetic pathways, notably including the lignin in wood. The Pentose Phosphate Pathway

Dietary pentose sugars derived from the digestion of nucleic

acids may be metabolized through the pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates
may be converted into glycolytic/gluconeogenic intermediates.
In mammals, the PPP occurs exclusively in the cytoplasm, and is found to be most active in the liver, mammary
gland and adrenal cortex in the human. However, the pathway is absent in skeletal muscle tissue. The PPP is one of
the three main ways the body creates molecules with reducing power, accounting for approximately 60% of NADPH
production in humans.
One of the uses of NADPH in the cell is to prevent oxidative stress. It reduces glutathione via glutathione reductase,
which converts reactive H2O2 into H2O by glutathione peroxidase. If absent, the H2O2 would be converted to
hydroxyl free radicals by Fenton chemistry, which can attack the cell.
In a significant step, erythrocytes generate, through the pentose phosphate pathway, a large amount of NADPH used
in the reduction of glutathione.
Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst.[2]
Pentose phosphate pathway 242

Phases

Oxidative phase
In this phase, two molecules of NADP+ are reduced to NADPH, utilizing the energy from the conversion of
glucose-6-phosphate into ribulose 5-phosphate.

Oxidative phase of pentose phosphate pathway. glucose-6-phosphate (1), 6-phosphoglucono-δ-lactone (2), 6-phosphogluconate (3),
ribulose 5-phosphate (4).

The entire set of reactions can be summarized as follows:

Reactants Products Enzyme Description

Glucose 6-phosphate + → glucose 6-phosphate Dehydrogenation. The hemiacetal hydroxyl group

NADP+ 6-phosphoglucono-δ-lactone + dehydrogenase located on carbon 1 of glucose 6-phosphate is
NADPH converted into a carbonyl group, generating a
lactone, and, in the process, NADPH is generated.

6-phosphoglucono-δ-lactone 6-phosphogluconolactonase Hydrolysis

→ 6-phosphogluconate + H+
+ H2O

→ ribulose 5-phosphate + 6-phosphogluconate

6-phosphogluconate + Oxidative decarboxylation. NADP+ is the electron
NADPH + CO2 dehydrogenase
NADP+ acceptor, generating another molecule of NADPH,
a CO2, and ribulose 5-phosphate.

The overall reaction for this process is:

Glucose 6-phosphate + 2 NADP+ + H2O → ribulose 5-phosphate + 2 NADPH + 2 H+ + CO2
Pentose phosphate pathway 243

Non-oxidative phase

The pentose phosphate pathway's Nonoxidative phase

Reactants Products Enzymes

ribulose 5-phosphate → ribose 5-phosphate Ribulose 5-Phosphate Isomerase

ribulose 5-phosphate → xylulose 5-phosphate Ribulose 5-Phosphate

3-Epimerase

xylulose 5-phosphate + ribose 5-phosphate → glyceraldehyde 3-phosphate + sedoheptulose transketolase

7-phosphate

sedoheptulose 7-phosphate + glyceraldehyde → erythrose 4-phosphate + fructose 6-phosphate transaldolase

3-phosphate

xylulose 5-phosphate + erythrose 4-phosphate → glyceraldehyde 3-phosphate + fructose 6-phosphate transketolase

Net reaction: 3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate +

glyceraldehyde-3-phosphate
Pentose phosphate pathway 244

Regulation
Glucose-6-phosphate dehydrogenase is the rate-controlling enzyme of this pathway. It is allosterically stimulated by
NADP+. The ratio of NADPH:NADP+ is normally about 100:1 in liver cytosol. This makes the cytosol a
highly-reducing environment. An NADPH-utilizing pathway forms NADP+, which stimulates Glucose-6-phosphate
dehydrogenase to produce more NADPH.

Erythrocytes and the pentose phosphate pathway

Carbohydrates are metabolized in red blood cells mainly by glycolysis, the pentose phosphate pathway (PPP), and
2,3-bisphosphoglycerate (2,3-BPG) metabolism (refer to discussion of hemoglobin for the role of 2,3-BPG).
Glycolysis provides ATP for membrane ion pumps and NADH for reduction of methemoglobin. The PPP supplies
the red blood cell with NADPH, which in turn maintains the reduced state of glutathione. The inability to maintain
reduced glutathione in red blood cells leads to increased accumulation of peroxides, predominantly H2O2, that in
turn results in a weakening of the cell membrane and concomitant hemolysis. Accumulation of H2O2 also leads to
increased rates of oxidation of hemoglobin to methemoglobin that also weakens the cell wall. Glutathione removes
peroxides via the action of glutathione peroxidase. The PPP in erythrocytes is, in essence, the only pathway for these
cells to produce NADPH. Any defect in the production of NADPH could, therefore, have profound effects on
erythrocyte survival.
Several deficiencies in the level of activity (not function) of glucose-6-phosphate dehydrogenase have been observed
to be associated with resistance to the malarial parasite Plasmodium falciparum among individuals of Mediterranean
and African descent. The basis for this resistance may be a weakening of the red cell membrane (the erythrocyte is
the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth.[3]

References
[1] Kruger NJ, von Schaewen A (June 2003). "The oxidative pentose phosphate pathway: structure and organisation" (http:/ / linkinghub.
elsevier. com/ retrieve/ pii/ S1369526603000396). Curr. Opin. Plant Biol. 6 (3): 236–46. doi:10.1016/S1369-5266(03)00039-6.
PMID 12753973. .
[2] Immunology at MCG 1/cytotox (http:/ / www. lib. mcg. edu/ edu/ esimmuno/ ch1/ cytotox. htm)
[3] Cappadoro M, Giribaldi G, O'Brien E, et al. (October 1998). "Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient
erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency" (http:/ / bloodjournal.
hematologylibrary. org/ cgi/ content/ full/ 92/ 7/ 2527). Blood 92 (7): 2527–34. PMID 9746794. .

External links
• The chemical logic behind the pentose phosphate pathway (http://www2.ufp.pt/~pedros/bq/ppp.htm)
• MeSH Pentose+Phosphate+Pathway (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&
term=Pentose+Phosphate+Pathway)
• Pentose phosphate pathway Map - Homo sapiens (http://www.genome.jp/dbget-bin/
www_bget?path:hsa00030)
 245

Citric acid cycle

Citric acid cycle

The citric acid cycle — also known as
the tricarboxylic acid cycle (TCA
cycle), the Krebs cycle, or the
Szent-Györgyi-Krebs cycle[1] [2] — is
a series of chemical reactions which is
used by all aerobic living organisms to
generate energy through the
oxidization of acetate derived from
carbohydrates, fats and proteins into
carbon dioxide and water. In addition,
the cycle provides precursors for the
biosynthesis of compounds including
certain amino acids as well as the
reducing agent NADH that is used in
numerous biochemical reactions. Its
central importance to many
biochemical pathways suggests that it Overview of the citric acid cycle
was one of the earliest established
components of cellular metabolism and may have originated abiogenically.[3]

The name of this metabolic pathway is derived from citric acid (a type of tricarboxylic acid) which is first consumed
and then regenerated by this sequence of reactions to complete the cycle. In addition, the cycle consumes acetate in
the form of acetyl-CoA, reduces NAD+ to NADH, and produces carbon dioxide. The NADH generated by the TCA
cycle is fed into the oxidative phosphorylation pathway. The net result of these two closely linked pathways is the
oxidation of nutrients to produce energy in the form of ATP.
In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. Bacteria also use the TCA cycle
to generate energy, but since they lack mitochondria, the reaction sequence is performed in the cytosol.
The components and reactions of the citric acid cycle were established in the 1930s by seminal work from the Nobel
laureates Albert Szent-Györgyi[4] and Hans Adolf Krebs.[5]
Citric acid cycle 246

Evolution
Components of the TCA cycle were derived from anaerobic bacteria and the TCA cycle itself may have evolved
more than once.[6] Theoretically there are several alternatives to the TCA cycle, however the TCA cycle appears to
be the most efficient.[7] If several alternatives independently evolved, they all undoubtedly rapidly converged to the
TCA cycle.

Overview
The citric acid cycle is a key component of the metabolic pathway by which all aerobic organisms generate energy.
Through catabolism of sugars, fats, and proteins, a two carbon organic product acetate in the form of acetyl-CoA is
produced. Acetyl-CoA along with two equivalents of water (H2O) are consumed by the citric acid cycle producing
two equivalents of carbon dioxide (CO2) and one equivalent of HS-CoA. In addition, one complete turn of the cycle
converts three equivalents of nicotinamide adenine dinucleotide (NAD+) into three equivalents of reduced NAD+
(NADH), one equivalent of ubiquinone (Q) into one equivalent of reduced ubiquinone (QH2), and one equivalent
each of guanosine diphosphate (GDP) and inorganic phosphate (Pi) into one equivalent of guanosine triphosphate
(GTP). The NADH and QH2 that is generated by the citric acid cycle is in turn used by the oxidative phosphorylation
pathway to generate energy rich adenosine triphosphate (ATP).
One of the primary sources of acetyl-CoA are sugars that are broken down by glycolysis to produce pyruvate that in
turn is decarboxylated by the enzyme pyruvate dehydrogenase generating acetyl-CoA according to the following
reaction scheme:
• CH3C(=O)C(=O)O– (pyruvate) + HSCoA + NAD+ → CH3C(=O)SCoA (acetyl-CoA) + NADH + H+ + CO2
The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Below is a schematic outline of
the cycle:
• The citric acid cycle begins with the transfer of a two-carbon acetyl group from acetyl-CoA to the four-carbon
acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
• The citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The
carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA. The carbons donated by
acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of
the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle. However, because of the
role of the citric acid cycle in anabolism, they may not be lost, since many TCA cycle intermediates are also used
as precursors for the biosynthesis of other molecules.[8]
• Most of the energy made available by the oxidative steps of the cycle is transferred as energy-rich electrons to
NAD+, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are
produced.
• Electrons are also transferred to the electron acceptor Q, forming QH2.
• At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps
Two carbon atoms are oxidized to CO2, the energy from these reactions being transferred to other metabolic
processes by GTP (or ATP), and as electrons in NADH and QH2. The NADH generated in the TCA cycle may later
donate its electrons in oxidative phosphorylation to drive ATP synthesis; FADH2 is covalently attached to succinate
dehydrogenase, an enzyme functioning both in the TCA cycle and the mitochondrial electron transport chain in
oxidative phosphorylation. FADH2, therefore, facilitates transfer of electrons to coenzyme Q, which is the final
electron acceptor of the reaction catalyzed by the Succinate:ubiquinone oxidoreductase complex, also acting as an
intermediate in the electron transport chain.[9]
Citric acid cycle 247

The citric acid cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 1
below.[10]

Substrates Products Enzyme Reaction type Comment

1 Oxaloacetate + Citrate + Citrate synthase Aldol condensation irreversible,

Acetyl CoA + CoA-SH extends the 4C oxaloacetate to a 6C molecule
H2O

2 Citrate cis-Aconitate + Aconitase Dehydration reversible isomerisation

H2O

3 cis-Aconitate + Isocitrate Hydration

H2O

4 Isocitrate Oxidation generates NADH (equivalent of 2.5 ATP)

Isocitrate + Oxalosuccinate
dehydrogenase
NAD+ +
NADH + H +

5 Oxalosuccinate α-Ketoglutarate Decarboxylation rate-limiting, irreversible stage,

+ generates a 5C molecule
CO2

6 Succinyl-CoA + α-Ketoglutarate Oxidative irreversible stage,

α-Ketoglutarate
dehydrogenase decarboxylation generates NADH (equivalent of 2.5 ATP),
+ NADH + H+ +
regenerates the 4C chain (CoA excluded)
NAD+ + CO2
CoA-SH

7 Succinyl-CoA + Succinate + Succinyl-CoA substrate-level [9]

or ADP→ATP instead of GDP→GTP,
GDP + Pi CoA-SH + synthetase phosphorylation generates 1 ATP or equivalent
GTP

8 Succinate + Fumarate + Succinate Oxidation uses FAD as a prosthetic group (FAD→FADH2 in the
ubiquinone (Q) ubiquinol (QH2) dehydrogenase [9]
first step of the reaction) in the enzyme,
generates the equivalent of 1.5 ATP

9 Fumarate + L-Malate Fumarase Hydration

H2O

10 L-Malate + Malate dehydrogenase Oxidation reversible (in fact, equilibrium favors malate),
Oxaloacetate +
generates NADH (equivalent of 2.5 ATP)
NAD+ NADH + H+

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from
GDP, and another that produces ATP from ADP.[11] Plants have the type that produces ATP (ADP-forming
succinyl-CoA synthetase).[10] Several of the enzymes in the cycle may be loosely-associated in a multienzyme
protein complex within the mitochondrial matrix.[12]
The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase
to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).[9]
Citric acid cycle 248

Products
Products of the first turn of the cycle are: one GTP (or ATP), three NADH, one QH2, two CO2.
Because two acetyl-CoA molecules are produced from each glucose molecule, two cycles are required per glucose
molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two QH2, and four CO2

Description Reactants Products

The sum of all reactions in the citric acid cycle is: Acetyl-CoA + 3 NAD+ + Q + → CoA-SH + 3 NADH + 3
GDP + Pi + 2 H2O H+ + QH2 + GTP + 2 CO2

Combining the reactions occurring during the pyruvate oxidation with those Pyruvate ion + 4 NAD+ + Q + → 4 NADH + 4 H+ + QH2 +
occurring during the citric acid cycle, the following overall pyruvate oxidation GDP + Pi + 2 H2O GTP + 3 CO2
reaction is obtained:

Combining the above reaction with the ones occurring in the course of glycolysis, Glucose + 10 NAD+ + 2 Q + 2 → 10 NADH + 10 H+ + 2
the following overall glucose oxidation reaction (excluding reactions in the ADP + 2 GDP + 4 Pi + 2 H2O QH2 + 2 ATP + 2 GTP + 6
respiratory chain) is obtained: CO2

The above reactions are balanced if Pi represents the H2PO4- ion, ADP and GDP the ADP2- and GDP2- ions,
respectively, and ATP and GTP the ATP3- and GTP3- ions, respectively.
The total number of ATP obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and
oxidative phosphorylation is estimated to be between 30 and 38. A recent assessment of the total ATP yield with the
updated proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.[13]

Regulation
Although pyruvate dehydrogenase is not technically a part of the citric acid cycle, its regulation is included here.
The regulation of the TCA cycle is largely determined by substrate availability and product inhibition. NADH, a
product of all dehydrogenases in the TCA cycle with the exception of succinate dehydrogenase, inhibits pyruvate
dehydrogenase, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and also citrate synthase. Acetyl-coA
inhibits pyruvate dehydrogenase, while succinyl-CoA inhibits succinyl-CoA synthetase and citrate synthase. When
tested in vitro with TCA enzymes, ATP inhibits citrate synthase and α-ketoglutarate dehydrogenase; however, ATP
levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known allosteric
mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration
changes less than 10%.[14]
Calcium is used as a regulator. It activates pyruvate dehydrogenase, isocitrate dehydrogenase and α-ketoglutarate
dehydrogenase.[15] This increases the reaction rate of many of the steps in the cycle, and therefore increases flux
throughout the pathway.
Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that
catalyses formation of fructose 1,6-bisphosphate,a precursor of pyruvate. This prevents a constant high rate of flux
when there is an accumulation of citrate and a decrease in substrate for the enzyme.
Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of
hypoxia-inducible factors (HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription
factor that targets angiogenesis, vascular remodeling, glucose utilization, iron transport and apoptosis. HIF is
synthesized consititutively, and hydroxylation of at least one of two critical proline residues mediates their
interaction with the von Hippel Lindau E3 ubiquitin ligase complex, which targets them for rapid degradation. This
reaction is catalysed by prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of
prolyl hydroxylases, thus leading to the stabilisation of HIF.[16]
Citric acid cycle 249

Major metabolic pathways converging on the TCA cycle

Several catabolic pathways converge on the TCA cycle. Reactions that form intermediates of the TCA cycle in order
to replenish them (especially during the scarcity of the intermediates) are called anaplerotic reactions.
The citric acid cycle is the third step in carbohydrate catabolism (the breakdown of sugars). Glycolysis breaks
glucose (a six-carbon-molecule) down into pyruvate (a three-carbon molecule). In eukaryotes, pyruvate moves into
the mitochondria. It is converted into acetyl-CoA by decarboxylation and enters the citric acid cycle.
In protein catabolism, proteins are broken down by proteases into their constituent amino acids. The carbon
backbone of these amino acids can become a source of energy by being converted to acetyl-CoA and entering into
the citric acid cycle.
In fat catabolism, triglycerides are hydrolyzed to break them into fatty acids and glycerol. In the liver the glycerol
can be converted into glucose via dihydroxyacetone phosphate and glyceraldehyde-3-phosphate by way of
gluconeogenesis. In many tissues, especially heart tissue, fatty acids are broken down through a process known as
beta oxidation, which results in acetyl-CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids
with an odd number of methylene groups produces propionyl CoA, which is then converted into succinyl-CoA and
fed into the citric acid cycle.[17]
The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the citric acid cycle,
and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The citric acid cycle is called an
amphibolic pathway because it participates in both catabolism and anabolism.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.[18]
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Citric acid cycle 251

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{{{bSize}}}px

Citric_acid_cycle edit [19]

Citric acid cycle 252

References
[1] Lowenstein JM (1969). Methods in Enzymology, Volume 13: Citric Acid Cycle. Boston: Academic Press. ISBN 0-12-181870-5.
[2] Krebs HA, Weitzman PDJ (1987). Krebs' citric acid cycle: half a century and still turning. London: Biochemical Society.
ISBN 0-904498-22-0.
[3] Lane, Nick (2009). Life Ascending: The Ten Great Inventions of Evolution. New York: W.W. Norton & Co. ISBN 0-393-06596-0.
[4] "The Nobel Prize in Physiology or Medicine 1937" (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1937/ ). The Nobel
Foundation. . Retrieved 2011-10-26.
[5] "The Nobel Prize in Physiology or Medicine 1953" (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1953/ ). The Nobel
Foundation. . Retrieved 2011-10-26.
[6] Gest H (1987). "Evolutionary roots of the citric acid cycle in prokaryotes". Biochem. Soc. Symp. 54: 3–16. PMID 3332996.
[7] Meléndez-Hevia E, Waddell TG, Cascante M (September 1996). "The puzzle of the Krebs citric acid cycle: assembling the pieces of
chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution". J. Mol. Evol. 43 (3): 293–303.
doi:10.1007/BF02338838. PMID 8703096.
[8] Wolfe RR, Jahoor F (February 1990). "Recovery of labeled CO2 during the infusion of C-1- vs C-2-labeled acetate: implications for tracer
studies of substrate oxidation". Am. J. Clin. Nutr. 51 (2): 248–52. PMID 2106256.
[9] Stryer L, Berg J, Tymoczko JL (2002). Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0.
[10] Jones RC, Buchanan BB, Gruissem W (2000). Biochemistry & molecular biology of plants (1st ed.). Rockville, Md: American Society of
Plant Physiologists. ISBN 0-943088-39-9.
[11] Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (October 1998). "Genetic evidence for the expression of ATP- and GTP-specific
succinyl-CoA synthetases in multicellular eucaryotes". J. Biol. Chem. 273 (42): 27580–6. doi:10.1074/jbc.273.42.27580. PMID 9765291.
[12] Barnes SJ, Weitzman PD (June 1986). "Organization of citric acid cycle enzymes into a multienzyme cluster". FEBS Lett. 201 (2): 267–70.
doi:10.1016/0014-5793(86)80621-4. PMID 3086126.
[13] Rich PR (December 2003). "The molecular machinery of Keilin's respiratory chain". Biochem. Soc. Trans. 31 (Pt 6): 1095–105.
doi:10.1042/BST0311095. PMID 14641005.
[14] Voet D, Voet JG (2004). Biochemistry (3rd ed.). New York: John Wiley & Sons, Inc.. p. 615.
[15] Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, Severson DL, Stansbie D, Whitehouse S (October 1975).
"Regulation of mammalian pyruvate dehydrogenase". Mol. Cell. Biochem. 9 (1): 27–53. doi:10.1007/BF01731731. PMID 171557.
[16] Koivunen P, Hirsilä M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J (February 2007). "Inhibition of hypoxia-inducible factor (HIF)
hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF". J. Biol. Chem. 282 (7):
4524–32. doi:10.1074/jbc.M610415200. PMID 17182618.
[17] Halarnkar PP, Blomquist GJ (1989). "Comparative aspects of propionate metabolism". Comp. Biochem. Physiol., B 92 (2): 227–31.
doi:10.1016/0305-0491(89)90270-8. PMID 2647392.
[18] The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78" (http:/ / www. wikipathways. org/ index. php/
Pathway:WP78). .
[19] http:/ / www. wikipathways. org/ index. php/ Pathway:WP78

External links
• Citric acid cycle Animation (http://www.1lec.com/Biochemistry/How the Krebs Cycle Works/index.
html)(flash required)
• An animation of the citric acid cycle (http://www.science.smith.edu/departments/Biology/Bio231/krebs.
html) at Smith College
• Notes on citric acid cycle (http://www.rahulgladwin.com/blog/2007/01/notes-on-citric-acid-cycle-glyoxylate.
html) at rahulgladwin.com
• Citric acid cycle variants (http://biocyc.org/META/NEW-IMAGE?object=TCA-VARIANTS) at MetaCyc
• Pathways connected to the citric acid cycle (http://www.genome.ad.jp/kegg/pathway/map/map00020.html)
at Kyoto Encyclopedia of Genes and Genomes
• A more detailed tutorial animation (http://www.johnkyrk.com/krebs.html) at johnkyrk.com
• A citric-acid cycle self quiz flash applet (http://www.pitt.edu/AFShome/j/b/jbrodsky/public/html/1820/tca.
htm) at University of Pittsburgh
• The chemical logic behind the citric acid cycle (http://www2.ufp.pt/~pedros/bq/tca.htm)
• The Krebs cycle song (http://www.science-groove.org/Now/) by Lynda Jones.
 253

Oxidative phosphorylation

Oxidative phosphorylation
Oxidative phosphorylation (or
OXPHOS in short) is a metabolic
pathway that uses energy released by
the oxidation of nutrients to produce
adenosine triphosphate (ATP).
Although the many forms of life on
earth use a range of different nutrients,
almost all aerobic organisms carry out
oxidative phosphorylation to produce
ATP, the molecule that supplies energy
to metabolism. This pathway is
probably so pervasive because it is a
highly efficient way of releasing
energy, compared to alternative
fermentation processes such as
anaerobic glycolysis.

During oxidative phosphorylation,

electrons are transferred from electron
The electron transport chain in the mitochondrion is the site of oxidative phosphorylation
donors to electron acceptors such as in eukaryotes. The NADH and succinate generated in the citric acid cycle are oxidized,
oxygen, in redox reactions. These releasing energy to power the ATP synthase.
redox reactions release energy, which
is used to form ATP. In eukaryotes, these redox reactions are carried out by a series of protein complexes within
mitochondria, whereas, in prokaryotes, these proteins are located in the cells' inner membranes. These linked sets of
proteins are called electron transport chains. In eukaryotes, five main protein complexes are involved, whereas in
prokaryotes many different enzymes are present, using a variety of electron donors and acceptors.

The energy released by electrons flowing through this electron transport chain is used to transport protons across the
inner mitochondrial membrane, in a process called chemiosmosis. This generates potential energy in the form of a
pH gradient and an electrical potential across this membrane. This store of energy is tapped by allowing protons to
flow back across the membrane and down this gradient, through a large enzyme called ATP synthase. This enzyme
uses this energy to generate ATP from adenosine diphosphate (ADP), in a phosphorylation reaction. This reaction is
driven by the proton flow, which forces the rotation of a part of the enzyme; the ATP synthase is a rotary mechanical
motor.

Although oxidative phosphorylation is a vital part of metabolism, it produces reactive oxygen species such as
superoxide and hydrogen peroxide, which lead to propagation of free radicals, damaging cells and contributing to
disease and, possibly, aging (senescence). The enzymes carrying out this metabolic pathway are also the target of
many drugs and poisons that inhibit their activities.
Oxidative phosphorylation 254

Overview of energy transfer by chemiosmosis

Further information: Chemiosmosis and Bioenergetics
Oxidative phosphorylation works by using energy-releasing chemical reactions to drive energy-requiring reactions:
The two sets of reactions are said to be coupled. This means one cannot occur without the other. The flow of
electrons through the electron transport chain, from electron donors such as NADH to electron acceptors such as
oxygen, is an exergonic process – it releases energy, whereas the synthesis of ATP is an endergonic process, which
requires an input of energy. Both the electron transport chain and the ATP synthase are embedded in a membrane,
and energy is transferred from electron transport chain to the ATP synthase by movements of protons across this
membrane, in a process called chemiosmosis.[1] In practice, this is like a simple electric circuit, with a current of
protons being driven from the negative N-side of the membrane to the positive P-side by the proton-pumping
enzymes of the electron transport chain. These enzymes are like a battery, as they perform work to drive current
through the circuit. The movement of protons creates an electrochemical gradient across the membrane, which is
often called the proton-motive force. This gradient has two components: a difference in proton concentration (a H+
gradient) and a difference in electric potential, with the N-side having a negative charge. The energy is stored largely
as the difference of electric potentials in mitochondria, but also as a pH gradient in chloroplasts.[2]
ATP synthase releases this stored energy by completing the circuit and allowing protons to flow down the
electrochemical gradient, back to the N-side of the membrane.[3] This enzyme is like an electric motor as it uses the
proton-motive force to drive the rotation of part of its structure and couples this motion to the synthesis of ATP.
The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by
anaerobic fermentation. Glycolysis produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are
produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one
molecule of glucose to carbon dioxide and water,[4] while each cycle of beta oxidation of a fatty acid yields about 14
ATPs. These ATP yields are theoretical maximum values; in practice, some protons leak across the membrane,
lowering the yield of ATP.[5]

Electron and proton transfer molecules

Further information: Coenzyme and Cofactor
The electron transport chain carries both protons and
electrons, passing electrons from donors to acceptors,
and transporting protons across a membrane. These
processes use both soluble and protein-bound transfer
molecules. In mitochondria, electrons are transferred
within the intermembrane space by the water-soluble
electron transfer protein cytochrome c.[6] This carries
only electrons, and these are transferred by the
reduction and oxidation of an iron atom that the protein
holds within a heme group in its structure. Cytochrome
c is also found in some bacteria, where it is located
within the periplasmic space.[7]
Reduction of coenzyme Q from its ubiquinone form (Q) to the
reduced ubiquinol form (QH2). Within the inner mitochondrial membrane, the
lipid-soluble electron carrier coenzyme Q10 (Q) carries
[8]
both electrons and protons by a redox cycle. This small benzoquinone molecule is very hydrophobic, so it diffuses
freely within the membrane. When Q accepts two electrons and two protons, it becomes reduced to the ubiquinol
form (QH2); when QH2 releases two electrons and two protons, it becomes oxidized back to the ubiquinone (Q)
form. As a result, if two enzymes are arranged so that Q is reduced on one side of the membrane and QH2 oxidized
Oxidative phosphorylation 255

on the other, ubiquinone will couple these reactions and shuttle protons across the membrane.[9] Some bacterial
electron transport chains use different quinones, such as menaquinone, in addition to ubiquinone.[10]
Within proteins, electrons are transferred between flavin cofactors,[3] [11] iron–sulfur clusters, and cytochromes.
There are several types of iron–sulfur cluster. The simplest kind found in the electron transfer chain consists of two
iron atoms joined by two atoms of inorganic sulfur; these are called [2Fe–2S] clusters. The second kind, called
[4Fe–4S], contains a cube of four iron atoms and four sulfur atoms. Each iron atom in these clusters is coordinated
by an additional amino acid, usually by the sulfur atom of cysteine. Metal ion cofactors undergo redox reactions
without binding or releasing protons, so in the electron transport chain they serve solely to transport electrons
through proteins. Electrons move quite long distances through proteins by hopping along chains of these
cofactors.[12] This occurs by quantum tunnelling, which is rapid over distances of less than 1.4×10−9 m.[13]

Eukaryotic electron transport chains

Further information: Electron transport chain and Chemiosmosis
Many catabolic biochemical processes, such as glycolysis, the citric acid cycle, and beta oxidation, produce the
reduced coenzyme NADH. This coenzyme contains electrons that have a high transfer potential; in other words, they
will release a large amount of energy upon oxidation. However, the cell does not release this energy all at once, as
this would be an uncontrollable reaction. Instead, the electrons are removed from NADH and passed to oxygen
through a series of enzymes that each release a small amount of the energy. This set of enzymes, consisting of
complexes I through IV, is called the electron transport chain and is found in the inner membrane of the
mitochondrion. Succinate is also oxidized by the electron transport chain, but feeds into the pathway at a different
point.
In eukaryotes, the enzymes in this electron transport system use the energy released from the oxidation of NADH to
pump protons across the inner membrane of the mitochondrion. This causes protons to build up in the
intermembrane space, and generates an electrochemical gradient across the membrane. The energy stored in this
potential is then used by ATP synthase to produce ATP. Oxidative phosphorylation in the eukaryotic mitochondrion
is the best-understood example of this process. The mitochondrion is present in almost all eukaryotes, with the
exception of anaerobic protozoa such as Trichomonas vaginalis that instead reduce protons to hydrogen in a remnant
mitochondrion called a hydrogenosome.[14]

Typical respiratory enzymes and substrates in eukaryotes.

Respiratory enzyme Redox pair Midpoint potential  (Volts)

NADH dehydrogenase [15]

NAD+ / NADH −0.32

Succinate dehydrogenase FMN or FAD / FMNH2 or FADH2 [15]

−0.20

Cytochrome bc1 complex Coenzyme Q10ox / Coenzyme Q10red [15]

+0.06

Cytochrome bc1 complex Cytochrome box / Cytochrome bred [15]

+0.12

Complex IV Cytochrome cox / Cytochrome cred [15]

+0.22

Complex IV Cytochrome aox / Cytochrome ared [15]

+0.29

Complex IV [15]
O2 / HO− +0.82

[15]
Conditions: pH = 7
Oxidative phosphorylation 256

NADH-coenzyme Q oxidoreductase (complex I)

NADH-coenzyme Q oxidoreductase,
also known as NADH dehydrogenase
or complex I, is the first protein in the
electron transport chain.[16] Complex I
is a giant enzyme with the mammalian
complex I having 46 subunits and a
molecular mass of about 1,000
kilodaltons (kDa).[17] The structure is
known in detail only from a
bacterium;[18] [19] in most organisms
the complex resembles a boot with a
large “ball” poking out from the
membrane into the mitochondrion.[20]
[21]
The genes that encode the
individual proteins are contained in
both the cell nucleus and the
mitochondrial genome, as is the case
for many enzymes present in the Complex I or NADH-Q oxidoreductase. The abbreviations are discussed in the text. In all
mitochondrion. diagrams of respiratory complexes in this article, the matrix is at the bottom, with the
intermembrane space above.

The reaction that is catalyzed by this

enzyme is the two electron reduction by NADH of coenzyme Q10 or ubiquinone (represented as Q in the equation
below), a lipid-soluble quinone that is found in the mitochondrion membrane:

The start of the reaction, and indeed of the entire electron chain, is the binding of a NADH molecule to complex I
and the donation of two electrons. The electrons enter complex I via a prosthetic group attached to the complex,
flavin mononucleotide (FMN). The addition of electrons to FMN converts it to its reduced form, FMNH2. The
electrons are then transferred through a series of iron–sulfur clusters: the second kind of prosthetic group present in
the complex.[18] There are both [2Fe–2S] and [4Fe–4S] iron–sulfur clusters in complex I.
As the electrons pass through this complex, four protons are pumped from the matrix into the intermembrane space.
Exactly how this occurs is unclear, but it seems to involve conformational changes in complex I that cause the
protein to bind protons on the N-side of the membrane and release them on the P-side of the membrane.[22] Finally,
the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane.[16]
Reduction of ubiquinone also contributes to the generation of a proton gradient, as two protons are taken up from the
matrix as it is reduced to ubiquinol (QH2).
Oxidative phosphorylation 257

Succinate-Q oxidoreductase (complex II)

Succinate-Q oxidoreductase, also known as complex II
or succinate dehydrogenase, is a second entry point to
the electron transport chain.[23] It is unusual because it
is the only enzyme that is part of both the citric acid
cycle and the electron transport chain. Complex II
consists of four protein subunits and contains a bound
flavin adenine dinucleotide (FAD) cofactor, iron–sulfur
clusters, and a heme group that does not participate in
electron transfer to coenzyme Q, but is believed to be
important in decreasing production of reactive oxygen
species.[24] [25] It oxidizes succinate to fumarate and
reduces ubiquinone. As this reaction releases less
energy than the oxidation of NADH, complex II does
not transport protons across the membrane and does not
contribute to the proton gradient.
Complex II: Succinate-Q oxidoreductase.

In some eukaryotes, such as the parasitic worm Ascaris suum, an enzyme similar to complex II, fumarate reductase
(menaquinol:fumarate oxidoreductase, or QFR), operates in reverse to oxidize ubiquinol and reduce fumarate. This
allows the worm to survive in the anaerobic environment of the large intestine, carrying out anaerobic oxidative
phosphorylation with fumarate as the electron acceptor.[26] Another unconventional function of complex II is seen in
the malaria parasite Plasmodium falciparum. Here, the reversed action of complex II as an oxidase is important in
regenerating ubiquinol, which the parasite uses in an unusual form of pyrimidine biosynthesis.[27]

Electron transfer flavoprotein-Q oxidoreductase

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-Q oxidoreductase), also known as electron
transferring-flavoprotein dehydrogenase, is a third entry point to the electron transport chain. It is an enzyme that
accepts electrons from electron-transferring flavoprotein in the mitochondrial matrix, and uses these electrons to
reduce ubiquinone.[28] This enzyme contains a flavin and a [4Fe–4S] cluster, but, unlike the other respiratory
complexes, it attaches to the surface of the membrane and does not cross the lipid bilayer.[29]

In mammals, this metabolic pathway is important in beta oxidation of fatty acids and catabolism of amino acids and
choline, as it accepts electrons from multiple acetyl-CoA dehydrogenases.[30] [31] In plants, ETF-Q oxidoreductase is
also important in the metabolic responses that allow survival in extended periods of darkness.[32]
Oxidative phosphorylation 258

Q-cytochrome c oxidoreductase (complex III)

Q-cytochrome c oxidoreductase is also
known as cytochrome c reductase,
cytochrome bc1 complex, or simply
complex III.[33] [34] In mammals, this
enzyme is a dimer, with each subunit
complex containing 11 protein
subunits, an [2Fe-2S] iron–sulfur
cluster and three cytochromes: one
cytochrome c1 and two b
[35]
cytochromes. A cytochrome is a
kind of electron-transferring protein
The two electron transfer steps in complex III: Q-cytochrome c oxidoreductase. After
that contains at least one heme group.
each step, Q (in the upper part of the figure) leaves the enzyme.
The iron atoms inside complex III’s
heme groups alternate between a
reduced ferrous (+2) and oxidized ferric (+3) state as the electrons are transferred through the protein.

The reaction catalyzed by complex III is the oxidation of one molecule of ubiquinol and the reduction of two
molecules of cytochrome c, a heme protein loosely associated with the mitochondrion. Unlike coenzyme Q, which
carries two electrons, cytochrome c carries only one electron.

As only one of the electrons can be transferred from the QH2 donor to a cytochrome c acceptor at a time, the reaction
mechanism of complex III is more elaborate than those of the other respiratory complexes, and occurs in two steps
called the Q cycle.[36] In the first step, the enzyme binds three substrates, first, QH2, which is then oxidized, with one
electron being passed to the second substrate, cytochrome c. The two protons released from QH2 pass into the
intermembrane space. The third substrate is Q, which accepts the second electron from the QH2 and is reduced to Q.-,
which is the ubisemiquinone free radical. The first two substrates are released, but this ubisemiquinone intermediate
remains bound. In the second step, a second molecule of QH2 is bound and again passes its first electron to a
cytochrome c acceptor. The second electron is passed to the bound ubisemiquinone, reducing it to QH2 as it gains
two protons from the mitochondrial matrix. This QH2 is then released from the enzyme.[37]
As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, a
net transfer of protons across the membrane occurs, adding to the proton gradient.[3] The rather complex two-step
mechanism by which this occurs is important, as it increases the efficiency of proton transfer. If, instead of the Q
cycle, one molecule of QH2 were used to directly reduce two molecules of cytochrome c, the efficiency would be
halved, with only one proton transferred per cytochrome c reduced.[3]
Oxidative phosphorylation 259

Cytochrome c oxidase (complex IV)

Cytochrome c oxidase, also known as complex IV, is the final protein
complex in the electron transport chain.[38] The mammalian enzyme
has an extremely complicated structure and contains 13 subunits, two
heme groups, as well as multiple metal ion cofactors – in all three
atoms of copper, one of magnesium and one of zinc.[39]
This enzyme mediates the final reaction in the electron transport chain
and transfers electrons to oxygen, while pumping protons across the
membrane.[40] The final electron acceptor oxygen, which is also called
the terminal electron acceptor, is reduced to water in this step. Both
the direct pumping of protons and the consumption of matrix protons
in the reduction of oxygen contribute to the proton gradient. The
reaction catalyzed is the oxidation of cytochrome c and the reduction
of oxygen:
Complex IV: cytochrome c oxidase.

Alternative reductases and oxidases

Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes
described above. For example, plants have alternative NADH oxidases, which oxidize NADH in the cytosol rather
than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool.[41] These enzymes do not transport
protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner
membrane.[42]
Another example of a divergent electron transport chain is the alternative oxidase, which is found in plants, as well
as some fungi, protists, and possibly some animals.[43] [44] This enzyme transfers electrons directly from ubiquinol to
oxygen.[45]
The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower ATP
yields than the full pathway. The advantages produced by a shortened pathway are not entirely clear. However, the
alternative oxidase is produced in response to stresses such as cold, reactive oxygen species, and infection by
pathogens, as well as other factors that inhibit the full electron transport chain.[46] [47] Alternative pathways might,
therefore, enhance an organisms' resistance to injury, by reducing oxidative stress.[48]

Organization of complexes
The original model for how the respiratory chain complexes are organized was that they diffuse freely and
independently in the mitochondrial membrane.[17] However, recent data suggest that the complexes might form
higher-order structures called supercomplexes or "respirasomes."[49] In this model, the various complexes exist as
organized sets of interacting enzymes.[50] These associations might allow channeling of substrates between the
various enzyme complexes, increasing the rate and efficiency of electron transfer.[51] Within such mammalian
supercomplexes, some components would be present in higher amounts than others, with some data suggesting a
ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4.[52] However, the debate over
this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model.[17] [53]
Oxidative phosphorylation 260

Prokaryotic electron transport chains

Further information: Microbial metabolism
In contrast to the general similarity in structure and function of the electron transport chains in eukaryotes, bacteria
and archaea possess a large variety of electron-transfer enzymes. These use an equally wide set of chemicals as
substrates.[54] In common with eukaryotes, prokaryotic electron transport uses the energy released from the
oxidation of a substrate to pump ions across a membrane and generate an electrochemical gradient. In the bacteria,
oxidative phosphorylation in Escherichia coli is understood in most detail, while archaeal systems are at present
poorly understood.[55]
The main difference between eukaryotic and prokaryotic oxidative phosphorylation is that bacteria and archaea use
many different substances to donate or accept electrons. This allows prokaryotes to grow under a wide variety of
environmental conditions.[56] In E. coli, for example, oxidative phosphorylation can be driven by a large number of
pairs of reducing agents and oxidizing agents, which are listed below. The midpoint potential of a chemical measures
how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and
oxidizing agents positive potentials.

Respiratory enzymes and substrates in E. coli.[57]

Respiratory enzyme Redox pair Midpoint potential  (Volts)

Formate dehydrogenase Bicarbonate / Formate −0.43

Hydrogenase Proton / Hydrogen −0.42

NADH dehydrogenase −0.32

NAD+ / NADH

Glycerol-3-phosphate dehydrogenase DHAP / Gly-3-P −0.19

Pyruvate oxidase Acetate + Carbon dioxide / Pyruvate ?

Lactate dehydrogenase Pyruvate / Lactate −0.19

D-amino acid dehydrogenase 2-oxoacid + ammonia / D-amino acid ?

Glucose dehydrogenase Gluconate / Glucose −0.14

Succinate dehydrogenase Fumarate / Succinate +0.03

Ubiquinol oxidase Oxygen / Water +0.82

Nitrate reductase Nitrate / Nitrite +0.42

Nitrite reductase Nitrite / Ammonia +0.36

Dimethyl sulfoxide reductase DMSO / DMS +0.16

Trimethylamine N-oxide reductase TMAO / TMA +0.13

Fumarate reductase Fumarate / Succinate +0.03

As shown above, E. coli can grow with reducing agents such as formate, hydrogen, or lactate as electron donors, and
nitrate, DMSO, or oxygen as acceptors.[56] The larger the difference in midpoint potential between an oxidizing and
reducing agent, the more energy is released when they react. Out of these compounds, the succinate/fumarate pair is
unusual, as its midpoint potential is close to zero. Succinate can therefore be oxidized to fumarate if a strong
oxidizing agent such as oxygen is available, or fumarate can be reduced to succinate using a strong reducing agent
such as formate. These alternative reactions are catalyzed by succinate dehydrogenase and fumarate reductase,
respectively.[58]
Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, nitrifying
bacteria such as Nitrobacter oxidize nitrite to nitrate, donating the electrons to oxygen. The small amount of energy
released in this reaction is enough to pump protons and generate ATP, but not enough to produce NADH or NADPH
Oxidative phosphorylation 261

directly for use in anabolism.[59] This problem is solved by using a nitrite oxidoreductase to produce enough
proton-motive force to run part of the electron transport chain in reverse, causing complex I to generate NADH.[60]
[61]

Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced, in
response to environmental conditions.[62] This flexibility is possible because different oxidases and reductases use
the same ubiquinone pool. This allows many combinations of enzymes to function together, linked by the common
ubiquinol intermediate.[57] These respiratory chains therefore have a modular design, with easily interchangeable sets
of enzyme systems.
In addition to this metabolic diversity, prokaryotes also possess a range of isozymes – different enzymes that
catalyze the same reaction. For example, in E. coli, there are two different types of ubiquinol oxidase using oxygen
as an electron acceptor. Under highly aerobic conditions, the cell uses an oxidase with a low affinity for oxygen that
can transport two protons per electron. However, if levels of oxygen fall, they switch to an oxidase that transfers
only one proton per electron, but has a high affinity for oxygen.[63]

ATP synthase (complex V)

Further information: ATP synthase
ATP synthase, also called complex V, is the final enzyme in the oxidative phosphorylation pathway. This enzyme is
found in all forms of life and functions in the same way in both prokaryotes and eukaryotes.[64] The enzyme uses the
energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and phosphate (Pi).
Estimates of the number of protons required to synthesize one ATP have ranged from three to four,[65] [66] with some
suggesting cells can vary this ratio, to suit different conditions.[67]

This phosphorylation reaction is an equilibrium, which can be shifted by altering the proton-motive force. In the
absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and
pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the
reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their
concentration gradient and turning ADP into ATP.[64] Indeed, in the closely related vacuolar type H+-ATPases, the
same reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP.[68]
ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains
16 subunits and has a mass of approximately 600 kilodaltons.[69] The portion embedded within the membrane is
called FO and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called
F1 and is the site of ATP synthesis. The ball-shaped complex at the end of the F1 portion contains six proteins of two
different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with
the tip of the stalk extending into the ball of α and β subunits.[70] Both the α and β subunits bind nucleotides, but
only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F1 portion and back into the
membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme.
As protons cross the membrane through the channel in the base of ATP synthase, the FO proton-driven motor
rotates.[71] Rotation might be caused by changes in the ionization of amino acids in the ring of c subunits causing
electrostatic interactions that propel the ring of c subunits past the proton channel.[72] This rotating ring in turn drives
the rotation of the central axle (the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented
from rotating themselves by the side-arm, which acts as a stator. This movement of the tip of the γ subunit within the
ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements
that produces and then releases ATP.[2]
Oxidative phosphorylation 262

This ATP synthesis reaction is called the binding change

mechanism and involves the active site of a β subunit cycling
between three states.[73] In the "open" state, ADP and
phosphate enter the active site (shown in brown in the
diagram). The protein then closes up around the molecules
and binds them loosely – the "loose" state (shown in red). The
enzyme then changes shape again and forces these molecules
together, with the active site in the resulting "tight" state
(shown in pink) binding the newly produced ATP molecule
with very high affinity. Finally, the active site cycles back to
the open state, releasing ATP and binding more ADP and
phosphate, ready for the next cycle.
Mechanism of ATP synthase. ATP is shown in red, ADP and
In some bacteria and archaea, ATP synthesis is driven by the phosphate in pink and the rotating γ subunit in black.
movement of sodium ions through the cell membrane, rather
than the movement of protons.[74] [75] Archaea such as Methanococcus also contain the A1Ao synthase, a form of the
enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP
synthase subunits. It is possible that, in some species, the A1Ao form of the enzyme is a specialized sodium-driven
ATP synthase,[76] but this might not be true in all cases.[75]

Reactive oxygen species

Further information: Oxidative stress and Antioxidant
Molecular oxygen is an ideal terminal electron acceptor because it is a strong oxidizing agent. The reduction of
oxygen does involve potentially harmful intermediates.[77] Although the transfer of four electrons and four protons
reduces oxygen to water, which is harmless, transfer of one or two electrons produces superoxide or peroxide anions,
which are dangerously reactive.

These reactive oxygen species and their reaction products, such as the hydroxyl radical, are very harmful to cells, as
they oxidize proteins and cause mutations in DNA. This cellular damage might contribute to disease and is proposed
as one cause of aging.[78] [79]
The cytochrome c oxidase complex is highly efficient at reducing oxygen to water, and it releases very few partly
reduced intermediates; however small amounts of superoxide anion and peroxide are produced by the electron
transport chain.[80] Particularly important is the reduction of coenzyme Q in complex III, as a highly reactive
ubisemiquinone free radical is formed as an intermediate in the Q cycle. This unstable species can lead to electron
"leakage" when electrons transfer directly to oxygen, forming superoxide.[81] As the production of reactive oxygen
species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that
mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP
production against oxidant generation.[82] For instance, oxidants can activate uncoupling proteins that reduce
membrane potential.[83]
To counteract these reactive oxygen species, cells contain numerous antioxidant systems, including antioxidant
vitamins such as vitamin C and vitamin E, and antioxidant enzymes such as superoxide dismutase, catalase, and
peroxidases,[77] which detoxify the reactive species, limiting damage to the cell.
Oxidative phosphorylation 263

Inhibitors
There are several well-known drugs and toxins that inhibit oxidative phosphorylation. Although any one of these
toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest
of the process. For example, if oligomycin inhibits ATP synthase, protons cannot pass back into the
mitochondrion.[84] As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them
to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration
of NAD+ falls below the concentration that these enzymes can use.

Compounds Use Effect on oxidative phosphorylation

Cyanide Poisons Inhibit the electron transport chain by binding more strongly than oxygen to the Fe–Cu center in cytochrome c
Carbon monoxide [85]
oxidase, preventing the reduction of oxygen.
Azide

Oligomycin Antibiotic Inhibits ATP synthase by blocking the flow of protons through the F subunit.[84]
o

CCCP Poisons Ionophores that disrupt the proton gradient by carrying protons across a membrane. This ionophore uncouples
2,4-Dinitrophenol [86]
proton pumping from ATP synthesis because it carries protons across the inner mitochondrial membrane.

Rotenone Pesticide Prevents the transfer of electrons from complex I to ubiquinone by blocking the ubiquinone-binding site.[87]

Malonate and [88]

Competitive inhibitors of succinate dehydrogenase (complex II).
oxaloacetate

Not all inhibitors of oxidative phosphorylation are toxins. In brown adipose tissue, regulated proton channels called
uncoupling proteins can uncouple respiration from ATP synthesis.[89] This rapid respiration produces heat, and is
particularly important as a way of maintaining body temperature for hibernating animals, although these proteins
may also have a more general function in cells' responses to stress.[90]

History
Further information: History of biochemistry and History of molecular biology
The field of oxidative phosphorylation began with the report in 1906 by Arthur Harden of a vital role for phosphate
in cellular fermentation, but initially only sugar phosphates were known to be involved.[91] However, in the early
1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by Herman
Kalckar,[92] confirming the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in
1941.[93] Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NADH linked metabolic
pathways such as the citric acid cycle and the synthesis of ATP.[94]
For another twenty years, the mechanism by which ATP is generated remained mysterious, with scientists searching
for an elusive "high-energy intermediate" that would link oxidation and phosphorylation reactions.[95] This puzzle
was solved by Peter D. Mitchell with the publication of the chemiosmotic theory in 1961.[96] At first, this proposal
was highly controversial, but it was slowly accepted and Mitchell was awarded a Nobel prize in 1978.[97] [98]
Subsequent research concentrated on purifying and characterizing the enzymes involved, with major contributions
being made by David E. Green on the complexes of the electron-transport chain, as well as Efraim Racker on the
ATP synthase.[99] A critical step towards solving the mechanism of the ATP synthase was provided by Paul D.
Boyer, by his development in 1973 of the "binding change" mechanism, followed by his radical proposal of
rotational catalysis in 1982.[73] [100] More recent work has included structural studies on the enzymes involved in
oxidative phosphorylation by John E. Walker, with Walker and Boyer being awarded a Nobel Prize in 1997.[101]
Oxidative phosphorylation 264

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Further reading
Introductory
• Nelson DL; Cox MM (2004). Lehninger Principles of Biochemistry (4th ed.). W. H. Freeman.
ISBN 0-7167-4339-6.
• Schneider ED; Sagan D (2006). Into the Cool: Energy Flow, Thermodynamics and Life (1st ed.). University of
Chicago Press. ISBN 0-226-73937-6.
• Lane N (2006). Power, Sex, Suicide: Mitochondria and the Meaning of Life (1st ed.). Oxford University Press,
USA. ISBN 0-19-920564-7.
Advanced
• Nicholls DG; Ferguson SJ (2002). Bioenergetics 3 (1st ed.). Academic Press. ISBN 0-12-518121-3.
• Haynie D (2001). Biological Thermodynamics (1st ed.). Cambridge University Press. ISBN 0-521-79549-4.
• Rajan SS (2003). Introduction to Bioenergetics (1st ed.). Anmol. ISBN 8-126-11364-2.
Oxidative phosphorylation 268

• Wikstrom M (Ed) (2005). Biophysical and Structural Aspects of Bioenergetics (1st ed.). Royal Society of
Chemistry. ISBN 0-85404-346-2.

External links
General resources
• Animated diagrams illustrating oxidative phosphorylation (http://www.wiley.com/legacy/college/boyer/
0470003790/animations/electron_transport/electron_transport.htm) Wiley and Co Concepts in Biochemistry
• ATP synthase - the rotary engine in the cell (http://www.res.titech.ac.jp/~seibutu/) Brief introduction,
including videos of microscope images of the enzyme rotating, at Tokyo Institute of Technology
• On-line biophysics lectures (http://www.life.uiuc.edu/crofts/bioph354/) Antony Crofts, University of Illinois
at Urbana-Champaign
Structural resources
• Animations of the ATP synthase (http://nature.berkeley.edu/~hongwang/Project/ATP_synthase/) Hongyun
Wang and George Oster, University of California, Berkeley
• PDB molecule of the month:
• ATP synthase (http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/
pdb72_1.html)
• Cytochrome c (http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/
pdb36_1.html)
• Cytochrome c oxidase (http://www.rcsb.org/pdb/static.do?p=education_discussion/
molecule_of_the_month/pdb5_1.html)
• Interactive molecular models at Universidade Fernando Pessoa:
• NADH dehydrogenase (http://www2.ufp.pt/~pedros/anim/2frame-ien.htm)
• succinate dehydrogenase (http://www2.ufp.pt/~pedros/anim/2frame-iien.htm)
• Coenzyme Q - cytochrome c reductase (http://www2.ufp.pt/~pedros/anim/2frame-iiien.htm)
• cytochrome c oxidase (http://www2.ufp.pt/~pedros/anim/2frame-iven.htm)
 269

Photosynthesis

Photosynthesis
Photosynthesis (English pronunciation:
/foʊtoʊˈsɪnθəsɪs/; from the Greek
φώτο- [photo-], "light," and σύνθεσις
[synthesis], "putting together",
"composition") is a chemical process
that converts carbon dioxide into
organic compounds, especially sugars,
using the energy from sunlight.[1]
Photosynthesis occurs in plants, algae,
and many species of bacteria, but not
in archaea. Photosynthetic organisms
are called photoautotrophs, since they
can create their own food. In plants,
algae, and cyanobacteria, Composite image showing the global distribution of photosynthesis, including both
photosynthesis uses carbon dioxide oceanic phytoplankton and vegetation

and water, releasing oxygen as a waste

product. Photosynthesis is vital for all
aerobic life on Earth. In addition to
maintaining normal levels of oxygen in
the atmosphere, photosynthesis is the
Overall equation for the type of photosynthesis that occurs in plants
source of energy for nearly all life on
earth, either directly, through primary
production, or indirectly, as the ultimate source of the energy in their food,[2] the exceptions being chemoautotrophs
that live in rocks or around deep sea hydrothermal vents. The rate of energy capture by photosynthesis is immense,
approximately 100 terawatts,[3] which is about six times larger than the power consumption of human civilization.[4]
As well as energy, photosynthesis is also the source of the carbon in all the organic compounds within organisms'
bodies. In all, photosynthetic organisms convert around 100–115  petagrams of carbon into biomass per year.[5] [6]

Although photosynthesis can happen in different ways in different species, some features are always the same. For
example, the process always begins when energy from light is absorbed by proteins called photosynthetic reaction
centers that contain chlorophylls. In plants, these proteins are held inside organelles called chloroplasts, while in
bacteria they are embedded in the plasma membrane. Some of the light energy gathered by chlorophylls is stored in
the form of adenosine triphosphate (ATP). The rest of the energy is used to remove electrons from a substance such
as water. These electrons are then used in the reactions that turn carbon dioxide into organic compounds. In plants,
algae and cyanobacteria, this is done by a sequence of reactions called the Calvin cycle, but different sets of
reactions are found in some bacteria, such as the reverse Krebs cycle in Chlorobium. Many photosynthetic organisms
have adaptations that concentrate or store carbon dioxide. This helps reduce a wasteful process called
photorespiration that can consume part of the sugar produced during photosynthesis.
Photosynthesis 270

The first photosynthetic organisms probably evolved about 3500 [7]

million years ago, early in the evolutionary history of life, when all
forms of life on Earth were microorganisms and the atmosphere had
much more carbon dioxide. They most likely used hydrogen or
hydrogen sulfide as sources of electrons, rather than water.[8]
Cyanobacteria appeared later, around 3000 [9] million years ago, and
drastically changed the Earth when they began to oxygenate the
atmosphere, beginning about 2400 [10] million years ago.[11] This new
atmosphere allowed the evolution of complex life such as protists.
Eventually, no later than a billion years ago, one of these protists
formed a symbiotic relationship with a cyanobacterium, producing the
ancestor of many plants and algae.[12] The chloroplasts in modern
plants are the descendants of these ancient symbiotic cyanobacteria.[13]

Schematic of photosynthesis in plants

Overview
Photosynthetic organisms are photoautotrophs, which means that they
are repositories of energy, they are able to synthesize food directly
from carbon dioxide, water, and using energy from light. They accrue
it as part of their potential energy. However, not all organisms that use
light as a source of energy carry out photosynthesis, since
photoheterotrophs use organic compounds, rather than carbon dioxide,
as a source of carbon.[2] In plants, algae and cyanobacteria,
photosynthesis releases oxygen. This is called oxygenic photosynthesis.
Although there are some differences between oxygenic photosynthesis
in plants, algae and cyanobacteria, the overall process is quite similar
in these organisms. However, there are some types of bacteria that
carry out anoxygenic photosynthesis, which consumes carbon dioxide
but does not release oxygen.

Carbon dioxide is converted into sugars in a process called carbon Photosynthesis changes sunlight into chemical
fixation. Carbon fixation is a redox reaction, so photosynthesis needs energy, splits water to liberate O2, and fixes CO2
to supply both a source of energy to drive this process, and the into sugar.

electrons needed to convert carbon dioxide into a carbohydrate, which

is a reduction reaction. In general outline, photosynthesis is the opposite of cellular respiration, where glucose and
other compounds are oxidized to produce carbon dioxide, water, and release chemical energy. However, the two
processes take place through a different sequence of chemical reactions and in different cellular compartments.

The general equation for photosynthesis is therefore:

2n CO2 + 2n DH2 + photons → 2(CH2O)n + 2n DO
Carbon dioxide + electron donor + light energy → carbohydrate + oxidized electron donor
In oxygenic photosynthesis water is the electron donor and, since its hydrolysis releases oxygen, the equation for this
process is:
Photosynthesis 271

2n CO2 + 4n H2O + photons → 2(CH2O)n + 2n O2 + 2n H2O

carbon dioxide + water + light energy → carbohydrate + oxygen + water
Often 2n water molecules are cancelled on both sides, yielding:
2n CO2 + 2n H2O + photons → 2(CH2O)n + 2n O2
carbon dioxide + water + light energy → carbohydrate + oxygen
Other processes substitute other compounds (such as arsenite) for water in the electron-supply role; the microbes use
sunlight to oxidize arsenite to arsenate:[14] The equation for this reaction is:
CO2 + (AsO33–) + photons → (AsO43–) + CO [15]
carbon dioxide + arsenite + light energy → arsenate + carbon monoxide (used to build other compounds in
subsequent reactions)
Photosynthesis occurs in two stages. In the first stage, light-dependent reactions or light reactions capture the energy
of light and use it to make the energy-storage molecules ATP and NADPH. During the second stage, the
light-independent reactions use these products to capture and reduce carbon dioxide.
Most organisms that utilize photosynthesis to produce oxygen use visible light to do so, although at least three use
infrared radiation.[16]

Photosynthetic membranes and organelles

The proteins that gather light for photosynthesis
are embedded within cell membranes. The
simplest way these are arranged is in
photosynthetic bacteria, where these proteins are
held within the plasma membrane.[17] However,
this membrane may be tightly folded into
cylindrical sheets called thylakoids,[18] or
bunched up into round vesicles called
intracytoplasmic membranes.[19] These structures
can fill most of the interior of a cell, giving the Chloroplast ultrastructure: 1. outer membrane 2. intermembrane space3.
inner membrane (1+2+3: envelope) 4. stroma (aqueous fluid) 5. thylakoid
membrane a very large surface area and therefore
lumen (inside of thylakoid) 6. thylakoid membrane 7. granum (stack of
increasing the amount of light that the bacteria thylakoids) 8. thylakoid (lamella) 9. starch 10. ribosome 11. plastidial DNA
can absorb.[18] 12. plastoglobule (drop of lipids)

In plants and algae, photosynthesis takes place in

organelles called chloroplasts. A typical plant cell contains about 10 to 100 chloroplasts. The chloroplast is enclosed
by a membrane. This membrane is composed of a phospholipid inner membrane, a phospholipid outer membrane,
and an intermembrane space between them. Within the membrane is an aqueous fluid called the stroma. The stroma
contains stacks (grana) of thylakoids, which are the site of photosynthesis. The thylakoids are flattened disks,
bounded by a membrane with a lumen or thylakoid space within it. The site of photosynthesis is the thylakoid
membrane, which contains integral and peripheral membrane protein complexes, including the pigments that absorb
light energy, which form the photosystems.

Plants absorb light primarily using the pigment chlorophyll, which is the reason that most plants have a green color.
Besides chlorophyll, plants also use pigments such as carotenes and xanthophylls.[20] Algae also use chlorophyll, but
various other pigments are present as phycocyanin, carotenes, and xanthophylls in green algae, phycoerythrin in red
algae (rhodophytes) and fucoxanthin in brown algae and diatoms resulting in a wide variety of colors.
These pigments are embedded in plants and algae in special antenna-proteins. In such proteins all the pigments are
ordered to work well together. Such a protein is also called a light-harvesting complex.
Photosynthesis 272

Although all cells in the green parts of a plant have chloroplasts, most of the energy is captured in the leaves. The
cells in the interior tissues of a leaf, called the mesophyll, can contain between 450,000 and 800,000 chloroplasts for
every square millimeter of leaf. The surface of the leaf is uniformly coated with a water-resistant waxy cuticle that
protects the leaf from excessive evaporation of water and decreases the absorption of ultraviolet or blue light to
reduce heating. The transparent epidermis layer allows light to pass through to the palisade mesophyll cells where
most of the photosynthesis takes place.

Light reactions
In the light reactions, one molecule of
the pigment chlorophyll absorbs one
photon and loses one electron. This
electron is passed to a modified form
of chlorophyll called pheophytin,
which passes the electron to a quinone
molecule, allowing the start of a flow
of electrons down an electron transport
chain that leads to the ultimate
reduction of NADP to NADPH. In
addition, this creates a proton gradient
across the chloroplast membrane; its
Light-dependent reactions of photosynthesis at the thylakoid membrane
dissipation is used by ATP synthase
for the concomitant synthesis of ATP.
The chlorophyll molecule regains the lost electron from a water molecule through a process called photolysis, which
releases a dioxygen (O2) molecule. The overall equation for the light-dependent reactions under the conditions of
non-cyclic electron flow in green plants is:[21]

2 H2O + 2 NADP+ + 3 ADP + 3 Pi + light → 2 NADPH + 2 H+ + 3 ATP + O2

Not all wavelengths of light can support photosynthesis. The photosynthetic action spectrum depends on the type of
accessory pigments present. For example, in green plants, the action spectrum resembles the absorption spectrum for
chlorophylls and carotenoids with peaks for violet-blue and red light. In red algae, the action spectrum overlaps with
the absorption spectrum of phycobilins for red blue-green light, which allows these algae to grow in deeper waters
that filter out the longer wavelengths used by green plants. The non-absorbed part of the light spectrum is what gives
photosynthetic organisms their color (e.g., green plants, red algae, purple bacteria) and is the least effective for
photosynthesis in the respective organisms.
Photosynthesis 273

Z scheme

The "Z scheme"

In plants, light-dependent reactions occur in the thylakoid membranes of the chloroplasts and use light energy to
synthesize ATP and NADPH. The light-dependent reaction has two forms: cyclic and non-cyclic. In the non-cyclic
reaction, the photons are captured in the light-harvesting antenna complexes of photosystem II by chlorophyll and
other accessory pigments (see diagram at right). When a chlorophyll molecule at the core of the photosystem II
reaction center obtains sufficient excitation energy from the adjacent antenna pigments, an electron is transferred to
the primary electron-acceptor molecule, pheophytin, through a process called photoinduced charge separation. These
electrons are shuttled through an electron transport chain, the so-called Z-scheme shown in the diagram, that initially
functions to generate a chemiosmotic potential across the membrane. An ATP synthase enzyme uses the
chemiosmotic potential to make ATP during photophosphorylation, whereas NADPH is a product of the terminal
redox reaction in the Z-scheme. The electron enters a chlorophyll molecule in Photosystem I. The electron is excited
due to the light absorbed by the photosystem. A second electron carrier accepts the electron, which again is passed
down lowering energies of electron acceptors. The energy created by the electron acceptors is used to move
hydrogen ions across the thylakoid membrane into the lumen. The electron is used to reduce the co-enzyme NADP,
which has functions in the light-independent reaction. The cyclic reaction is similar to that of the non-cyclic, but
differs in the form that it generates only ATP, and no reduced NADP (NADPH) is created. The cyclic reaction takes
place only at photosystem I. Once the electron is displaced from the photosystem, the electron is passed down the
electron acceptor molecules and returns to photosystem I, from where it was emitted, hence the name cyclic reaction.

Water photolysis
The NADPH is the main reducing agent in chloroplasts, providing a source of energetic electrons to other reactions.
Its production leaves chlorophyll with a deficit of electrons (oxidized), which must be obtained from some other
reducing agent. The excited electrons lost from chlorophyll in photosystem I are replaced from the electron transport
chain by plastocyanin. However, since photosystem II includes the first steps of the Z-scheme, an external source of
electrons is required to reduce its oxidized chlorophyll a molecules. The source of electrons in green-plant and
cyanobacterial photosynthesis is water. Two water molecules are oxidized by four successive charge-separation
reactions by photosystem II to yield a molecule of diatomic oxygen and four hydrogen ions; the electron yielded in
each step is transferred to a redox-active tyrosine residue that then reduces the photoxidized paired-chlorophyll a
species called P680 that serves as the primary (light-driven) electron donor in the photosystem II reaction center. The
oxidation of water is catalyzed in photosystem II by a redox-active structure that contains four manganese ions and a
calcium ion; this oxygen-evolving complex binds two water molecules and stores the four oxidizing equivalents that
are required to drive the water-oxidizing reaction. Photosystem II is the only known biological enzyme that carries
out this oxidation of water. The hydrogen ions contribute to the transmembrane chemiosmotic potential that leads to
ATP synthesis. Oxygen is a waste product of light-dependent reactions, but the majority of organisms on Earth use
Photosynthesis 274

oxygen for cellular respiration, including photosynthetic organisms.[22] [23]

Light-independent reactions

The Calvin Cycle

In the light-independent or dark reactions the enzyme RuBisCO captures CO2 from the atmosphere and in a process
that requires the newly formed NADPH, called the Calvin-Benson Cycle, releases three-carbon sugars, which are
later combined to form sucrose and starch. The overall equation for the light-independent reactions in green plants
is:[21]
3 CO2 + 9 ATP + 6 NADPH + 6 H+ → C3H6O3-phosphate + 9 ADP + 8 Pi + 6 NADP+ + 3 H2O
To be more specific, carbon fixation
produces an intermediate product,
which is then converted to the final
carbohydrate products. The carbon
skeletons produced by photosynthesis
are then variously used to form other
organic compounds, such as the
building material cellulose, as
precursors for lipid and amino acid
biosynthesis, or as a fuel in cellular
respiration. The latter occurs not only
in plants but also in animals when the
energy from plants gets passed through
a food chain.

The fixation or reduction of carbon

dioxide is a process in which carbon
dioxide combines with a five-carbon
sugar, ribulose 1,5-bisphosphate
Overview of the Calvin cycle and carbon fixation
(RuBP), to yield two molecules of a
three-carbon compound, glycerate
3-phosphate (GP), also known as 3-phosphoglycerate (PGA). GP, in the presence of ATP and NADPH from the
light-dependent stages, is reduced to glyceraldehyde 3-phosphate (G3P). This product is also referred to as
3-phosphoglyceraldehyde (PGAL) or even as triose phosphate. Triose is a 3-carbon sugar (see carbohydrates). Most
(5 out of 6 molecules) of the G3P produced is used to regenerate RuBP so the process can continue (see
Calvin-Benson cycle). The 1 out of 6 molecules of the triose phosphates not "recycled" often condense to form
hexose phosphates, which ultimately yield sucrose, starch and cellulose. The sugars produced during carbon
metabolism yield carbon skeletons that can be used for other metabolic reactions like the production of amino acids
and lipids.
Photosynthesis 275

Carbon concentrating mechanisms

On land

In hot and dry conditions, plants close their stomata

to prevent the loss of water. Under these conditions,
CO2 will decrease, and oxygen gas, produced by
the light reactions of photosynthesis, will decrease
in the stem, not leaves, causing an increase of
photorespiration by the oxygenase activity of
ribulose-1,5-bisphosphate carboxylase/oxygenase
and decrease in carbon fixation. Some plants have
evolved mechanisms to increase the CO2
concentration in the leaves under these conditions.

C4 plants chemically fix carbon dioxide in the cells

of the mesophyll by adding it to the three-carbon
molecule phosphoenolpyruvate (PEP), a reaction
catalyzed by an enzyme called PEP carboxylase,
creating the four-carbon organic acid oxaloacetic
acid. Oxaloacetic acid or malate synthesized by this
process is then translocated to specialized bundle
sheath cells where the enzyme RuBisCO and other
Calvin cycle enzymes are located, and where CO2
released by decarboxylation of the four-carbon
acids is then fixed by RuBisCO activity to the
three-carbon sugar 3-phosphoglyceric acids. The
physical separation of RuBisCO from the Overview of C4 carbon fixation
oxygen-generating light reactions reduces
photorespiration and increases CO2 fixation and, thus, photosynthetic capacity of the leaf.[24] C4 plants can produce
more sugar than C3 plants in conditions of high light and temperature. Many important crop plants are C4 plants,
including maize, sorghum, sugarcane, and millet. Plants that do not use PEP-carboxylase in carbon fixation are
called C3 plants because the primary carboxylation reaction, catalyzed by RuBisCO, produces the three-carbon sugar
3-phosphoglyceric acids directly in the Calvin-Benson cycle. Over 90% of plants use C3 carbon fixation, compared
to 3% that use C4 carbon fixation.[25]

Xerophytes, such as cacti and most succulents, also use PEP carboxylase to capture carbon dioxide in a process
called Crassulacean acid metabolism (CAM). In contrast to C4 metabolism, which physically separates the CO2
fixation to PEP from the Calvin cycle, CAM temporally separates these two processes. CAM plants have a different
leaf anatomy from C3 plants, and fix the CO2 at night, when their stomata are open. CAM plants store the CO2
mostly in the form of malic acid via carboxylation of phosphoenolpyruvate to oxaloacetate, which is then reduced to
malate. Decarboxylation of malate during the day releases CO2 inside the leaves, thus allowing carbon fixation to
3-phosphoglycerate by RuBisCO. Sixteen thousand species of plants use CAM.[26]
Photosynthesis 276

In water
Cyanobacteria possess carboxysomes, which increase the concentration of CO2 around RuBisCO to increase the rate
of photosynthesis. This operates by carbonic anhydrase, producing hydrocarbonate ions (HCO3–), which are then
pumped into the carboxysome, before being processed by a different carbonic anhydrase to produce CO2.[27]
Pyrenoids in algae and hornworts also act to concentrate CO2 around rubisco.[28]

Order and kinetics

The overall process of photosynthesis takes place in four stages:[6]

Stage Description Time scale

1 Energy transfer in antenna chlorophyll (thylakoid membranes) femtosecond to picosecond

2 Transfer of electrons in photochemical reactions (thylakoid membranes) picosecond to nanosecond

3 Electron transport chain and ATP synthesis (thylakoid membranes) microsecond to millisecond

4 Carbon fixation and export of stable products millisecond to second

Efficiency
Plants usually convert light into chemical energy with a photosynthetic efficiency of 3–6%.[29] Actual plants'
photosynthetic efficiency varies with the frequency of the light being converted, light intensity, temperature and
proportion of carbon dioxide in the atmosphere, and can vary from 0.1% to 8%.[30] By comparison, solar panels
convert light into electric energy at an efficiency of approximately 6–20% for mass-produced panels, and above 40%
in laboratory devices.

Evolution
Early photosynthetic systems, such as those
from green and purple sulfur and green and
purple nonsulfur bacteria, are thought to
have been anoxygenic, using various
molecules as electron donors. Green and
purple sulfur bacteria are thought to have
used hydrogen and sulfur as an electron
donor. Green nonsulfur bacteria used
various amino and other organic acids.
Purple nonsulfur bacteria used a variety of
nonspecific organic molecules. The use of
these molecules is consistent with the
geological evidence that the atmosphere was
highly reduced at that time.
Plant cells with visible chloroplasts (from a moss, Plagiomnium affine)
Fossils of what are thought to be
filamentous photosynthetic organisms have
been dated at 3.4 billion years old.[31] [32]
The main source of oxygen in the atmosphere is oxygenic photosynthesis, and its first appearance is sometimes
referred to as the oxygen catastrophe. Geological evidence suggests that oxygenic photosynthesis, such as that in
cyanobacteria, became important during the Paleoproterozoic era around 2 billion years ago. Modern photosynthesis
Photosynthesis 277

in plants and most photosynthetic prokaryotes is oxygenic. Oxygenic photosynthesis uses water as an electron donor,
which is oxidized to molecular oxygen (O2) in the photosynthetic reaction center.

Symbiosis and the origin of chloroplasts

Several groups of animals have formed symbiotic relationships with photosynthetic algae. These are most common
in corals, sponges and sea anemones. It is presumed that this is due to the particularly simple body plans and large
surface areas of these animals compared to their volumes.[33] In addition, a few marine mollusks Elysia viridis and
Elysia chlorotica also maintain a symbiotic relationship with chloroplasts they capture from the algae in their diet
and then store in their bodies. This allows the mollusks to survive solely by photosynthesis for several months at a
time.[34] [35] Some of the genes from the plant cell nucleus have even been transferred to the slugs, so that the
chloroplasts can be supplied with proteins that they need to survive.[36]
An even closer form of symbiosis may explain the origin of chloroplasts. Chloroplasts have many similarities with
photosynthetic bacteria, including a circular chromosome, prokaryotic-type ribosomes, and similar proteins in the
photosynthetic reaction center.[37] [38] The endosymbiotic theory suggests that photosynthetic bacteria were acquired
(by endocytosis) by early eukaryotic cells to form the first plant cells. Therefore, chloroplasts may be photosynthetic
bacteria that adapted to life inside plant cells. Like mitochondria, chloroplasts still possess their own DNA, separate
from the nuclear DNA of their plant host cells and the genes in this chloroplast DNA resemble those in
cyanobacteria.[39] DNA in chloroplasts codes for redox proteins such as photosynthetic reaction centers. The CoRR
Hypothesis proposes that this Co-location is required for Redox Regulation.

Cyanobacteria and the evolution of photosynthesis

The biochemical capacity to use water as the source for electrons in photosynthesis evolved once, in a common
ancestor of extant cyanobacteria. The geological record indicates that this transforming event took place early in
Earth's history, at least 2450–2320 million years ago (Ma), and, it is speculated, much earlier.[40] Available evidence
from geobiological studies of Archean (>2500 Ma) sedimentary rocks indicates that life existed 3500 Ma, but the
question of when oxygenic photosynthesis evolved is still unanswered. A clear paleontological window on
cyanobacterial evolution opened about 2000 Ma, revealing an already-diverse biota of blue-greens. Cyanobacteria
remained principal primary producers throughout the Proterozoic Eon (2500–543 Ma), in part because the redox
structure of the oceans favored photoautotrophs capable of nitrogen fixation. Green algae joined blue-greens as
major primary producers on continental shelves near the end of the Proterozoic, but only with the Mesozoic (251–65
Ma) radiations of dinoflagellates, coccolithophorids, and diatoms did primary production in marine shelf waters take
modern form. Cyanobacteria remain critical to marine ecosystems as primary producers in oceanic gyres, as agents
of biological nitrogen fixation, and, in modified form, as the plastids of marine algae.[41]
A 2010 study by researchers at Tel Aviv University discovered that the Oriental hornet (Vespa orientalis) converts
sunlight into electric power using a pigment called xanthopterin. This is the first scientific evidence of a member of
the animal kingdom engaging in photosynthesis.[42]

Discovery
Although some of the steps in photosynthesis are still not completely understood, the overall photosynthetic equation
has been known since the 19th century.
Jan van Helmont began the research of the process in the mid-17th century when he carefully measured the mass of
the soil used by a plant and the mass of the plant as it grew. After noticing that the soil mass changed very little, he
hypothesized that the mass of the growing plant must come from the water, the only substance he added to the potted
plant. His hypothesis was partially accurate — much of the gained mass also comes from carbon dioxide as well as
water. However, this was a signaling point to the idea that the bulk of a plant's biomass comes from the inputs of
photosynthesis, not the soil itself.
Photosynthesis 278

Joseph Priestley, a chemist and minister, discovered that, when he isolated a volume of air under an inverted jar, and
burned a candle in it, the candle would burn out very quickly, much before it ran out of wax. He further discovered
that a mouse could similarly "injure" air. He then showed that the air that had been "injured" by the candle and the
mouse could be restored by a plant.
In 1778, Jan Ingenhousz, court physician to the Austrian Empress, repeated Priestley's experiments. He discovered
that it was the influence of sunlight on the plant that could cause it to revive a mouse in a matter of hours.
In 1796, Jean Senebier, a Swiss pastor, botanist, and naturalist, demonstrated that green plants consume carbon
dioxide and release oxygen under the influence of light. Soon afterward, Nicolas-Théodore de Saussure showed that
the increase in mass of the plant as it grows could not be due only to uptake of CO2 but also to the incorporation of
water. Thus, the basic reaction by which photosynthesis is used to produce food (such as glucose) was outlined.
Cornelis Van Niel made key discoveries explaining the chemistry of photosynthesis. By studying purple sulfur
bacteria and green bacteria he was the first scientist to demonstrate that photosynthesis is a light-dependent redox
reaction, in which hydrogen reduces carbon dioxide.
Robert Emerson discovered two light reactions by testing plant productivity using different wavelengths of light.
With the red alone, the light reactions were suppressed. When blue and red were combined, the output was much
more substantial. Thus, there were two photosystems, one absorbing up to 600 nm wavelengths, the other up to 700
nm. The former is known as PSII, the latter is PSI. PSI contains only chlorophyll a, PSII contains primarily
chlorophyll a with most of the available chlorophyll b, among other pigment. These include phycobilins, which are
the red and blue pigments of red and blue algae respectively, and fucoxanthol for brown algae and diatoms. The
process is most productive when absorption of quanta are equal in both the PSII and PSI, assuring that input energy
from the antenna complex is divided between the PSI and PSII system, which in turn powers the photochemistry.[6]
Robert Hill thought that a complex of reactions consisting of an intermediate to cytochrome b6 (now a
plastoquinone), another is from cytochrome f to a step in the carbohydrate-generating mechanisms. These are linked
by plastoquinone, which does require energy to reduce cytochrome f for it is a sufficient reductant. Further
experiments to prove that the oxygen developed during the photosynthesis of green plants came from water, were
performed by Hill in 1937 and 1939. He showed that isolated chloroplasts give off oxygen in the presence of
unnatural reducing agents like iron oxalate, ferricyanide or benzoquinone after exposure to light. The Hill reaction is
as follows:
2 H2O + 2 A + (light, chloroplasts) → 2 AH2 + O2
where A is the electron acceptor. Therefore, in light, the electron acceptor is reduced and oxygen is evolved.
Samuel Ruben and Martin Kamen used radioactive isotopes to determine that the oxygen liberated in photosynthesis
came from the water.
Melvin Calvin and Andrew Benson, along with James Bassham, elucidated the path of carbon assimilation (the
photosynthetic carbon reduction cycle) in plants. The carbon reduction cycle is known as the Calvin cycle, which
ignores the contribution of Bassham and Benson. Many scientists refer to the cycle as the Calvin-Benson Cycle,
Benson-Calvin, and some even call it the Calvin-Benson-Bassham (or CBB) Cycle.
Nobel Prize-winning scientist Rudolph A. Marcus was able to discover the function and significance of the electron
transport chain.
Otto Heinrich Warburg and Dean Burk discovered the I-quantum photosynthesis reaction that splits the CO2,
activated by the respiration.[43]
Louis N.M. Duysens and Jan Amesz discovered that chlorophyll a will absorb one light, oxidize cytochrome f,
chlorophyll a (and other pigments) will absorb another light, but will reduce this same oxidized cytochrome, stating
the two light reactions are in series.
Photosynthesis 279

Factors
There are three main factors affecting photosynthesis and several
corollary factors. The three main are:
• Light irradiance and wavelength
• Carbon dioxide concentration
• Temperature.

Light intensity (irradiance), wavelength and

temperature
In the early 20th century, Frederick Frost Blackman along with Albert The leaf is the primary site of photosynthesis in
plants.
Einstein investigated the effects of light intensity (irradiance) and
temperature on the rate of carbon assimilation.
• At constant temperature, the rate of carbon assimilation varies with irradiance, initially increasing as the
irradiance increases. However, at higher irradiance, this relationship no longer holds and the rate of carbon
assimilation reaches a plateau.
• At constant irradiance, the rate of carbon assimilation increases as the temperature is increased over a limited
range. This effect is seen only at high irradiance levels. At low irradiance, increasing the temperature has little
influence on the rate of carbon assimilation.
These two experiments illustrate vital points: First, from research it is known that, in general, photochemical
reactions are not affected by temperature. However, these experiments clearly show that temperature affects the rate
of carbon assimilation, so there must be two sets of reactions in the full process of carbon assimilation. These are, of
course, the light-dependent 'photochemical' stage and the light-independent, temperature-dependent stage. Second,
Blackman's experiments illustrate the concept of limiting factors. Another limiting factor is the wavelength of light.
Cyanobacteria, which reside several meters underwater, cannot receive the correct wavelengths required to cause
photoinduced charge separation in conventional photosynthetic pigments. To combat this problem, a series of
proteins with different pigments surround the reaction center. This unit is called a phycobilisome.

Carbon dioxide levels and photorespiration

As carbon dioxide concentrations rise, the rate at which sugars are made by the light-independent reactions increases
until limited by other factors. RuBisCO, the enzyme that captures carbon dioxide in the light-independent reactions,
has a binding affinity for both carbon dioxide and oxygen. When the concentration of carbon dioxide is high,
RuBisCO will fix carbon dioxide. However, if the carbon dioxide concentration is low, RuBisCO will bind oxygen
instead of carbon dioxide. This process, called photorespiration, uses energy, but does not produce sugars.
RuBisCO oxygenase activity is disadvantageous to plants for several reasons:
1. One product of oxygenase activity is phosphoglycolate (2 carbon) instead of 3-phosphoglycerate (3 carbon).
Phosphoglycolate cannot be metabolized by the Calvin-Benson cycle and represents carbon lost from the cycle. A
high oxygenase activity, therefore, drains the sugars that are required to recycle ribulose 5-bisphosphate and for
the continuation of the Calvin-Benson cycle.
2. Phosphoglycolate is quickly metabolized to glycolate that is toxic to a plant at a high concentration; it inhibits
photosynthesis.
3. Salvaging glycolate is an energetically expensive process that uses the glycolate pathway, and only 75% of the
carbon is returned to the Calvin-Benson cycle as 3-phosphoglycerate. The reactions also produce ammonia (NH3),
which is able to diffuse out of the plant, leading to a loss of nitrogen.
A highly simplified summary is:
Photosynthesis 280

2 glycolate + ATP → 3-phosphoglycerate + carbon dioxide + ADP + NH3

The salvaging pathway for the products of RuBisCO oxygenase activity is more commonly known as
photorespiration, since it is characterized by light-dependent oxygen consumption and the release of carbon dioxide.

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Further reading

Books
• Asimov, Isaac (1968). Photosynthesis. New York, London: Basic Books, Inc.. ISBN 0-465-05703-9.
• Bidlack JE; Stern KR, Jansky S (2003). Introductory plant biology. New York: McGraw-Hill.
ISBN 0-07-290941-2.
• Blankenship RE (2008). Molecular Mechanisms of Photosynthesis (2nd ed.). John Wiley & Sons Inc.
ISBN 0-470-71451-4.
• Govindjee (1975). Bioenergetics of photosynthesis. Boston: Academic Press. ISBN 0-12-294350-3.
• Govindjee Beatty JT,Gest H, Allen JF (2006). Discoveries in Photosynthesis. Advances in Photosynthesis and
Respiration. 20. Berlin: Springer. ISBN 1-4020-3323-0.
• Gregory RL (1971). Biochemistry of photosynthesis. New York: Wiley-Interscience. ISBN 0-471-32675-5.
• Rabinowitch E, Govindjee (1969). Photosynthesis. London: J. Wiley. ISBN 0-471-70424-5.
• Reece, J, Campbell, N (2005). Biology. San Francisco: Pearson, Benjamin Cummings. ISBN 0-8053-7146-X.
Photosynthesis 282

Papers
• Evolutionary relationships among photosynthetic prokaryotes : implications regarding the origin of
photosynthesis. (http://www.ncbi.nlm.nih.gov/pubmed/10361294)
• Origin and early evolution of photosynthesis. (http://www.ncbi.nlm.nih.gov/pubmed/11538390)
• Photosystem II: evolutionary perspectives (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693113/
?tool=pmcentrez)

External links
• A collection of photosynthesis pages for all levels from a renowned expert (Govindjee) (http://www.life.uiuc.
edu/govindjee/linksPSed.htm)
• In depth, advanced treatment of photosynthesis, also from Govindjee (http://www.life.uiuc.edu/govindjee/
paper/gov.html)
• Science Aid: Photosynthesis (http://scienceaid.co.uk/biology/biochemistry/photosynthesis.html) Article
appropriate for high school science
• Metabolism, Cellular Respiration and Photosynthesis – The Virtual Library of Biochemistry and Cell Biology
(http://www.biochemweb.org/metabolism.shtml)
• Overall examination of Photosynthesis at an intermediate level (http://www.chemsoc.org/networks/learnnet/
cfb/Photosynthesis.htm)
• Overall Energetics of Photosynthesis (http://www.life.uiuc.edu/govindjee/photosynBook.html)
• Photosynthesis Discovery Milestones (http://www.juliantrubin.com/bigten/photosynthesisexperiments.html)
– experiments and background
• The source of oxygen produced by photosynthesis (http://bcs.whfreeman.com/thelifewire/content/chp08/
0802001.html) Interactive animation, a textbook tutorial
• Jessica Marshall (2011-03-29). "First practical artificial leaf makes debut" (http://news.discovery.com/earth/
artificial-leaf-technology-solar-110329.html). Discovery News.
• Photosynthesis – Light Dependent & Light Independent Stages (http://www.biology-innovation.co.uk/pages/
plant-biology-ecology/photosynthesis/)
• Khan Academy, video introduction (http://www.khanacademy.org/video/photosynthesis?playlist=Biology)
 283

Lipid metabolism

Fatty acid synthesis

Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and malonyl-CoA precursors through action of
enzymes called fatty acid synthases. It is an important part of the lipogenesis process, which - together with
glycolysis - stands behind creating fats from blood sugar in living organisms.

Straight-Chain Fatty Acids

Straight-chain fatty acids occur in two types; saturated and unsaturated.

Saturated Straight-Chain Fatty Acids

Much like β-oxidation, straight-chain fatty acid synthesis occurs via
the six recurring reactions shown below, until the 16 carbon palmitic
acid is produced.[1]
The diagrams presented show how fatty acids are synthesized in
microorganisms and list the enzymes found in Escherichia coli.[1]
These reactions are performed by fatty acid synthase II (FASII), which
contain multiple enzymes that generally act as one complex. FASII is
present in prokaryotes, plants, fungi, parasites, as well as in
mitochondria.[2]
Synthesis of saturated fatty acids via Fatty Acid
In animals, as well as yeast and some fungi, these same reactions occur
Synthase II in E. coli
on fatty acid synthase I (FASI), a large dimeric protein, which has all
of the enzymatic activities required to create a fatty acid. FASI is less
efficient than FASII, however, it allows for the formation of more molecules, including “medium-chain” fatty acids
via early chain termination.[2]
Once a 16:0 carbon fatty acid has been formed it can undergo a number of modifications; particularly, by fatty acid
synthase III (FASIII), which uses 2 carbon molecules to elongate preformed fatty acids.[2]

Step Enzyme Reaction Description

(a) Acetyl CoA:ACP transacylase Activates acetyl CoA for reaction with malonyl-ACP

(b) Malonyl CoA:ACP Activates malonyl CoA for reaction with acetyl-ACP
transacylase
Fatty acid synthesis 284

(c) 3-ketoacyl-ACP synthetase Reacts priming acetyl-ACP with chain extending

malonyl-ACP.

(d) 3-ketoacyl-ACP reductase Reduces the carbon 3 ketone to a hydroxyl group

(e) 3-hydroxyacyl-ACP dehydrase Removes water

(f) Enoyl-ACP reductase Reduces the C3-C4 double bond.

Regulation
Acetyl-CoA is formed into malonyl-CoA by acetyl-CoA carboxylase, at which point malonyl-CoA is destined to
feed into the fatty acid synthesis pathway. Acetyl-CoA carboxylase is the point of regulation in saturated
straight-chain fatty acid synthesis, by both phosphorylation and allosteric regulation. Regulation by phosphorylation
occurs mostly in mammals, while allosteric regulation occurs in most organisms. Allosteric control occurs as
feedback inhibition by palmitol-CoA and activation by citrate. When there are high levels of palmitol-CoA, the final
product of saturated fatty acid synthesis, it allosterically inactivates acetyl-CoA carboxylase to prevent a build up of
fatty acids in cells. Citrate acts to activate acetyl-CoA carboxylase under high levels, because high levels indicate
there is enough acetyl-CoA to feed into the Krebs cycle and produce energy.[3]
De Novo Synthesis in Humans
In humans, fatty acids are predominantly formed in the liver and lactating mammary glands, and, to a lesser extent,
the adipose tissue. Most acetyl-CoA is formed from pyruvate by pyruvate dehydrogenase in the mitochondria.
Acetyl-CoA produced in the mitochondria is condensed with oxaloacetate by citrate synthase to form citrate, which
is then transported into the cytosol and broken down to yield acetyl-CoA and oxaloacetate by ATP citrate lyase.
Oxaloacetate in the cytosol is reduced to malate by cytoplasmic malate dehydrogenase, and malate is transported
back into the mitochondria to participate in the Citric acid cycle.[4]
Fatty acid synthesis 285

Desaturation
Unsaturated fatty acids are essential components to prokaryotic and eukaryotic cell membranes. These fatty acids
primarily function in maintaining membrane fluidity.[5] They have also been associated with serving as signaling
molecules in other processes such as cell differentiation and DNA replication.[5] There are two pathways organisms
use for desaturation: Aerobic and Anaerobic.

Anaerobic Desaturation
Many bacteria use the anaerobic pathway for synthesizing unsaturated fatty acids. This pathway does not utilize
oxygen and is dependent on enzymes to insert the double bond before elongation utilizing the normal fatty acid
synthesis machinery. In Escherichia coli, this pathway is well understood.
• FabA is a β-hydroxydecanoyl-ACP dehydrase- it is specific for the
10 carbon saturated fatty acid synthesis intermediate
(β-hydroxydecanoyl-ACP).
• FabA catalyzes the dehydration of β-hydroxydecanoyl-ACP causing
the release of water and insertion of the double bond between C7
and C8 counting from the methyl end. This creates the
trans-2-decenoyl intermediate.
• The trans-2-decenoyl intermediate can either be shunted to the
normal saturated fatty acid synthesis pathway by FabB, where the
double bond will be hydrolyzed and the final product will be a
saturated fatty acid, or FabA will catalyze the isomerization into the
Synthesis of unsaturated fatty acids via anaerobic cis-3-decenoyl intermediate.
desaturation
• FabB is a β-ketoacyl-ACP synthase which elongates and channels
intermediates into the mainstream fatty acid synthesis pathway.
When FabB reacts with the cis-decenoyl intermediate the final product after elongation will be an unsaturated
fatty acid.[6]
• The two main unsaturated fatty acids made are Palmitoleoyl-ACP (16:1ω7) and cis-vaccenoyl-ACP (18:1ω7).[7]
Most bacteria that undergo anaerobic desaturation contain homologues of FabA and FabB.[8] Clostridia are the main
exception; they have a novel enzyme, yet to be identified, that catalyzes the formation of the cis double bond.[7]
Regulation
This pathway undergoes transcriptional regulation by FadR and FabR. FadR is the more extensively studied protein
and has been attributed bifunctional characteristics. It acts as an activator of fabA and fabB transcription and as a
repressor for the β-oxidation regulon. FabR, conversely, acts as a repressor for the transcription of fabA and fabB.[6]
Fatty acid synthesis 286

Aerobic Desaturation

Aerobic desaturation is the most widespread pathway for the synthesis

of unsaturated fatty acids. It is utilized in all eukaryotes and some
prokaryotes. This pathway utilizes desaturases to synthesize
unsaturated fatty acids from full length saturated fatty acid
substrates.[9] All desaturases require oxygen and reducing equivalents
acquired from the electron transport chain. Desaturases are specific for
the double bond they induce in the substrate. In Bacillus subtilis, the
desaturase, Δ5-Des, is specific for inducing a cis-double bond at the Δ5
position.[5] [9] Saccharomyces cerevisiae contains one desaturase,
Ole1p, which induces the cis-double bond at Δ9.[5]

Regulation
In B. subtilis, this pathway is regulated by a two-component system:
DesK and DesR. DesK is a membrane associated kinase and DesR is a
Synthesis of unsaturated fatty acids via aerobic
transcriptional regulator of the des gene.[5] [9] The regulation responds desaturation
to temperature; when there is a drop in temperature this gene is
upregulated. Unsaturated fatty acids decrease the fluidity of the membrane and stabilize it under lower temperatures.
DesK is the sensor protein that when there is a decrease in temperature, will autophosphorylate. DesK-P will transfer
its phosphoryl group to DesR. Two DesR-P proteins will dimerize and bind to the DNA promoters of the des gene
and recruit RNA polymerase to begin transcription.[5] [9]

Pseudomonas aeruginosa
Generally, both anaerobic and aerobic unsaturated fatty acid synthesis will not occur within the same system,
however Pseudomonas aeruginosa and Vibrio ABE-1 are exceptions.[10] [11] [12] While, P. aeruginosa primarily
undergoes anaerobic desaturation, it also undergoes two aerobic pathways. One pathway utilizes a Δ9 desaturase
(DesA) that catalyzes a double bond formation in membrane lipids. Another pathway uses two proteins, DesC and
DesB, together to act as a Δ9 desaturase which inserts a double bond into a saturated fatty acid-CoA molecule. This
second pathway is regulated by repressor protein, DesT. DesT is also a repressor of fabAB expression for anaerobic
desaturation when in presence of exogenous unsaturated fatty acids. This functions to coordinate the expression of
the two pathways within the organism.[11] [13]

Branched chain fatty acids

Branched-chain fatty acids are usually saturated and are found in two distinct families; the iso-series and
anteiso-series. It has been found that Actinomycetales contain unique branch chain fatty acid synthesis mechanisms,
including that which forms tuberculosteric acid.

Branch-Chain Fatty Acid Synthesizing System

Fatty acid synthesis 287

Valine primer

Leucine primer

Isoleucine primer

The branched-chain fatty acid synthesizing system uses α-keto acids as primers. This system is distinct from the
branched-chain fatty acid synthetase which utilizes short-chain acyl-CoA esters as primers.[14] α-keto acid primers
are derived from the transamination and decarboxylation of valine, leucine, and isoleucine to form
2-methylpropanyl-CoA, 3-methylbutyryl-CoA, and 2-Methylbutyryl-CoA, respectively.[15] 2-methylpropanyl-CoA
primers derived from valine are elongated to produce even-numbered iso-series fatty acids such as
14-methyl-pentadecanoic (isopalmitic) acid, and 3-methylbutyryl-CoA primers from leucine may be used to form
odd numbered iso-series fatty acids such as 13-methyl-tetradecanoic acid. 2-Methylbutyryl-CoA primers from
isoleucine are elongated to form anteiso-series fatty acids containing an odd number of carbon atoms such as
12-Methyl tetradecanoic acid.[16] Decarboxylation of the primer precursors occurs through the branched-chain
α-keto acid decarboxylase (BCKA) enzyme. Elongation of the fatty acid follows the same biosynthetic pathway in
Escherichia coli used to produce straight-chain fatty acids where malonyl-CoA is used as a chain extender.[17] The
major end products are 12-17 carbon branched-chain fatty acids and their composition tends to be uniform and
characteristic for many bacterial species.[16]
BCKA decarboxylase and relative activities of α-keto acid substrates
The BCKA decarboxylase enzyme is composed of two subunits in a tetrameric structure (A2B2) and is essential for
the synthesis of branched-chain fatty acids. It is responsible for the decarboxylation of α-keto acids formed by the
transamination of valine, leucine, and isoleucine and produces the primers used for branched-chain fatty acid
synthesis. The activity of this enzyme is much higher with branched-chain α-keto acid substrates than straight-chain
substrates, and in Bacillus species its specificity is highest for the isoleucine-derived α-keto-β-methylvaleric acid,
followed by α-ketoisocaproate and α-ketoisovalerate.[16] [17] The enzyme’s high affinity toward branched-chain
Fatty acid synthesis 288

α-keto acids allows it to function as the primer donating system for branched-chain fatty acid synthetase.[17]

Substrate BCKA activity CO2 Produced (nmol/min mg) Km (μM) Vmax (nmol/min mg)

L-α-keto-β-methyl-valerate 100% 19.7 <1 17.8

α-Ketoisovalerate 63% 12.4 <1 13.3

α-Ketoisocaproate 38% 7.4 <1 5.6

Pyruvate 25% 4.9 51.1 15.2

Factors affecting chain length and pattern distribution

α-keto acid primers are used to produce branched-chain fatty acids that are generally between 12 and 17 carbons in
length. The proportions of these branched-chain fatty acids tend to be uniform and consistent among a particular
bacterial species but may be altered due to changes in malonyl-CoA concentration, temperature, or heat-stable
factors (HSF) present.[16] All of these factors may affect chain length, and HSF’s have been demonstrated to alter the
specificity of BCKA decarboxylase for a particular α-keto acid substrate, thus shifting the ratio of branched-chain
fatty acids produced.[16] An increase in malonyl-CoA concentration has been shown to result in a larger proportion
of C17 fatty acids produced, up until the optimal concentration (≈20μM) of malonyl-CoA is reached. Decreased
temperatures also tend to shift the fatty-acid distribution slightly toward C17 fatty-acids in Bacillus species.[14] [16]

Branch-Chain Fatty Acid Synthase

This system functions similarly to the branch-chain fatty acid synthesizing system, however it uses short chain
carboxylic acids as primers instead of alpha-keto acids. This method is generally used by bacteria that do not have
the ability to perform the branch-chain fatty acid system using alpha-keto primers. Typical short chain primers
include isovalerate, isobutyrate and 2-methyl butyrate. The acids needed for these primers are generally taken up
from the environment; this is often seen in ruminal bacteria.[18]
The over all reaction is: Isobutyryl-CoA + 6 malonyl-CoA +12 NADPH + 12H+ = Isoplmitic acid + 6CO2 12NADP
+ 5H2O + 7CoA[14]
The difference between (straight-chain) fatty acid synthase and branch-chain fatty acid synthase is substrate
specificity of the enzyme that catalyzes the reaction of acyl-CoA to acyl-ACP.[14]

Omega-alicyclic fatty acids

Omega-alicyclic fatty acids typically contain an omega-terminal propyl
or butyryl cyclic group and are some of the major membrane fatty
acids found in several species of bacteria. The fatty acid synthetase
used to produce omega-alicyclic fatty acids is also used to produce
membrane branched-chain fatty acids. In bacteria with membranes
composed mainly of omega-alicyclic fatty acids, the supply of cyclic
carboxylic acid-CoA esters is much greater than that of branched-chain primers.[14] The synthesis of cyclic primers
is not well understood but it has been suggested that mechanism involves the conversion of sugars to shikimic acid
which is then converted to cyclohexylcarboxylic acid-CoA esters that serve as primers for omega-alicyclic fatty acid
synthesis [18]
Fatty acid synthesis 289

Tuberculostearic Acid Synthesis

Tuberculostearic acid (D-10-Methylstearic acid) is a saturated fatty
acid that is known to be produced by Mycobacterium spp. and two
species of Streptomyces. It is formed from the precursor oleic acid (a
monosaturated fatty acid).[19] After oleic acid is esterified to a
phospholipid, S-adenosyl-methionine donates a methyl group to the
double bond of oleic acid.[20] This methylation reaction forms the
intermediate 10-methylene-octadecanoyal. Successive reduction of the
residue, with NADPH as a cofactor, results in 10-methylstearic acid
[15]

References
[1] Dijkstra, Albert J., R. J. Hamilton, and Wolf Hamm. "Fatty Acid Biosynthesis." Mechanism of the synthesis of Tuberculostearic
Trans Fatty Acids. Oxford: Blackwell Pub., 2008. 12. Print. acid
[2] "Fatty Acids: Straight-chain Saturated, Structure, Occurrence and Biosynthesis."
Lipid Library - Lipid Chemistry, Biology, Technology and Analysis. Web. 30 Apr.
2011. <http://lipidlibrary.aocs.org/lipids/fa_sat/index.htm>.
[3] Diwan, Joyce J. "Fatty Acid Synthesis." Rensselaer Polytechnic Institute (RPI) :: Architecture, Business, Engineering, IT, Humanities,
Science. Web. 30 Apr. 2011. <http://rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm>.
[4] Ferre, P.; F. Foufelle (2007). "SREBP-1c Transcription Factor and Lipid Homeostasis: Clinical Perspective" (http:/ / content. karger. com/
ProdukteDB/ produkte. asp?Aktion=ShowFulltext& ArtikelNr=100426& Ausgabe=232805& ProduktNr=224036). Hormone Research 68 (2):
72–82. doi:10.1159/000100426. PMID 17344645. . Retrieved 2010-08-30. "this process is outlined graphically in page 73"
[5] Aguilar, Pablo S, and Diegode Mendoza. "Control of fatty acid desaturation: a mechanism conserved from bacteria to humans." Molecular
microbiology 62.6 (2006):1507-14.
[6] Feng, Youjun, and John ECronan. "Complex binding of the FabR repressor of bacterial unsaturated fatty acid biosynthesis to its cognate
promoters." Molecular microbiology 80.1 (2011):195-218.
[7] Zhu, Lei, et al. "Functions of the Clostridium acetobutylicium FabF and FabZ proteins in unsaturated fatty acid biosynthesis." BMC
microbiology 9(2009):119.
[8] Wang, Haihong, and John ECronan. "Functional replacement of the FabA and FabB proteins of Escherichia coli fatty acid synthesis by
Enterococcus faecalis FabZ and FabF homologues." Journal of biological chemistry 279.33 (2004):34489-95.
[9] Mansilla, Mara C, and Diegode Mendoza. "The Bacillus subtilis desaturase: a model to understand phospholipid modification and
temperature sensing." Archives of microbiology 183.4 (2005):229-35.
[10] Wada, M, N. Fukunaga, and S. Sasaki. "Mechanism of biosynthesis of unsaturated fatty acids in Pseudomonas sp. strain E-3, a
psychrotrophic bacterium." Journal of bacteriology 171.8 (1989):4267-71.
[11] Subramanian, Chitra, Charles ORock, and Yong-MeiZhang. "DesT coordinates the expression of anaerobic and aerobic pathways for
unsaturated fatty acid biosynthesis in Pseudomonas aeruginosa." Journal of bacteriology 192.1 (2010):280-5.
[12] Morita, N, et al. "Both the anaerobic pathway and aerobic desaturation are involved in the synthesis of unsaturated fatty acids in Vibrio sp.
strain ABE-1." FEBS letters 297.1-2 (1992):9-12.
[13] Zhu, Kun, et al. "Two aerobic pathways for the formation of unsaturated fatty acids in Pseudomonas aeruginosa." Molecular microbiology
60.2 (2006):260-73.
[14] Kaneda, Toshi. "Iso- and Anteiso-Fatty Acids in Bacteria: Biosynthesis, Function, and Taxonomic Significance." Microbiological Reviews
55.2 (1991): 288-302
[15] "Branched-chain Fatty Acids, Phytanic Acid, Tuberculostearic Acid Iso/anteiso- Fatty Acids." Lipid Library - Lipid Chemistry, Biology,
Technology and Analysis. Web. 01 May 2011. http:/ / lipidlibrary. aocs. org/ lipids/ fa_branc/ index. htm.
[16] Naik, Devaray N., and Toshi Kaneda. "Biosynthesis of Branched Long-chain Fatty Acids by Species of Bacillus: Relative Activity of Three
α-keto Acid Substrates and Factors Affecting Chain Length." Can. J. Microbiol. 20 (1974): 1701-708.
[17] Oku, Hirosuke, and Toshi Kaneda. "Biosynthesis of Branched-chain Fatty Acids in Bacillis Subtilis." The Journal of Biological Chemistry
263.34 (1988): 18386-8396.
[18] Christie, William W. "Fatty Acids: Natural Alicyclic Structures, Occurrence, and Biochemistry." The AOCS Lipid Library. 5 Apr. 2011.
Web. 24 Apr. 2011. <http://lipidlibrary.aocs.org/lipids/fa_cycl/file.pdf>.
[19] Ratledge, Colin, and John Stanford. The Biology of the Mycobacteria. London: Academic, 1982. Print.
[20] Kubica, George P., and Lawrence G. Wayne. The Mycobacteria: a Sourcebook. New York: Dekker, 1984. Print.
Fatty acid synthesis 290

External links
• Overview (http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm) at Rensselaer
Polytechnic Institute
• Overview (http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#synthesis) at Indiana State University

Lipogenesis
Lipogenesis is the process by which acetyl-CoA is converted to fats. The former is an intermediate stage in
metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis, the
energy can be efficiently stored in the form of fats. Lipogenesis encompasses the processes of fatty acid synthesis
and subsequent triglyceride synthesis (when fatty acids are esterified with glycerol to form fats).[1] The products are
secreted from the liver in the form of very-low-density lipoproteins (VLDL).

Fatty acid synthesis

Fatty acids synthesis starts with acetyl-CoA and builds up by the addition of two carbon units. The synthesis occurs
in the cytoplasm in contrast to the degradation (oxidation), which occurs in the mitochondria. Many of the enzymes
for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase.[2]

Control and regulation

Insulin is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood
sugar levels. Thus, a large insulin level is associated with the fed state. As one might expect, therefore, it increases
the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in two main ways: The enzymes
pyruvate dehydrogenase (PDH), which forms acetyl-CoA, and acetyl-CoA carboxylase (ACC), which forms
malonyl-CoA, are obvious control points. These are activated by insulin. So a high insulin level leads to an overall
increase in the levels of malonyl-CoA, which is the substrate required for fatty acids synthesis.

PDH dephosphorylation
Pyruvate dehydrogenase dephosphorylation is increased with the release of insulin. The dephosphorylated form is
more active.
As insulin binds to cellular surface transmembrane receptors that intracellularly activate the adenylate cyclase
enzyme that catalyze cAMP (cyclic AMP) production from ATP. The increased intracellular cAMP, acts as a second
messenger, in response to the insulin binding. cAMP activates protein kinase enzyme that in turn activates
phosporylase enzyme that phosphorylates and in doing so activates a number of different intracellular enzymes such
as the pyruvate dehydrogenase that dehydrates pyruvate to form AcCoa. So, an extracellular hormone, insulin, can in
multistep activation (cascade) activate an enzyme in the cellular matrix.
This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-CoA.
Increased levels of acetyl-CoA will increase the flux through not only the fat synthesis pathway but also the citric
acid cycle.
Lipogenesis 291

Acetyl-CoA carboxylase
Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation which activates the enzyme. Glucagon
has an antagonistic effect and increases phosphorylation, deactivation, thereby inhibiting ACC and slowing fat
synthesis.
Affecting ACC affects the rate of acetyl-CoA conversion to malonyl-CoA. Increased malonyl-CoA level pushes the
equilibrium over to increase production of fatty acids through biosynthesis. Long chain fatty acids are negative
allosteric regulators of ACC and so when the cell has sufficient long chain fatty acids, they will eventually inhibit
ACC activity and stop fatty acid synthesis.
AMP and ATP concentrations of the cell act as a measure of the ATP needs of a cell and as ATP levels get low it
activates the ATP synthetase which in turn phosphorylates ACC. When ATP is depleted, there is a rise in 5'AMP.
This rise activates AMP-activated protein kinase, which phosphorylates ACC, thereby inhibits fat synthesis. This is a
useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.
ACC is also activated by citrate. This means that, when there is abundant acetyl-CoA in the cell cytoplasm for fat
synthesis, it proceeds at an appropriate rate.
Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's
influence on lipogenic enzyme genes, can induce the gene products for liver's pyruvate kinase, acetyl-CoA
carboxylase, and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high
blood glucose levels[3] and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also
involved in cholesterol metabolism.

Fatty acid esterification

Experiments were conducted to study in vivo the over-all fatty acid specificity of the mechanisms involved in
chylomicron cholesterol ester and triglyceride formation during fat absorption in the rat. Mixtures containing similar
amounts of two, three, or four C14-labeled fatty acids (palmitic, stearic, oleic, and linoleic acids), but with varying
ratios of unlabeled fatty acids, were given by gastric intubation to rats with cannulated thoracic ducts. The chyle or
chylomicron lipid so obtained was chromatographed on silicic acid columns to separate cholesterol esters and
glycerides (the latter being 98.2% triglycerides). After assaying each lipid class for total radioactivity, gas-liquid
chromatography was employed to measure the total mass and the distribution of mass and of radioactivity in the
individual fatty acid components of each lipid fraction. The specific radioactivity of each fatty acid in each fraction
could then be calculated. The data provided quantitative information on the relative specificity of incorporation of
each fatty acid into each chylomicron lipid class and on the relative extent to which each fatty acid in each lipid
fraction was diluted with endogenous fatty acid. With the exception of a slight discrimination against stearic acid, the
processes of fatty acid absorption and chylomicron triglyceride formation displayed no specificity for one fatty acid
relative to another. In contrast, chylomicron cholesterol ester formation showed marked specificity for oleic acid,
relative to the other three fatty acids. This specificity was not significantly altered by varying the composition of the
test meal, by including cholesterol in the test meal, or by feeding the animal a high-cholesterol diet for several weeks
preceding the study. Considerable dilution of the dietary fatty acids with endogenous fatty acids was observed. In
one experiment, 43% of the chylomicron triglyceride fatty acids was of endogenous origin. Relatively more (54%) of
the cholesterol ester fatty acids was of endogenous origin.
About 100,000 metric tons of the natural fatty acids are consumed in the preparation of various fatty acid esters. The
simple esters with lower chain alcohols (methyl-, ethyl-, n-propyl-, isopropyl- and butyl esters) are used as
emollients in cosmetics and other personal care products and as lubricants. Esters of fatty acids with more complex
alcohols, such as sorbitol, ethylene glycol, diethylene glycol and polyethylene glycol are consumed in foods,
personal care, paper, water treatment, metal working fluids, rolling oils and synthetic lubricants.
Lipogenesis 292

References
[1] Kersten S (April 2001). "Mechanisms of nutritional and hormonal regulation of lipogenesis". EMBO Rep. 2 (4): 282–6.
doi:10.1093/embo-reports/kve071. PMC 1083868. PMID 11306547.
[2] Elmhurst College. "Lipogenesis" (http:/ / www. elmhurst. edu/ ~chm/ vchembook/ 623acetylCoAfate. html). . Retrieved 2007-12-22.
[3] Work from Howard Towle, Catherine Postic, and K. Uyeda.

Acetyl-CoA carboxylase
Acetyl-CoA carboxylase
Identifiers

EC number [1]
6.4.1.2

CAS number [2]

9023-93-2

Databases

IntEnz [3]
IntEnz view

BRENDA [4]
BRENDA entry

ExPASy [5]
NiceZyme view

KEGG [6]
KEGG entry

MetaCyc [7]
metabolic pathway

PRIAM [8]
profile

PDB structures RCSB PDB [9] PDBe [10] PDBsum [11]

Gene Ontology AmiGO [12] / EGO [13]

Search

PMC [14]
articles

PubMed articles [15]

Acetyl-CoA carboxylase
alpha
Identifiers

Symbol ACACA

Alt. symbols ACAC, ACC1, ACCA

Entrez [16]
31

HUGO [17]
84

OMIM [18]
601557

RefSeq [19]
NM_198839

UniProt [20]
Q13085
Acetyl-CoA carboxylase 293

Other data

EC number [21]
6.4.1.2

Locus [22]
Chr. 17 q21

Acetyl-CoA
carboxylase beta
Identifiers

Symbol ACACB

Alt. symbols ACC2, ACCB

Entrez [23]
32

HUGO [24]
85

OMIM [25]
200350

RefSeq [26]
NM_001093

UniProt [27]
O00763

Other data

EC number [21]
6.4.1.2

Locus [28]
Chr. 12 q24.1

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of
acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and
carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants
and algae, whereas it is a large, multi-domain enzyme in the endoplasmic reticulum of most eukaryotes. The most
important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids.[29] The
activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent
modification. The human genome contains the genes for two different ACCs[30] — ACACA[31] and ACACB.[32]

Structure
Prokaryotes and plants have multi-subunit ACCs composed of several polypeptides encoded by distinct genes. Biotin
carboxylase (BC) activity, biotin carboxyl carrier protein (BCCP), and carboxyl transferase (CT) activity are each
contained on a different subunit. The stoichiometry of these subunits in the ACC holoenzyme differs amongst
organisms.[29] Humans and most eukaryotes have evolved an ACC with CT and BC catalytic domains and biotin
carboxyl carrier domains on a single polypeptide. ACC functional regions, starting from the N-terminus to
C-terminus are the biotin carboxylase (BC), biotin binding (BB), carboxyltransferase (CT), and ATP-binding (AB).
AB lies within BC. Biotin is covalently attached through an amide bond to the long side chain of a lysine reside in
BB. As BB is between BC and CT regions, biotin can be easily translocate to both of the active sites where it is
required.
In mammals where two isoforms of ACC are expressed, the main structural difference between these isoforms is the
extended ACC2 N-terminus containing a mitochondria targeting sequence.[29]
Acetyl-CoA carboxylase 294

Crystallographic structures of E. Coli Acetyl CoA Carboxylase

Cartoon diagram of Biotin Carboxylase of E.Coli Acetyl

CoA Carboxylase  
Acetyl-CoA carboxylase 295

Biotin Carboxyl Carrier Protein of E. Coli Acetyl CoA

Carboxylase  

Carboxyltransferase Subunit of E. Coli Acetyl CoA

Carboxylase  
Acetyl-CoA carboxylase 296

Mechanism
The overall reaction of ACAC(A,B) proceeds by a two-step mechanism.[33] The first reaction is carried out by BC
and involves the ATP-dependent carboxylation of biotin with bicarbonate serving as the source of CO2. The
carboxyl group is transferred from biotin to acetyl CoA to form malonyl CoA in the second reaction, which is
catalyzed by CT.

The reaction mechanism of ACAC(A,B).The color scheme is as follows: enzyme, coenzymes, substrate names, metal ions, phosphate, and carbonate

In the context of the active site, the reaction proceeds with extensive interaction of the residues Glu296 and
positively charged Arg338 and Arg292 with the substrates.[34] Two Mg2+ are coordinated by the phosphate groups
on the ATP, and are required for ATP binding to the enzyme. Bicarbonate is deprotonated by Glu296, although in
solution, this proton transfer is unlikely as the pKa of bicarbonate is 10.3. The enzyme apparently manipulates pKas
to facilitate the deprotonation of bicarbonate. The pKa of bicarbonate is decreased by its interaction with positively
charged side chains of Arg338 and Arg292. Furthermore, Glu296 interacts with the side chain of Glu211, an
interaction that has been shown to cause an increase in the apparent pKa. Following deprotonation of bicarbonate,
the oxygen of the bicarbonate acts as a nucleophile and attacks the gamma phosphate on ATP. The
carboxyphosphate intermediate quickly decomposes to CO2 and PO43-. The PO43- deprotonates biotin, creating an
enolate, stabilized by Arg338, that subsequently attacks CO₂ resulting in the production of
carboxybiotin.[34] The carboxybiotin translocates to the carboxytransferase (CT) active site, where the carboxyl
group is transferred to acetyl-CoA. In contrast to the BC domain, little is known about the reaction mechanism of
CT. A proposed mechanism is the release of carbon dioxide from biotin, which subsequently abstracts a proton from
the methyl group from acetyl CoA carboxylase. The resulting enolate attacks CO2 to form malonyl CoA. In a
competing mechanism, proton abstraction is concerted with the attack of acetyl CoA.

Function
The function of ACAC is to regulate the metabolism of fatty acids. When the enzyme is active, the product,
malonyl-CoA is produced which is a building block for new fatty acids and can inhibit the transfer of the fatty acyl
group from acyl CoA to carnitine with carnitine acyltransferase, which inhibits the beta-oxidation of fatty acids in
the mitochondria.
In mammals, two main isoforms of ACC are expressed, ACC1 and ACC2, which differ in both tissue distribution
and function. ACC1 is found in the cytoplasm of all cells but is enriched in lipogenic tissue, such as adipose tissue
and lactating mammary glands, where fatty acid synthesis is important.[35] In oxidative tissues, such as the skeletal
muscle and the heart, the ratio of ACC2 expressed is higher. ACC1 and ACC2 are both highly expressed in the liver
where both fatty acid oxidation and synthesis is important.[36] The differences in tissue distribution indicate that
Acetyl-CoA carboxylase 297

ACC1 maintains regulation of fatty acid synthesis whereas ACC2 mainly regulates fatty acid oxidation.

Regulation
The regulation of mammalian ACC is
complex, in order to control two
distinct pools of malonyl CoA that
direct either the inhibition of beta
oxidation or the activation of lipid
biosynthesis. Control of Acetyl CoA Carboxylase. The AMP regulated kinase triggers the
phosphorylation of the enzyme (thus inactivating it) and the phosphatase enzyme removes
Mammalian ACC1 and ACC2 are the phosphate group.
regulated transcriptionally by multiple
promoters which mediate ACC abundance in response to the cells nutritional status. Activation of gene expression
through different promoters results in alternative splicing; however, the physiological significance of specific ACC
isozymes remains unclear.[36] The sensitivity to nutritional status results from the control of these promoters by
transcription factors such as SREBP1c, controlled by insulin at the transcriptional level, and ChREBP, which
increases in expression with high carbohydrates diets.[37] [38]

Through a feedforward loop, citrate allosterically activates ACC.[39] Citrate may increase ACC polymerization to
increases enzymatic activity; however, it is unclear if polymerization is citrate's main mechanism of increasing ACC
activity or if polymerization is an artifact of in vitro experiments. Other allosteric activators include glutamate and
other dicarboxylic acids.[40] Long and short chain fatty acyl CoAs are negative feedback inhibitors of ACC.[41]
Phosphorylation can result when the hormones glucagon or epinephrine bind to cell surface receptors, but the main
cause of phosphorylation is due to a rise in AMP levels when the energy status of the cell is low, leading to the
activation of the AMP-activated protein kinase (AMPK). AMPK is the main kinase regulator of ACC, able to
phosphorylate a number of serine residues on both isoforms of ACC.[42] On ACC1, AMPK phosphorylates Ser79,
Ser1200, and Ser1215. On ACC2, AMPK phosphorylates Ser218.[43] Protein kinase A also has the ability to
phosphorylate ACC, with a much greater ability to phosphorylate ACC2 than ACC1. However, the physiological
significance of protein kinase A in the regulation of ACC is currently unknown. Researchers hypothesize there are
other ACC kinases important to its regulation as there are many other possible phosphorylation sites on ACC.[44]
When insulin binds to its receptors on the cellular membrane, it activates a phosphatase to dephosphorylate the
enzyme; thereby removing the inhibitory effect.

Clinical implications
At the juncture of lipid synthesis and oxidation pathways, ACC presents many clinical possibilities for the
production of novel antibiotics and the development of new therapies for diabetes, obesity, and other manifestations
of metabolic syndrome.[45] Researchers aim to take advantage of structural differences between bacterial and human
ACCs to create antibiotics specific to the bacterial ACC, in efforts to minimize side effects to patients. Promising
results for the usefulness of an ACC inhibitor include the finding that ACC2 -/- mice (mice with no expression of
ACC2) have continuous fatty acid oxidation, reduced body fat mass, and reduced body weight despite an increase in
food consumption. ACC2 -/- mice are also protected from diabetes.[46] It should be noted that mutant mice lacking
ACC1 are embryonically lethal. However, it is unknown whether drugs targeting ACCs in humans must be specific
for ACC2.[47]
Acetyl-CoA carboxylase 298

References
[1] http:/ / www. chem. qmul. ac. uk/ iubmb/ enzyme/ EC6/ 4/ 1/ 2. html
[2] http:/ / toolserver. org/ ~magnus/ cas. php?language=en& cas=9023-93-2& title=
[3] http:/ / www. ebi. ac. uk/ intenz/ query?cmd=SearchEC& ec=6. 4. 1. 2
[4] http:/ / www. brenda-enzymes. org/ php/ result_flat. php4?ecno=6. 4. 1. 2
[5] http:/ / www. expasy. org/ enzyme/ 6. 4. 1. 2
[6] http:/ / www. genome. ad. jp/ dbget-bin/ www_bget?enzyme+ 6. 4. 1. 2
[7] http:/ / biocyc. org/ META/ substring-search?type=NIL& object=6. 4. 1. 2
[8] http:/ / priam. prabi. fr/ cgi-bin/ PRIAM_profiles_CurrentRelease. pl?EC=6. 4. 1. 2
[9] http:/ / www. rcsb. org/ pdb/ search/ smartSubquery. do?smartSearchSubtype=EnzymeClassificationQuery& Enzyme_Classification=6. 4. 1.
2
[10] http:/ / www. ebi. ac. uk/ pdbe-srv/ view/ search?EC_number=6. 4. 1. 2& id_type=EC_number& id_value=6. 4. 1. 2&
search_type=advanced
[11] http:/ / www. ebi. ac. uk/ thornton-srv/ databases/ cgi-bin/ enzymes/ GetPage. pl?ec_number=6. 4. 1. 2
[12] http:/ / amigo. geneontology. org/ cgi-bin/ amigo/ go. cgi?query=GO:0003989& view=details
[13] http:/ / www. ebi. ac. uk/ ego/ DisplayGoTerm?id=GO:0003989& format=normal
[14] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=pubmed& term=6. 4. 1. 2%5BEC/
RN%20Number%5D%20AND%20pubmed%20pmc%20local%5Bsb%5D
[15] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=pubmed& term=6. 4. 1. 2%5BEC/ RN%20Number%5D
[16] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=31& rn=1
[17] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=84
[18] http:/ / www. ncbi. nlm. nih. gov/ omim/ 601557
[19] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_198839& rn=1
[20] http:/ / www. uniprot. org/ uniprot/ Q13085
[21] http:/ / www. genome. jp/ dbget-bin/ www_bget?enzyme+ 6. 4. 1. 2
[22] http:/ / omim. org/ search?index=geneMap& search=17q21
[23] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=gene& amp;cmd=retrieve& amp;dopt=default& amp;list_uids=32& rn=1
[24] http:/ / www. genenames. org/ data/ hgnc_data. php?hgnc_id=85
[25] http:/ / www. ncbi. nlm. nih. gov/ omim/ 200350
[26] http:/ / genome. ucsc. edu/ cgi-bin/ hgTracks?Submit=Submit& position=NM_001093& rn=1
[27] http:/ / www. uniprot. org/ uniprot/ O00763
[28] http:/ / omim. org/ search?index=geneMap& search=12q24. 1
[29] Tong L (August 2005). "Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery". Cell. Mol. Life
Sci. 62 (16): 1784–803. doi:10.1007/s00018-005-5121-4. PMID 15968460.
[30] Brownsey RW, Zhande R, Boone AN (November 1997). "Isoforms of acetyl-CoA carboxylase: structures, regulatory properties and
metabolic functions". Biochem. Soc. Trans. 25 (4): 1232–8. PMID 9449982.
[31] Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ (April 1995). "Human acetyl-CoA carboxylase: characterization, molecular
cloning, and evidence for two isoforms". Proc. Natl. Acad. Sci. U.S.A. 92 (9): 4011–5. doi:10.1073/pnas.92.9.4011. PMC 42092.
PMID 7732023.
[32] Widmer J, Fassihi KS, Schlichter SC, Wheeler KS, Crute BE, King N, Nutile-McMenemy N, Noll WW, Daniel S, Ha J, Kim KH, Witters
LA (June 1996). "Identification of a second human acetyl-CoA carboxylase gene" (http:/ / www. biochemj. org/ bj/ 316/ 0915/ bj3160915.
htm). Biochem. J.. 316 ( Pt 3): 915–22. PMC 1217437. PMID 8670171. .
[33] Lee CK, Cheong HK, Ryu KS, Lee JI, Lee W, Jeon YH, Cheong C (August 2008). "Biotinoyl domain of human acetyl-CoA carboxylase:
Structural insights into the carboxyl transfer mechanism". Proteins 72 (2): 613–24. doi:10.1002/prot.21952. PMID 18247344.
[34] Chou CY, Yu LP, Tong L (April 2009). "Crystal structure of biotin carboxylase in complex with substrates and implications for its catalytic
mechanism". J. Biol. Chem. 284 (17): 11690–7. doi:10.1074/jbc.M805783200. PMC 2670172. PMID 19213731.
[35] Kim TS, Leahy P, Freake HC (August 1996). "Promoter usage determines tissue specific responsiveness of the rat acetyl-CoA carboxylase
gene". Biochem. Biophys. Res. Commun. 225 (2): 647–53. doi:10.1006/bbrc.1996.1224. PMID 8753813.
[36] Barber MC, Price NT, Travers MT (March 2005). "Structure and regulation of acetyl-CoA carboxylase genes of metazoa". Biochim.
Biophys. Acta 1733 (1): 1–28. doi:10.1016/j.bbalip.2004.12.001. PMID 15749055.
[37] Field F. J., Born E., Murthy S. and Mathur S. N. (December 2002). "Polyunsaturated fatty acids decrease the expression of sterol regulatory
element binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport.". Biochem. J. 386 (Pt 3): 855–64.
doi:10.1042/BJ20020731. PMC 1223029. PMID 12213084.
[38] Ishii S, Iizuka K, Miller BC, Uyeda K (October 2004). "Carbohydrate response element binding protein directly promotes lipogenic enzyme
gene transcription". Proc Natl Acad Sci USA 101 (44): 15597–602. doi:10.1073/pnas.0405238101. PMC 524841. PMID 15496471.
[39] Martin DB, Vagelos PR (June 1962). "The Mechanism of Tricarboxylic Acid Cycle Regulation of Fatty Acid Synthesis". J Biol Chem 237:
1787–92. PMID 14470343.
Acetyl-CoA carboxylase 299

[40] Boone AN, Chan A, Kulpa JE, Brownsey RW (April 2000). "Bimodal Activation of Acetyl-CoA Carboxylase by Glutamate". J Biol Chem
275 (15): 10819–25. doi:10.1074/jbc.275.15.10819. PMID 10753875.
[41] Faergeman NJ, Knudsen J (April 1997). "Role of long chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling".
Biochem J. 323 (Pt 1): 1–12. PMC 1218279. PMID 9173866.
[42] Park SH, Gammon SR, Knippers JD, Paulsen SR, Rubink DS, Winder WW (June 2002). "Phosphorylation-activity relationships of AMPK
and acetyl-CoA carboxylase in muscle". J. Appl. Physiol. 92 (6): 2475–82. doi:10.1152/japplphysiol.00071.2002. PMID 12015362.
[43] Hardie DG (February 1992). "Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase". Biochim. Biophys.
Acta 1123 (3): 231–8. PMID 1536860.
[44] Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (April 2006). "Regulation of acetyl-CoA carboxylase". Biochem. Soc. Trans. 34
(Pt 2): 223–7. doi:10.1042/BST20060223. PMID 16545081.
[45] Corbett JW, Harwood JH (November 2007). "Inhibitors of mammalian acetyl-CoA carboxylase". Recent Patents Cardiovasc Drug Discov 2
(3): 162–80. doi:10.2174/157489007782418928. PMID 18221116.
[46] L Abu-Elheiga, M M Matzuk, K A Abo-Hashema, S J Wakil (March 2001). "Continuous Fatty Acid Oxidation and Reduced Fat Storage in
Mice Lacking Acetyl-CoA Carboxylase 2". Science 291 (5513): 2613–6. doi:10.1126/science.1056843. PMID 11283375.
[47] Lutfi Abu-Elheiga, Martin M Matzuk, Parichher Kordari, WonKeun Oh, Tattym Shaikenov, Ziwei Gu, Salih J Wakil (August 2005).
"Mutant Mice Lacking Acetyl CoA Carboxylase are Embryonically Lethal". Proc Natl Acad Sci 102 (34): 1211–6.
doi:10.1073/pnas.0505714102. PMC 1189351. PMID 16103361.

Further reading
• Voet, Donald; Voet, Judith G. (2004). Biochemistry (3rd ed.). Wiley. ISBN 0-471-19350-x.
• edited by (2000). Buchanan, Bob B.; Gruissem, Wilhelm; Jones, Russell L.. eds. Biochemistry and molecular
biology of plants. American Society of Plant Physiologists. ISBN 0-943088-37-2.
• Levert K, Waldrop G, Stephens J (2002). "A biotin analog inhibits acetyl-CoA carboxylase activity and
adipogenesis". J. Biol. Chem. 277 (19): 16347–50. doi:10.1074/jbc.C200113200. PMID 11907024.

Fatty acid degradation

Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end
generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of animals. It includes
three major steps:
• Lipolysis of and release from adipose tissue
• Activation and transport into mitochondria
• β-oxidation

Lipolysis and release

Initially in the process of degradation, fatty acids are stored in fat cells (adipocytes). The breakdown of this fat is
known as lipolysis. The products of lipolysis, free fatty acids, are released into the bloodstream and circulate
throughout the body.

Activation and transport into mitochondria

Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs.
This process occurs in two steps catalyzed by the enzyme fatty acyl-CoA synthetase.
Fatty acid degradation 300

Formation of an activated thioester bond

The enzyme first catalyzes nucleophilic attack on the α-phosphate of ATP to form pyrophosphate and an acyl chain
linked to AMP. The next step is formation of an activated thioester bond between the fatty acyl chain and Coenzyme
A.

The formula for the above is:

RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + PPi + 2H+
This two-step reaction is freely reversible and its equilibrium lies near 1. To drive the reaction forward, the reaction
is coupled to a strongly exergonic hydrolysis reaction: the enzyme inorganic pyrophosphatase cleaves the
pyrophosphate liberated from ATP to two phosphate ions. Thus the net reaction becomes:
RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + 2Pi + 2H+

Transport into the mitochondrial matrix

The inner mitochondrial membrane is impermeable to fatty acids and a specialized carnitine carrier system
operates to transport activated fatty acids from cytosol to mitochondria.
Once activated, the acyl CoA is transported into the mitochondrial matrix. This occurs via a series of similar steps:
1. Acyl CoA is conjugated to carnitine by carnitine acyltransferase (palmitoyltransferase) I located on the outer
mitochondrial membrane
2. Acyl carnitine is shuttled inside by a translocase
3. Acyl carnitine (such as Palmitoylcarnitine) is converted to acyl CoA by carnitine acyltransferase
(palmitoyltransferase) II located on the inner mitochondrial membrane. The liberated carnitine returns to the
cytosol.
It is important to note that carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl-CoA, an
intermediate in fatty acid biosynthesis, in order to prevent futile cycling between beta-oxidation and fatty acid
synthesis.
Fatty acid degradation 301

β-oxidation
Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:
1. Oxidation by FAD,
2. Hydration,
3. Oxidation by NAD+,
4. Thiolysis,
5. The final product is acetyl-CoA, the entry molecule for the citric acid cycle.

Beta oxidation
Beta oxidation is the process by which
fatty acids, in the form of Acyl-CoA
molecules, are broken down in
mitochondria and/or in peroxisomes to
generate Acetyl-CoA, the entry
molecule for the Citric Acid cycle.

The beta oxidation of fatty acids

involve three stages:
1. Activation of fatty acids in the
cytosol
2. Transport of fatty acids into
mitochondria (carnitine shuttle)
3. Beta oxidation proper in the
mitochondrial matrix Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of
long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, LCHAD deficiency
Fatty acids are oxidized by most of the
tissues in the body. However, the brain
can hardly utilize fatty acids for energy requirements, while erythrocytes and adrenal medulla cannot use them at all.

Activation of fatty acids

Free fatty acids can penetrate the plasma membrane due to their poor water solubility and high fat solubility. Once in
the cytosol, activation of the fatty acid is catalyzed by long fatty acyl CoA synthetase. A fatty acid reacts with ATP
to give a fatty acyl adenylate, plus inorganic pyrophosphate, which then reacts with free coenzyme A to give a fatty
acyl-CoA ester plus AMP. The fatty acyl-CoA is then reacted with carnitine to form acylcarnitine, which is
transported across the inner mitochondrial membrane by a monosodium glutamate.
Beta oxidation 302

Four recurring steps

Once inside the mitochondria, each cycle of β-oxidation, liberating a two carbon unit-acetyl CoA, occurs in a
sequence of four reactions:

Description Diagram Enzyme End product

Dehydrogenation by FAD: The first step is the acyl CoA trans-Δ2-enoyl-CoA

oxidation of the fatty acid by dehydrogenase
Acyl-CoA-Dehydrogenase. The enzyme catalyzes
the formation of a double bond between the C-2
and C-3.

Hydration: The next step is the hydration of the enoyl CoA L-β-hydroxyacyl CoA
bond between C-2 and C-3. The reaction is hydratase
stereospecific, forming only the L isomer.

L-β-hydroxyacyl β-ketoacyl CoA

Oxidation by NAD+: The third step is the oxidation
CoA
of L-β-hydroxyacyl CoA by NAD+. This converts
dehydrogenase
the hydroxyl group into a keto group.

Thiolysis: The final step is the cleavage of β-ketothiolase An acetyl CoA molecule,
β-ketoacyl CoA by the thiol group of another and an acyl CoA molecule
molecule of CoA. The thiol is inserted between that is two carbons shorter
C-2 and C-3.

This process continues until the entire chain is cleaved into acetyl CoA units. The final cycle produces two separate
acetyl CoAs, instead of one acyl CoA and one acetyl CoA. For every cycle, the Acyl CoA unit is shortened by two
carbon atoms. Concomitantly, one molecule of FADH2, NADH and acetyl CoA are formed.

β-Oxidation of unsaturated fatty acids

β-Oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a
trans-Δ2 bond. These situations are handled by an additional two enzymes.
Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of
the presence of a double bond) is not an appropriate substrate for acyl CoA dehydrogenase, or enoyl CoA hydratase:
• If the acyl CoA contains a cis-Δ3 bond, then cis-Δ3-Enoyl CoA isomerase will convert the bond to a trans-Δ2
bond, which is a regular substrate.
• If the acyl CoA contains a cis-Δ4 double bond, then its dehydrogenation yields a 2,4-dienoyl intermediate, which
is not a substrate for enoyl CoA hydratase. However, the enzyme 2,4 Dienoyl CoA reductase reduces the
intermediate, using NADPH, into trans-Δ3-enoyl CoA. As in the above case, this compound is converted into a
suitable intermediate by 3,2-Enoyl CoA isomerase.
To summarize:
• Odd-numbered double bonds are handled by the isomerase.
• Even-numbered double bonds by the reductase (which creates an odd-numbered double bond)
Beta oxidation 303

β-Oxidation of odd-numbered chains

In general, fatty acids with an odd number of carbon are found in the lipids of plants and some marine organisms.
Many ruminant animals form large amount of 3-carbon propionate during fermentation of carbohydrate in rumen.[1]
Chains with an odd-number of carbons are oxidized in the same manner as even-numbered chains, but the final
products are propionyl-CoA and acetyl-CoA.
Propionyl-CoA is first carboxylated using a bicarbonate ion into D-stereoisomer of methylmalonyl-CoA, in a
reaction that involves a biotin co-factor, ATP, and the enzyme propionyl-CoA carboxylase. The bicarbonate ion's
carbon is added to the middle carbon of propionyl-CoA, forming a D-methylmalonyl-CoA. However, the D
conformation is enzymatically converted into the L conformation by methylmalonyl-CoA epimerase, then it
undergoes intramolecular rearrangement, which is catalyzed by methylmalonyl-CoA mutase (requiring B12 as a
coenzyme) to form succinyl-CoA. The succinyl-CoA formed can then enter the citric acid cycle.
Because it cannot be completely metabolized in the citric acid cycle, the products of its partial reaction must be
removed in a process called cataplerosis. This allows regeneration of the citric acid cycle intermediates, possibly an
important process in certain metabolic diseases.

Oxidation in peroxisomes
Fatty acid oxidation also occurs in peroxisomes, when the fatty acid chains are too long to be handled by the
mitochondria. However, the oxidation ceases at octanyl CoA. It is believed that very long chain (greater than C-22)
fatty acids undergo initial oxidation in peroxisomes which is followed by mitochondrial oxidation.
One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis. Instead, the
high-potential electrons are transferred to O2, which yields H2O2. The enzyme catalase, found exclusively in
peroxisomes, converts the hydrogen peroxide into water and oxygen.
Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids. There are
three key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation:
1. β-oxidation in the peroxisome requires the use of a peroxisomal carnitine acyltransferase (instead of carnitine
acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the peroxisome.
2. The first oxidation step in the peroxisome is catalyzed by the enzyme acyl CoA oxidase.
3. The β-ketothiolase used in peroxisomal β-oxidation has an altered substrate specificity, different from the
mitochondrial β-ketothiolase.
Peroxisomal oxidation is induced by high-fat diet and administration of hypolipidemic drugs like clofibrate.

Energy yield
The ATP yield for every oxidation cycle is 14 ATP (according to the P/O ratio), broken down as follows:
Beta oxidation 304

Source ATP Total

1 FADH2 x 1.5 ATP = 1.5 ATP (some sources say 2 ATP)

1 NADH x 2.5 ATP = 2.5 ATP (some sources say 3 ATP)

1 acetyl CoA x 10 ATP = 10 ATP (some sources say 12 ATP)

TOTAL = 14 ATP

For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary, and the final process yields an additional
acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total
ATP yield can be stated as:
(n - 1) * 14 + 10 - 2 = total ATP
For instance, the ATP yield of palmitate (C16, n = 8) is:
(8 - 1) * 14 + 10 - 2 = 106 ATP
Represented in table form:

Source ATP Total

7 FADH2 x 1.5 ATP = 10.5 ATP

7 NADH x 2.5 ATP = 17.5 ATP

8 acetyl CoA x 10 ATP = 80 ATP

Activation = -2 ATP

NET = 106 ATP

For sources that use the larger ATP production numbers described above, the total would be 129 ATP
={(8-1)*17+12-2} equivalents per palmitate.
Beta-oxidation of unsaturated fatty acids changes the ATP yield due to the requirement of two possible additional
enzymes.

External links
• The chemical logic behind fatty acid metabolism [2] at ufp.pt
• JEREMY M. BERG,JOHN L. TYMOCZKO and LUBERT STRYER Biochemistry, 2002 [3]
• Animations [4] at brookscole.com

References
[1] Nelson, D. L. & Cox, M. M. (2005). Lehninger Principles of Biochemistry, 4th Edition. New York: W. H. Freeman and Company, pp.
648-649. ISBN 0-7167-4339-6.
[2] http:/ / www2. ufp. pt/ ~pedros/ bq/ fatty. htm
[3] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search& db=books& doptcmdl=GenBookHL& term=oxidation+ yield+ AND+
stryer%5Bbook%5D+ AND+ 216592%5Buid%5D& rid=stryer. section. 3050#3060
[4] http:/ / www. brookscole. com/ chemistry_d/ templates/ student_resources/ shared_resources/ animations/ carnitine/ carnitine1. html
 305

Nitrogen metabolism

Nitrogen fixation
Nitrogen fixation is the natural process, either biological or abiotic, by which nitrogen (N2) in the atmosphere is
converted into ammonia (NH3).[1] This process is essential for life because fixed nitrogen is required to
biosynthesize the basic building blocks of life, e.g., nucleotides for DNA and RNA and amino acids for proteins.
Nitrogen fixation also refers to other biological conversions of nitrogen, such as its conversion to nitrogen dioxide.
Microorganisms that fix nitrogen are bacteria called diazotrophs. Some higher plants, and some animals (termites),
have formed associations (symbioses) with diazotrophs. Nitrogen fixation also occurs as a result of non-biological
processes. These include lightning, industrially through the Haber-Bosch Process, and combustion.[2] Biological
nitrogen fixation was discovered by the German agronomist Hermann Hellriegel and Dutch microbiologist Martinus
Beijerinck.

Biological nitrogen fixation

Biological nitrogen fixation (BNF)
occurs when atmospheric nitrogen is
converted to ammonia by an enzyme
called nitrogenase.[1] The reaction for
BNF is:
N2 + 8 H+ + 8 e− → 2 NH3 + H2
The process is coupled to the hydrolysis
of 16 equivalents of ATP and is
accompanied by the co-formation of
one molecule of H2. In free-living
diazotrophs, the nitrogenase-generated
ammonium is assimilated into
glutamate through the glutamine
synthetase/glutamate synthase pathway.

Enzymes responsible for nitrogenase

Schematic representation of the nitrogen cycle. Abiotic nitrogen fixation has been
action are very susceptible to omitted.
destruction by oxygen. (In fact, many
bacteria cease production of the enzyme in the presence of oxygen).[1] Many nitrogen-fixing organisms exist only in
anaerobic conditions, respiring to draw down oxygen levels, or binding the oxygen with a protein such as
Leghemoglobin.[1]
Nitrogen fixation 306

Microorganisms that fix nitrogen (diazotrophs)

• Cyanobacteria
• Azotobacteraceae
• Rhizobia
• Frankia

Nitrogen fixation by rhizobia and frankia

Rhizobia are Gram-negative soil bacteria with the ability to establish a N2-fixing symbiosis on legume roots and on
the stems of some aquatic legumes. During this interaction bacteroids, as rhizobia are called in the symbiotic state,
are contained in intracellular compartments within a specialized organ, the nodule, where they fix N2. Similarly,
Frankia, Gram-positive soil bacteria induce the formation of nitrogen-fixing nodules in actinorhizal plants.[3]

Nitrogen fixation by cyanobacteria

Cyanobacteria inhabit nearly all illuminated environments on Earth and play key roles in the carbon and nitrogen
cycle of the biosphere. In general, cyanobacteria are able to utilize a variety of inorganic and organic sources of
combined nitrogen, like nitrate, nitrite, ammonium, urea, or some amino acids. Several cyanobacterial strains are
also capable of diazotrophic growth. Genome sequencing has provided a large amount of information on the genetic
basis of nitrogen metabolism and its control in different cyanobacteria. Comparative genomics, together with
functional studies, has led to a significant advance in this field over the past years. 2-Oxoglutarate has turned out to
be the central signalling molecule reflecting the carbon/nitrogen balance of cyanobacteria. Central players of
nitrogen control are the global transcriptional factor NtcA, which controls the expression of many genes involved in
nitrogen metabolism, as well as the PII signalling protein, which fine-tunes cellular activities in response to changing
C/N conditions. These two proteins are sensors of the cellular 2-oxoglutarate level and have been conserved in all
cyanobacteria. In contrast, the adaptation to nitrogen starvation involves heterogeneous responses in different
strains.[4] Nitrogen fixation by cyanobacteria in coral reefs can fix twice the amount of nitrogen than on land–around
1.8 kg of nitrogen is fixed per hectare per day.

Root nodule symbioses

Legume family
Plants that contribute to nitrogen fixation include the legume family – Fabaceae – with taxa such as clovers,
soybeans, alfalfa, lupines, peanuts, and rooibos. They contain symbiotic bacteria called Rhizobia within nodules in
their root systems, producing nitrogen compounds that help the plant to grow and compete with other plants. When
the plant dies, the fixed nitrogen is released, making it available to other plants and this helps to fertilize the soil[1] [5]
The great majority of legumes have this association, but a few genera (e.g., Styphnolobium) do not. In many
traditional and organic farming practices, fields are rotated through various types of crops, which usually includes
one consisting mainly or entirely of clover or buckwheat (family Polygonaceae), which are often referred to as
"green manure."
Inga alley farming relies on the leguminous genus, Inga a small tropical, tough-leaved, nitrogen-fixing tree.[6]
Nitrogen fixation 307

Non-leguminous

Although by far the majority plants able to form nitrogen-fixing root

nodules are in the legume family Fabaceae, there are a few exceptions:
• Parasponia, a tropical Celtidaceae also able to interact with rhizobia
and form nitrogen-fixing nodules[7]
• Actinorhizal plants such as alder and bayberry, that can also forms
nitrogen-fixing nodules, thanks to a symbiotic association with
Frankia bacteria. These plants belong to 25 genera[8] distributed
among 8 plant families. The ability to fix nitrogen is far from
universally present in these families. For instance, of 122 genus in A sectioned alder tree root nodule.
the Rosaceae, only 4 genera are capable of fixing nitrogen. All these
families belong to the orders Cucurbitales, Fagales, and Rosales,
which together with the Fabales form a clade of eurosids. In this
clade, Fabales were the first lineage to branch off; thus, the ability
to fix nitrogen may be plesiomorphic and subsequently lost in most
descendants of the original nitrogen-fixing plant; however, it may
be that the basic genetic and physiological requirements were
present in an incipient state in the last common ancestors of all these
plants, but only evolved to full function in some of them:

A whole alder tree root nodule.

Family: Genera ...... Coriariaceae: Coriaria ...... Myricaceae: ...... Rhamnaceae: ...... Rosaceae:
Betulaceae: Alnus Datiscaceae: Datisca Comptonia Ceanothus Cercocarpus (mountain
(alders) Elaeagnaceae: (sweetfern) Colletia mahoganies)
Cannabaceae: Trema Elaeagnus Morella Discaria Chamaebatia
Casuarinaceae: (silverberries) Myrica (mountain miseries)
Kentrothamnus
Allocasuarina Hippophae (bayberries) Dryas
Retanilla
Casuarina (sea-buckthorns) Purshia/Cowania
Talguenea
Shepherdia (bitterbrushes/cliffroses)
Ceuthostoma Trevoa
(buffaloberries)
Gymnostoma

There are also several nitrogen-fixing symbiotic associations that involve cyanobacteria (such as Nostoc):
• Some lichens such as Lobaria and Peltigera
• Mosquito fern (Azolla species)
• Cycads
• Gunnera
Nitrogen fixation 308

Chemical nitrogen fixation

Haber process
Nitrogen can also be artificially fixed as ammonia for use in fertilizers, explosives, or in other products. The most
common method is the Haber process. Artificial fertilizer production is now the largest source of human-produced
fixed nitrogen in the Earth's ecosystem.[9]
The Haber process requires high pressures (around 200 atm) and high temperatures (at least 400 °C), routine
conditions for industrial catalysis. This highly efficient process uses natural gas as a hydrogen source and air as a
nitrogen source.

Dinitrogen complexes
Much research has been conducted on the discovery of catalysts for nitrogen fixation, often with the goal of reducing
the energy required for this conversion. However, such research has thus far failed to even approach the efficiency
and ease of the Haber process. Many compounds react with atmospheric nitrogen under ambient conditions. For
example, lithium metal converts to lithium nitride under an atmosphere of nitrogen. Treatment of the resulting nitride
gives ammonia.
The first dinitrogen complex was reported in 1965 based on ammonia coordinated to ruthenium
([Ru(NH3)5(N2)]2+).[10] Research in chemical fixation from then on focused on transition metal complexes. Since
then, a large number of transition metal compounds that contain dinitrogen as a ligand have been discovered. The
dinitrogen ligand can either be bound to a single metal or bridge two (or more) metals. The coordination chemistry
of dinitrogen is complex and currently under intense investigation. This research may lead to new ways of using
dinitrogen in synthesis and on an industrial scale.

Ambient nitrogen reduction

Catalytic chemical nitrogen fixation at temperatures considerably lower than the Haber process is an ongoing
scientific endeavor. Nitrogen was successfully converted to ammonia and hydrazine by Alexander E. Shilov in
1970.[11] [12] The first example of homolytic cleavage of dinitrogen under mild conditions was published in 1995.
Two equivalents of a molybdenum complex reacted with one equivalent of dinitrogen, creating a triple bonded MoN
complex.[13] Since then, this triple bounded complex has been used to make nitriles.[14]
The first catalytic system converting nitrogen to ammonia at room temperature and pressure was discovered in 2003
and is based on another molybdenum compound, a proton source, and a strong reducing agent.[15] [16] [17] [18]
However, this catalytic reduction fixates only a few nitrogen molecules.
Nitrogen fixation 309

In 2011 Arashiba et al. reported another system with a catalyst again based on molybdenum but with a diphosphorus
pincer ligand.[19]

References
[1] Postgate, J (1998). Nitrogen Fixation, 3rd Edition. Cambridge University Press, Cambridge UK.
[2] http:/ / helios. bto. ed. ac. uk/ bto/ microbes/ nitrogen. htm
[3] Moir, JWB (editor) (2011). Nitrogen cycling in bacteria: Molecular analysis. Caister Academic Press. ISBN 978-1-904455-86-8.
[4] Herrero A and Flores E (editor). (2008). The Cyanobacteria: Molecular Biology, Genomics and Evolution (http:/ / www. horizonpress. com/
cyan) (1st ed.). Caister Academic Press. ISBN 978-1-904455-15-8. . .
[5] Smil, V (2000). Cycles of Life. Scientific American Library.
[6] Elkan, Daniel. Slash-and-burn farming has become a major threat to the world's rainforest The Guardian 21 April 2004
[7] Op den Camp, Rik; et al.. "LysM-Type Mycorrhizal Receptor Recruited for Rhizobium Symbiosis in Nonlegume Parasponia". Science 331
(6019): 909–912. doi:10.1126/science.1198181.
[8] Dawson, J. O. (2008). "Ecology of actinorhizal plants". Nitrogen-fixing Actinorhizal Symbioses. 6. Springer. pp. 199–234.
doi:10.1007/978-1-4020-3547-0_8.
[9] http:/ / www. epa. gov/ watertrain/ nitroabstr. html US Enivronmental Protection Agency: Human Alteration of the Global Nitrogen Cycle:
Causes and Consequences by Peter M. Vitousek, Chair, John Aber, Robert W. Howarth, Gene E. Likens, Pamela A. Matson, David W.
Schindler, William H. Schlesinger, and G. David Tilman
[10] A. D. Allen, C. V. Senoff (1965). "Nitrogenopentammineruthenium(II) complexes". Journal of the Chemical Society, Chemical
Communications (24): 621. doi:10.1039/C19650000621.
[11] Catalytic reduction of molecular nitrogen in solutions A.E. Shilov Russian Chemical Bulletin Volume 52, Number 12, 2555-2562,
doi:10.1023/B:RUCB.0000019873.81002.60
[12] Reduction of dinitrogen Richard R. Schrock PNAS November 14, 2006 vol. 103 no. 46 17087 doi:10.1073/pnas.0603633103
[13] Dinitrogen Cleavage by a Three-Coordinate Molybdenum(III) Complex Catalina E. Laplaza and Christopher C. Cummins Science 12 May
1995: 861-863.10.1126/science.268.5212.861
[14] A Cycle for Organic Nitrile Synthesis via Dinitrogen Cleavage John J. Curley, Emma L. Sceats, and Christopher C. Cummins J. Am. Chem.
Soc., 2006, 128 (43), pp 14036–14037 doi:10.1021/ja066090a
Nitrogen fixation 310

[15] Synthesis and Reactions of Molybdenum Triamidoamine Complexes Containing Hexaisopropylterphenyl Substituents Dmitry V. Yandulov,
Richard R. Schrock, Arnold L. Rheingold, Christopher Ceccarelli, and William M. Davis Inorg. Chem.; 2003; 42(3) pp 796–813; (Article)
doi:10.1021/ic020505l
[16] Catalytic Reduction of Dinitrogen to Ammonia at a Single Molybdenum Center Dmitry V. Yandulov and Richard R. Schrock Science 4 July
2003: Vol. 301. no. 5629, pp. 76–78 doi:10.1126/science.1085326
[17] The catalyst is based on molybdenum(V) chloride and tris(2-aminoethyl)amine substituted with three very bulky hexa-isopropylterphenyl
(HIPT) groups. Nitrogen adds end-on to the molybdenum atom, and the bulky HIPT substituents prevent the formation of the stable and
nonreactive Mo-N=N-Mo dimer, and the nitrogen is reduced in an isolated pocket. The proton donor is a pyridinium cation, which is
accompanied by a tetraborate counter ion. The reducing agent is decamethylchromocene. All ammonia formed is collected as the HCl salt by
trapping the distillate with a HCl solution
[18] Note also that, although the dinitrogen complex is shown in brackets, this species can be isolated and characterized. Here the brackets do not
indicate that the intermediate is not observed.
[19] A molybdenum complex bearing PNP-type pincer ligands leads to the catalytic reduction of dinitrogen into ammonia Kazuya Arashiba,
Yoshihiro Miyake Yoshiaki Nishibayashi Nature Chemistry Volume: 3, Pages: 120–125 Year published:(2011 doi:10.1038/nchem.906

External links
• NITROGEN FIXATION (http://lupins-bk.blogspot.com/2006/07/nitrogen-fixation.html)

Amino acid synthesis

For the non-biological synthesis of amino acids see: Strecker amino acid synthesis
Amino acid synthesis is the set of biochemical processes (metabolic pathways) by which the various amino acids
are produced from other compounds. The substrates for these processes are various compounds in the organism's diet
or growth media. Not all organisms are able to synthesise all amino acids. For example, humans are able to
synthesise only 12 of the 20 standard amino acids.
A fundamental problem for biological systems is to obtain nitrogen in an easily usable form. This problem is solved
by certain microorganisms capable of reducing the inert N≡N molecule (nitrogen gas) to two molecules of ammonia
in one of the most remarkable reactions in biochemistry. Ammonia is the source of nitrogen for all the amino acids.
The carbon backbones come from the glycolytic pathway, the pentose phosphate pathway, or the citric acid cycle.
In amino acid production, one encounters an important problem in biosynthesis, namely stereochemical control.
Because all amino acids except glycine are chiral, biosynthetic pathways must generate the correct isomer with high
fidelity. In each of the 19 pathways for the generation of chiral amino acids, the stereochemistry at the α-carbon
atom is established by a transamination reaction that involves pyridoxal phosphate. Almost all the transaminases that
catalyze these reactions descend from a common ancestor, illustrating once again that effective solutions to
biochemical problems are retained throughout evolution.
Biosynthetic pathways are often highly regulated such that building-blocks are synthesized only when supplies are
low. Very often, a high concentration of the final product of a pathway inhibits the activity of enzymes that function
early in the pathway. Often present are allosteric enzymes capable of sensing and responding to concentrations of
regulatory species. These enzymes are similar in functional properties to aspartate transcarbamoylase and its
regulators. Feedback and allosteric mechanisms ensure that all twenty amino acids are maintained in sufficient
amounts for protein synthesis and other processes.
Amino acid synthesis 311

Amino acid synthesis

Amino acids are synthesized from α-ketoacids, and later transaminated from another aminoacid, usually Glutamate.
The enzyme involved in this reaction is an aminotransferase.
α-ketoacid + glutamate ⇄ amino acid + α-ketoglutarate
Glutamate itself is formed by amination of α-ketoglutarate:
α-ketoglutarate + NH ⇄ glutamate

Nitrogen fixation: Microorganisms use ATP and a powerful reductant to

reduce atmospheric nitrogen to ammonia
Microorganisms use ATP and reduced ferredoxin, a powerful reductant, to reduce N2 to NH3. An iron-molybdenum
cluster in nitrogenase deftly catalyzes the fixation of N2, a very inert molecule. Higher organisms consume the fixed
nitrogen to synthesize amino acids, nucleotides, and other nitrogen-containing biomolecules. The major points of
entry of NH4+ into metabolism are glutamine or glutamate.

Amino acids are made from intermediates of the citric acid cycle and other
major pathways
Of the basic set of 20 amino acids (not counting selenocysteine), there are 8 that human beings cannot synthesize. In
addition, the amino acids arginine, cysteine, glycine, glutamine, histidine, proline, serine, and tyrosine are considered
conditionally essential, meaning they are not normally required in the diet, but must be supplied exogenously to
specific populations that do not synthesize it in adequate amounts.[1] [2] For example, enough arginine is synthesized
by the urea cycle to meet the needs of an adult but perhaps not those of a growing child. Amino acids that must be
obtained from the diet are called essential amino acids. Nonessential amino acids are produced in the body. The
pathways for the synthesis of nonessential amino acids are quite simple. Glutamate dehydrogenase catalyzes the
reductive amination of α-ketoglutarate to glutamate. A transamination reaction takes place in the synthesis of most
amino acids. At this step, the chirality of the amino acid is established. Alanine and aspartate are synthesized by the
transamination of pyruvate and oxaloacetate, respectively. Glutamine is synthesized from NH4+ and glutamate, and
asparagine is synthesized similarly. Proline and arginine are derived from glutamate. Serine, formed from
3-phosphoglycerate, is the precursor of glycine and cysteine. Tyrosine is synthesized by the hydroxylation of
phenylalanine, an essential amino acid. The pathways for the biosynthesis of essential amino acids are much more
complex than those for the nonessential ones.
Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids
and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible: most
reduced—methyl; intermediate—methylene; and most oxidized—formyl, formimino, and methenyl. The major
donor of activated methyl groups is S-adenosylmethionine, which is synthesized by the transfer of an adenosyl group
from ATP to the sulfur atom of methionine. S-Adenosylhomocysteine is formed when the activated methyl group is
transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to
methionine to complete the activated methyl cycle.
Cortisol inhibits protein synthesis.[3]
Amino acid synthesis 312

Amino acid biosynthesis is regulated by feedback inhibition

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step
is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches
that includes both negative and positive regulation. The regulation of glutamine synthetase from E. coli is a striking
demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications.

Amino acids are precursors of many biomolecules

Amino acids are precursors of a variety of biomolecules. Glutathione (γ-Glu-Cys-Gly) serves as a sulfhydryl buffer
and detoxifying agent. Glutathione peroxidase, a selenoenzyme, catalyzes the reduction of hydrogen peroxide and
organic peroxides by glutathione. Nitric oxide, a short-lived messenger, is formed from arginine. Porphyrins are
synthesized from glycine and succinyl CoA, which condense to give δ-aminolevulinate. Two molecules of this
intermediate become linked to form porphobilinogen. Four molecules of porphobilinogen combine to form a linear
tetrapyrrole, which cyclizes to uroporphyrinogen III. Oxidation and side-chain modifications lead to the synthesis of
protoporphyrin IX, which acquires an iron atom to form heme. [4]

References
[1] Fürst P, Stehle P (1 June 2004). "What are the essential elements needed for the determination of amino acid requirements in humans?" (http:/
/ jn. nutrition. org/ cgi/ content/ full/ 134/ 6/ 1558S). J. Nutr. 134 (6 Suppl): 1558S–1565S. PMID 15173430. .
[2] Reeds PJ (1 July 2000). "Dispensable and indispensable amino acids for humans" (http:/ / jn. nutrition. org/ cgi/ content/ full/ 130/ 7/ 1835S).
J. Nutr. 130 (7): 1835S–40S. PMID 10867060. .
[3] Manchester, K.L., “Sites of Hormonal Regulation of Protein Metabolism. p. 229”, Mammalian Protein [Munro, H.N., Ed.]. Academic Press,
New York. On p273.
[4] Biochemistry. Berg, Jeremy M.; Tymoczko, John L.; and Stryer, Lubert. New York: W. H. Freeman and Co. ; c2002

External links
• NCBI Bookshelf Free Textbook Access (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=stryer.TOC&
depth=2)
Nucleotide 313

Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition,
nucleotides participate in cellular signaling (cGMP and cAMP), and are incorporated into important cofactors of
enzymatic reactions (coenzyme A, FAD, FMN, and NADP+). Nucleotide derivatives such as the nucleoside
triphosphates play central roles in metabolism, in which capacity they serve as sources of chemical energy (ATP and
GTP).[1]

Structural elements of the most common nucleotides

Nucleotide structure
A nucleotide is composed of a nucleobase (nitrogenous base), a
five-carbon sugar (either ribose or 2'-deoxyribose), and one phosphate
group.[2] Together, the nucleobase and sugar compose a nucleoside.
The phosphate groups form bonds with either the 2, 3, or 5-carbon of
the sugar, with the 5-carbon site most common. Cyclic nucleotides
form when the phosphate group is bound to two of the sugar's hydroxyl
groups.[1] Ribonucleotides are nucleotides where the sugar is ribose,
and deoxyribonucleotides contain the sugar deoxyribose. Nucleotides
can contain either a purine or a pyrimidine base.

Nucleic acids are polymeric macromolecules made from nucleotide

monomers. In DNA, the purine bases are adenine and guanine, while Ribose structure indicating numbering of carbon
atoms
the pyrimidines are thymine and cytosine. RNA uses uracil in place of
thymine. Adenine always pairs with thymine by 2 hydrogen bonds,
while guanine pairs with cytosine through 3 hydrogen bonds, each due to their unique structures.

Synthesis
Nucleotides can be synthesized by a variety of means both in vitro and in vivo.
In vivo, nucleotides can be synthesized de novo or recycled through salvage pathways.[3] The components used in de
novo nucleotide synthesis are derived from biosynthetic precursors of carbohydrate and amino acid metabolism, and
from ammonia and carbon dioxide. The liver is the major organ of de novo synthesis of all four nucleotides. De novo
synthesis of pyrimidines and purines follows two different pathways. Pyrimidines are synthesized first from aspartate
and carbamoyl-phosphate in the cytoplasm to the common precursor ring structure orotic acid, onto which a
phosphorylated ribosyl unit is covalently linked. Purines, however, are first synthesized from the sugar template onto
which the ring synthesis occurs. For reference, the syntheses of the purine and pyrimidine nucleotides are carried out
by several enzymes in the cytoplasm of the cell, not within a specific organelle. Nucleotides undergo breakdown
such that useful parts can be reused in synthesis reactions to create new nucleotides.
Nucleotide 314

In vitro, protecting groups may be used during laboratory production of nucleotides. A purified nucleoside is
protected to create a phosphoramidite, which can then be used to obtain analogues not found in nature and/or to
synthesize an oligonucleotide.

Pyrimidine ribonucleotide synthesis

The synthesis of the pyrimidines CTP
and UTP occurs in the cytoplasm and
starts with the formation of carbamoyl
phosphate from glutamine and CO2.
Next, aspartate undergoes a
condensation reaction with
carbamoyl-phosphate to form orotic
acid. In a subsequent cyclization
reaction, the enzyme Aspartate
carbamoyltransferase forms
N-carbamoyl-aspartate which is
converted into dihydroorotic acid by
Dihydroorotase. The latter is converted
to orotate by Dihydroorotate oxidase.
The net reaction is:

(S)-Dihydroorotate + O2 = Orotate +
H2O2
Orotate is covalently linked with a
phosphorylated ribosyl unit. The
covalent linkage between the ribose The synthesis of Uridine monophosphateUMP.The color scheme is as follows: enzymes,
coenzymes, substrate names, inorganic molecules
and pyrimidine occurs at position C1 of
the ribose unit, which contains a
pyrophosphate, and N1 of the pyrimidine ring. Orotate phosphoribosyltransferase (aka "PRPP transferase") catalyzes
the net reaction yielding orotidine monophosphate (OMP):

Orotate + 5-Phospho-α-D-ribose 1-diphosphate (aka. "PRPP") = Orotidine 5'-phosphate + Pyrophosphate

Orotidine-5-phosphate is decarboxylated by Orotidine-5'-phosphate decarboxylase to form uridine monophosphate
(UMP). PRPP transferase catalyzes both the ribosylation and decarboxylation reactions, forming UMP from orotic
acid in the presence of PRPP. It is from UMP that other pyrimidine nucleotides are derived. UMP is phosphorylated
by two kinases to uridine triphosphate (UTP) via two sequential reactions with ATP. First the diphosphate form UDP
is produced, which in turn is phosphorylated to UTP. Both steps are fueled by ATP hydrolysis:
ATP + UMP = ADP + UDP UDP + ATP = UTP + ADP
CTP is subsequently formed by amination of UTP by the catalytic activity of CTP synthetase. Glutamine is the NH3
donor and the reaction is fueled by ATP hydrolysis, too:
UTP + Glutamine + ATP + H2O = CTP + ADP + Pi
Cytidine monophosphate (CMP) is derived from cytidine triphosphate (CTP) with subsequent loss of two
phosphates.[4] [5]
Nucleotide 315

Purine ribonucleotide synthesis

The atoms which are used to build the purine nucleotides come from a variety of sources:

The synthesis of IMP. The color scheme is as follows: enzymes, coenzymes, substrate
names, metal ions, inorganic molecules

The biosynthetic origins of purine ring atoms

N1 arises from the amine group of Asp
C2 and C8 originate from formate
N3 and N9 are contributed by the amide group of
Gln
C4, C5 and N7 are derived from Gly
C6 comes from HCO3- (CO2)

The de novo synthesis of purine nucleotides by which these precursors are incorporated into the purine ring proceeds
by a 10-step pathway to the branch-point intermediate IMP, the nucleotide of the base hypoxanthine. AMP and GMP
are subsequently synthesized from this intermediate via separate, two-step pathways. Thus, purine moieties are
initially formed as part of the ribonucleotides rather than as free bases.
Six enzymes take part in IMP synthesis. Three of them are multifunctional:
• GART (reactions 2, 3, and 5)
• PAICS (reactions 6, and 7)
• ATIC (reactions 9, and 10)
The pathway starts with the formation of PRPP. PRPS1 is the enzyme that activates R5P, which is formed primarily
by the pentose phosphate pathway, to PRPP by reacting it with ATP. The reaction is unusual in that a
pyrophosphoryl group is directly transferred from ATP to C1 of R5P and that the product has the α configuration
about C1. This reaction is also shared with the pathways for the synthesis of Trp, His, and the pyrimidine
nucleotides. Being on a major metabolic crossroad and requiring much energy, this reaction is highly regulated.
Nucleotide 316

In the first reaction unique to purine nucleotide biosynthesis, PPAT catalyzes the displacement of PRPP's
pyrophosphate group (PPi) by an amide nitrogen donated from either glutamine (N), glycine (N&C), aspartate (N),
folic acid (C1), or CO2. This is the committed step in purine synthesis. The reaction occurs with the inversion of
configuration about ribose C1, thereby forming β-5-phosphorybosylamine (5-PRA) and establishing the anomeric
form of the future nucleotide.
Next, a glycine is incorporated fueled by ATP hydrolysis and the carboxyl group forms an amine bond to the NH2
previously introduced. A one-carbon unit from folic acid coenzyme N10-formyl-THF is then added to the amino
group of the substituted glycine followed by the closure of the imidazole ring. Next, a second NH2 group is
transferred from a glutamine to the first carbon of the glycine unit. A carboxylation of the second carbon of the
glycin unit is concomittantly added. This new carbon is modified by the additional of a third NH2 unit, this time
transferred from an aspartate residue. Finally, a second one-carbon unit from formyl-THF is added to the nitrogen
group and the ring covalently closed to form the common purine precursor inosine monophosphate (IMP).
Inosine monophosphate is converted to adenosine monophosphate in two steps. First, GTP hydrolysis fuels the
addition of aspartate to IMP by adenylosuccinate synthase, substituting the carbonyl oxygen for a nitrogen and
forming the intermediate adenylosuccinate. Fumarate is then cleaved off forming adenosine monophosphate. This
step is catalyzed by adenylosuccinate lyase.
Inosine monophosphate is converted to guanosine monophosphate by the oxidation of IMP forming xanthylate,
followed by the insertion of an amino group at C2. NAD+ is the electron acceptor in the oxidation reaction. The
amide group transfer from glutamine is fueled by ATP hydrolysis.

Pyramidine and purine degradation

In humans, pyrimidine rings (C, T, U) can be degraded completely to CO2 and NH3 (urea excretion). That having
been said, purine rings (G, A) cannot. Instead they are degraded to the metabolically inert uric acid which is then
excreted from the body. Uric acid is formed when GMP is split into the base guanine and ribose. Guanine is
deaminated to xanthine which in turn is oxidized to uric acid. This last reaction is irreversible. Similarly, uric acid
can be formed when AMP is deaminated to IMP from which the ribose unit is removed to form hypoxanthine.
Hypoxanthine is oxidized to xanthine and finally to uric acid. Instead of uric acid secretion, guanine and IMP can be
used for recycling purposes and nucleic acid synthesis in the presence of PRPP and aspartate (NH3 donor).

Length unit
Nucleotide (abbreviated nt) is a common length unit for single-stranded RNA, similar to how base pair is a length
unit for double-stranded DNA.

Abbreviation codes for degenerate bases

The IUPAC has designated the symbols for nucleotides.[6] Apart from the five (A, G, C, T/U) bases, often
degenerate bases are used especially for designing PCR primers. These nucleotide codes are listed here.
Nucleotide 317

IUPAC nucleotide code Base

A Adenine

C Cytosine

G Guanine

T (or U) Thymine (or Uracil)

R A or G [puRine]

Y C or T (U) [pYrimidine]

S G or C

W A or T (U)

K G or T (U)

M A or C

B C or G or T (U)

D A or G or T (U)

H A or C or T (U)

V A or C or G

N any base

. or - gap

References
[1] Alberts B, Johnson A, Lewis J, Raff M, Roberts K & Wlater P (2002). Molecular Biology of the Cell (4th ed.). Garland Science. ISBN
0-8153-3218-1. pp. 120-121.
[2] Coghill, Anne M.; Garson, Lorrin R., ed (2006). The ACS style guide: effective communication of scientific information (3rd ed.).
Washington, D.C.: American Chemical Society. p. 244. ISBN 9780841239999.
[3] Zaharevitz, DW; Anerson, LW; Manlinowski, NM; Hyman, R; Strong, JM; Cysyk, RL.. Contribution of de-novo and salvage synthesis to the
uracil nucleotide pool in mouse tissues and tumors in vivo.
[4] Jones, ME (1980). "Pyrimidine nucleotide biosynthesis in animals: Genes, enzymes, and regulation of UMP biosynthesis". Ann. Rev.
Biochem 49 (1): 253–79. doi:10.1146/annurev.bi.49.070180.001345. PMID 6105839.
[5] McMurry, JE; Begley, TP (2005). The organic chemistry of biological pathways. Roberts & Company. ISBN 9780974707716.
[6] IUPAC nucleotide code (http:/ / users. ox. ac. uk/ ~linc1775/ blueprint. htm)

External links
• Abbreviations and Symbols for Nucleic Acids, Polynucleotides and their Constituents (http://www.chem.qmul.
ac.uk/iupac/misc/naabb.html) (IUPAC)
• Provisional Recommendations 2004 (http://www.iupac.org/reports/provisional/abstract04/BB-prs310305/
Chapter10.pdf) (IUPAC)
• Chemistry explanation of nucleotide structure (http://dl.clackamas.cc.or.us/ch106-09/nucleoti.htm)
Urea cycle 318

Urea cycle
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals
that produces urea ((NH2)2CO) from ammonia (NH3). This cycle was the first metabolic cycle discovered (Hans
Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. In mammals, the urea cycle takes
place primarily in the liver, and to a lesser extent in the kidney.

Function
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like
urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn
errors of metabolism), and in liver failure. The result of liver failure is accumulation of nitrogenous waste, mainly
ammonia, which leads to hepatic encephalopathy.

Reactions
The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino
groups, one from NH4+ and one from Asp, and a carbon atom from HCO3−, to the relatively nontoxic excretion
product urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP).
Ornithine is the carrier of these carbon and nitrogen atoms.

Reactions of the urea cycle

Step Reactants Products Catalyzed by Location

1 carbamoyl phosphate + 2ADP + Pi CPS1 mitochondria

NH4+ + HCO3− + 2ATP

2 carbamoyl phosphate + ornithine citrulline + Pi OTC mitochondria

3 citrulline + aspartate + ATP argininosuccinate + AMP + PPi ASS cytosol

4 argininosuccinate Arg + fumarate ASL cytosol

5 Arg + H2O ornithine + urea ARG1 cytosol

The reactions of the urea cycle

Urea cycle 319

1 L-ornithine
2 carbamoyl phosphate
3 L-citrulline
4 argininosuccinate
5 fumarate
6 L-arginine
7 urea
L-Asp L-aspartate
CPS-1 carbamoyl phosphate synthetase I
OTC Ornithine transcarbamoylase
ASS argininosuccinate synthetase
ASL argininosuccinate lyase
ARG1 arginase 1

In the first reaction, NH4+ + HCO3− is equivalent to NH3

+ CO2 + H2O.
Thus, the overall equation of the urea cycle is:
• NH3 + CO2 + aspartate + 3 ATP + 2 H2O → urea +
fumarate + 2 ADP + 2 Pi + AMP + PPi
Since fumarate is obtained by removing NH3 from
aspartate (by means of reactions 3 and 4), and PPi + H2O
→ 2 Pi, the equation can be simplified as follows:
• 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi
+ AMP
Note that reactions related to the urea cycle also cause the oxidation of 2 NADH, so the urea cycle releases slightly
more energy than it consumes. These NADH are produced in two ways:
• One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to
ammonium and α-ketoglutarate. Glutamate is the non-toxic carrier of amine groups. This provides the ammonium
ion used in the initial synthesis of carbamoyl phosphate.
• The fumarate released in the cytosol is converted to malate by cytosolic fumarase. This malate is then converted
to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol. Oxaloacetate is
one of the keto acids preferred by transaminases, and so will be recycled to aspartate, maintained the flow of
nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5 ATP, a net production of one high-energy
phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing
equivalent is used to drive the reversal of the GAPDH step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via transamination or to be converted to phosphoenol pyruvate,
which is a substrate to glucose.
Urea cycle 320

Regulation

N-Acetylglutamic acid
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which
allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by both Arg, allosteric stimulator of
NAGS, and Glu, a product in the transamination reactions and one of NAGS's substrates, both of which are elevated
when free amino acids are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an
activator for the urea cycle.

Substrate concentrations
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited
deficiencies in the cycle enzymes other than ARG1 do not result in significant decrease in urea production (the total
lack of any cycle enzyme results in death shortly after birth). Rather, the deficient enzyme's substrate builds up,
increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the
way back up the cycle to NH4+, resulting in hyperammonemia (elevated [NH4+]P).
Although the root cause of NH4+ toxicity is not completely understood, a high [NH4+] puts an enormous strain on the
NH4+-clearing system, especially in the brain (symptoms of urea cycle enzyme deficiencies include mental
retardation and lethargy). This clearing system involves GLUD1 and GLUL, which decrease the 2-oxoglutarate
(2OG) and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the
rate of TCAC, whereas Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter.
[1](p.734)

Pathology
Anomalies of the urea cycle cause urea cycle disorders:
• ornithine transcarbamoylase deficiency
• Carbamoyl phosphate synthetase deficiency (Ornithine translocase deficiency)
• Argininosuccinic aciduria
• Argininemia
• Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (HHH syndrome)
• Lysinuric protein intolerance
• Citrullinemia
• N-Acetylglutamate synthase deficiency
Most of them are associated with hyperammonemia.
Urea cycle 321

Additional images

Urea cycle. Urea cycle colored.

External links
• The chemical logic behind the urea cycle [2]
• Basic Neurochemistry [3] - amino acid disorders

References
[1] http:/ / www. wiley. com/ college/ math/ chem/ cg/ sales/ voet. html
[2] http:/ / homepage. ufp. pt/ pedros/ bq/ urea. htm
[3] http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=bnchm. figgrp. 3102
 322

Integration of metabolism

Hormone
A hormone (from Greek ὁρμή "impetus") is a chemical released by a
cell or a gland in one part of the body that sends out messages that
affect cells in other parts of the organism. Only a small amount of
hormone is required to alter cell metabolism. In essence, it is a
chemical messenger that transports a signal from one cell to another.
All multicellular organisms produce hormones; plant hormones are
also called phytohormones. Hormones in animals are often transported
in the blood. Cells respond to a hormone when they express a specific
receptor for that hormone. The hormone binds to the receptor protein, Epinephrine (adrenaline), a catecholamine-type
hormone
resulting in the activation of a signal transduction mechanism that
ultimately leads to cell type-specific responses.

Endocrine hormone molecules are secreted (released) directly into the bloodstream, whereas exocrine hormones (or
ectohormones) are secreted directly into a duct, and, from the duct, they flow either into the bloodstream or from cell
to cell by diffusion in a process known as paracrine signalling.
Recently it has been found that a variety of exogenous modern chemical compounds have hormone-like effects on
both humans and wildlife. Their interference with the synthesis, secretion, transport, binding, action, or elimination
of natural hormones in the body can change the homeostasis, reproduction, development, and/or behavior the same
as endogenous produced hormones."[1]

Hormones as signals
Hormonal signaling involves the following:
1. Biosynthesis of a particular hormone in a particular tissue
2. Storage and secretion of the hormone
3. Transport of the hormone to the target cell(s)
4. Recognition of the hormone by an associated cell membrane or intracellular receptor protein
5. Relay and amplification of the received hormonal signal via a signal transduction process: This then leads to a
cellular response. The reaction of the target cells may then be recognized by the original hormone-producing
cells, leading to a down-regulation in hormone production. This is an example of a homeostatic negative feedback
loop.
6. Degradation of the hormone.
Hormone cells are typically of a specialized cell type, residing within a particular endocrine gland, such as thyroid
gland, ovaries, and testes. Hormones exit their cell of origin via exocytosis or another means of membrane transport.
The hierarchical model is an oversimplification of the hormonal signaling process. Cellular recipients of a particular
hormonal signal may be one of several cell types that reside within a number of different tissues, as is the case for
insulin, which triggers a diverse range of systemic physiological effects. Different tissue types may also respond
differently to the same hormonal signal. Because of this, hormonal signaling is elaborate and hard to dissect.
Hormone 323

Interactions with receptors

Most hormones initiate a cellular response by initially combining with either a specific intracellular or cell
membrane associated receptor protein. A cell may have several different receptors that recognize the same hormone
and activate different signal transduction pathways, or a cell may have several different receptors that recognize
different hormones and activate the same biochemical pathway.
For many hormones, including most protein hormones, the receptor is membrane-associated and embedded in the
plasma membrane at the surface of the cell. The interaction of hormone and receptor typically triggers a cascade of
secondary effects within the cytoplasm of the cell, often involving phosphorylation or dephosphorylation of various
other cytoplasmic proteins, changes in ion channel permeability, or increased concentrations of intracellular
molecules that may act as secondary messengers (e.g., cyclic AMP). Some protein hormones also interact with
intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism.
For hormones such as steroid or thyroid hormones, their receptors are located intracellularly within the cytoplasm of
their target cell. To bind their receptors, these hormones must cross the cell membrane. They can do so because they
are lipid-soluble. The combined hormone-receptor complex then moves across the nuclear membrane into the
nucleus of the cell, where it binds to specific DNA sequences, effectively amplifying or suppressing the action of
certain genes, and affecting protein synthesis.[2] However, it has been shown that not all steroid receptors are located
intracellularly. Some are associated with the plasma membrane.[3]
An important consideration, dictating the level at which cellular signal transduction pathways are activated in
response to a hormonal signal, is the effective concentration of hormone-receptor complexes that are formed.
Hormone-receptor complex concentrations are effectively determined by three factors:
1. The number of hormone molecules available for complex formation
2. The number of receptor molecules available for complex formation
3. The binding affinity between hormone and receptor.
The number of hormone molecules available for complex formation is usually the key factor in determining the level
at which signal transduction pathways are activated, the number of hormone molecules available being determined
by the concentration of circulating hormone, which is in turn influenced by the level and rate at which they are
secreted by biosynthetic cells. The number of receptors at the cell surface of the receiving cell can also be varied, as
can the affinity between the hormone and its receptor.

Physiology of hormones
Most cells are capable of producing one or more molecules, which act as signaling molecules to other cells, altering
their growth, function, or metabolism. The classical hormones produced by cells in the endocrine glands mentioned
so far in this article are cellular products, specialized to serve as regulators at the overall organism level. However,
they may also exert their effects solely within the tissue in which they are produced and originally released.
The rate of hormone biosynthesis and secretion is often regulated by a homeostatic negative feedback control
mechanism. Such a mechanism depends on factors that influence the metabolism and excretion of hormones. Thus,
higher hormone concentration alone cannot trigger the negative feedback mechanism. Negative feedback must be
triggered by overproduction of an "effect" of the hormone.
Hormone secretion can be stimulated and inhibited by:
• Other hormones (stimulating- or releasing -hormones)
• Plasma concentrations of ions or nutrients, as well as binding globulins
• Neurons and mental activity
• Environmental changes, e.g., of light or temperature
Hormone 324

One special group of hormones is the tropic hormones that stimulate the hormone production of other endocrine
glands. For example, thyroid-stimulating hormone (TSH) causes growth and increased activity of another endocrine
gland, the thyroid, which increases output of thyroid hormones.
A recently identified class of hormones is that of the "hunger hormones" - ghrelin, orexin, and PYY 3-36 - and
"satiety hormones" - e.g., cholecystokinin, leptin, nesfatin-1, obestatin.
To release active hormones quickly into the circulation, hormone biosynthetic cells may produce and store
biologically inactive hormones in the form of pre- or prohormones. These can then be quickly converted into their
active hormone form in response to a particular stimulus.

Effects of hormones
Hormones have the following effects on the body:
• stimulation or inhibition of growth
• mood swings
• induction or suppression of apoptosis (programmed cell death)
• activation or inhibition of the immune system
• regulation of metabolism
• preparation of the body for mating, fighting, fleeing, and other activity
• preparation of the body for a new phase of life, such as puberty, parenting, and menopause
• control of the reproductive cycle
• hunger cravings
• Sexual arousal
A hormone may also regulate the production and release of other hormones. Hormone signals control the internal
environment of the body through homeostasis.

Chemical classes of hormones

Vertebrate hormones fall into three chemical classes:
• Peptide hormones consist of chains of amino acids. Examples of small peptide hormones are TRH and
vasopressin. Peptides composed of scores or hundreds of amino acids are referred to as proteins. Examples of
protein hormones include insulin and growth hormone. More complex protein hormones bear carbohydrate
side-chains and are called glycoprotein hormones. Luteinizing hormone, follicle-stimulating hormone and
thyroid-stimulating hormone are glycoprotein hormones. There is also another type of hydrophilic hormone called
nonpeptide hormones. Although they don't have peptide connections, they are assimilated as peptide hormones.
• Lipid and phospholipid-derived hormones derive from lipids such as linoleic acid and arachidonic acid and
phospholipids. The main classes are the steroid hormones that derive from cholesterol and the eicosanoids.
Examples of steroid hormones are testosterone and cortisol. Sterol hormones such as calcitriol are a homologous
system. The adrenal cortex and the gonads are primary sources of steroid hormones. Examples of eicosanoids are
the widely studied prostaglandins.
• Monoamines derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan by the action of
aromatic amino acid decarboxylase enzymes.
Hormone 325

Pharmacology
Many hormones and their analogues are used as medication. The most commonly prescribed hormones are estrogens
and progestagens (as methods of hormonal contraception and as HRT), thyroxine (as levothyroxine, for
hypothyroidism) and steroids (for autoimmune diseases and several respiratory disorders). Insulin is used by many
diabetics. Local preparations for use in otolaryngology often contain pharmacologic equivalents of adrenaline, while
steroid and vitamin D creams are used extensively in dermatological practice.
A "pharmacologic dose" of a hormone is a medical usage referring to an amount of a hormone far greater than
naturally occurs in a healthy body. The effects of pharmacologic doses of hormones may be different from responses
to naturally occurring amounts and may be therapeutically useful. An example is the ability of pharmacologic doses
of glucocorticoid to suppress inflammation.

Important human hormones

See: List of human hormones

References
[1] Crisp TM, Clegg ED, Cooper RL, Wood WP, Anderson DG, Baetcke KP, Hoffmann JL, Morrow MS, Rodier DJ, Schaeffer JE, Touart LW,
Zeeman MG, Patel YM (1998). "Environmental endocrine disruption: An effects assessment and analysis". Environ. Health Perspect. 106
(Suppl 1): 11–56. PMC 1533291. PMID 9539004.
[2] Beato M, Chavez S and Truss M (1996). "Transcriptional regulation by steroid hormones". Steroids 61 (4): 240–251.
doi:10.1016/0039-128X(96)00030-X. PMID 8733009.
[3] Hammes SR (2003). "The further redefining of steroid-mediated signaling". Proc Natl Acad Sci USA 100 (5): 21680–2170.
doi:10.1073/pnas.0530224100. PMC 151311. PMID 12606724.

External links
• The Hormone Foundation (http://www.hormone.org)
• Article on hormones and their receptors (http://www.biomedcentral.com/1471-2164/10/307/)
• HMRbase: A database of hormones and their receptors (http://crdd.osdd.net/raghava/hmrbase/)
• MeSH Hormones (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Hormones)
Signal transduction 326

Signal transduction
Signal transduction occurs when an extracellular signaling molecule
activates a cell surface receptor. In turn, this receptor alters
intracellular molecules creating a response.[1] There are two stages in
this process:
1. A signaling molecule activates a specific receptor on the cell
membrane
2. Causing a second messenger to continue the signal into the cell and
elicit a physiological response.
In either step, the signal can be amplified. Thus, one signalling An overview of major signal transduction
molecule can cause many responses.[2] pathways.

History
In 1970, Martin Rodbell examined the
effects of glucagon on a rat's liver cell
membrane receptor. He noted that guanosine
triphosphate disassociated glucagon from
this receptor and stimulated the G-protein,
which strongly influenced the cell's
metabolism. Thus he deduced that the
G-protein was a transducer that accepted
glucagon molecules and affected the cell.[3]
For this he shared the 1994 Nobel Prize in
Physiology or Medicine with Alfred G.
Gilman. The current understanding of signal Occurrence of the term signal transduction in papers since 1977. These figures
transduction processes reflects contributions were extracted through an analysis of the papers contained within the MEDLINE
made by Rodbell and many other research database.

groups.

The earliest scientific paper recorded in the MEDLINE database as containing the specific term signal transduction
was published in 1972.[4] Some articles published before 1977 used the term signal transmission or sensory
transduction for signal transduction:[5] [6] a total of 48,377 scientific papers related to signal transduction were
published in 1977, of which 11,211 were reviews of other papers. That year the actual term signal transduction was
included in abstracts until in 1979 it appeared in a paper's title.[7] [8] One source attributes the widespread use of this
term to a 1980 review article by Rodbell:[9] [3] research papers directly addressing signal transduction processes
began to appear in large numbers in the late 1980s and early 1990s.
[10]
==Signaling molecules==Sordner (talk) 00:05, 7 December 2011 (UTC)

Signal transduction involves the binding of extracellular signalling molecules and ligands to cell-surface receptors
that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation
of the receptor, known as receptor activation. This activation is always the initial step (the cause) leading to the cell's
ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due
to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum
Signal transduction 327

interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.[11] Most steroid
hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter
region of steroid-responsive genes.[12] Examples of signaling molecules include the hormone melatonin,[13] the
neurotransmitter acetylcholine[14] and the cytokine interferon γ.[15]
The classifications of signalling molecules do not take into account the molecular nature of each class member;
neurotransmitters range in size from small molecules such as dopamine[16] to neuropeptides such as endorphins.[17]
Some molecules may fit into more than one class; for example, epinephrine is a neurotransmitter when secreted by
the central nervous system and a hormone when secreted by the adrenal medulla.

Environmental stimuli
With single-celled organisms, the variety of signal transduction processes influence its reaction to its environment.
With multicellular organisms, numerous processes are required for coordinating individual cells to support the
organism as a whole; the complexity of these processes tend to increase with the complexity of the organism.
Sensing of environments at the cellular level relies on signal transduction; many disease processes, such as diabetes
and heart disease arise from defects in these pathways, highlighting the importance of this process in biology and
medicine.
Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples
include photons hitting cells in the retina of the eye,[18] and odorants binding to odorant receptors in the nasal
epithelium.[19] Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune
system response against invading pathogens mediated by signal transduction processes. This may occur independent
of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help
from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling. Single-celled
organisms may respond to environmental stimuli through the activation of signal transduction pathways. For
example, slime molds secrete cyclic adenosine monophosphate upon starvation, stimulating individual cells in the
immediate environment to aggregate,[20] and yeast cells use mating factors to determine the mating types of other
cells and to participate in sexual reproduction.[21]

Receptors
Receptors can be roughly divided into two major classes: intracellular receptors and extracellular receptors.

Extracellular
Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma
membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal
transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane.
This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and
receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the
conformation of the inside part of the receptor.[22] These result in either the activation of an enzyme in the receptor
or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the
signal through the cytoplasm.
In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic
activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic
AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated
proteins interact with adapter proteins that facilitate signalling protein interactions and coordination of signalling
complexes necessary to respond to a particular stimulus. Enzymes and adapter proteins are both responsive to
various second messenger molecules.
Signal transduction 328

Many adapter proteins and enzymes activated as part of signal transduction possess specialized protein domains that
bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of
calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the
same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.

G protein-coupled
G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven
transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including
adrenergic receptors and chemokine receptors.
Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer
consisting of Gα, Gβ, and Gγ. Once the GPCR recognizes a ligand, the conformation of the receptor changes to
activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits.
The dissociation exposes sites on the subunits that can interact with other molecules.[23] The activated G protein
subunits detach from the receptor and initiate signalling from many downstream effector proteins such as
phospholipases and ion channels, the latter permitting the release of second messenger molecules.[24] The total
strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and
receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic
enzymatic activity.
A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2;
mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation
despite the absence of chemokine-binding. This meant that chemokine receptors participate in cancer
development.[25]

Tyrosine and histidine kinase

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an
extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.[26] To
perform signal transduction, RTKs need to form dimers in the plasma membrane;[27] the dimer is stabilized by
ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation
of tyrosines within the domains of the RTKs, causing conformational changes. The receptors' kinase domains are
subsequently activated, initiating phosphorylation signalling cascades of downstream cytoplasmic molecules that
facilitate various cellular processes such as cell differentiation and metabolism.[26]
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK
into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as
small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their
carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in
signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as
SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's
initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors
that exist in a constitutively-activate state; such mutated genes may act as oncogenes.[28]
Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes,
fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first
added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a
different protein or the kinase itself, thus activating the aspartate residue.[29]
Signal transduction 329

Integrin

Integrins are produced by a wide variety of

cells; they play a role in cell attachment to
other cells and the extracellular matrix and
in the transduction of signals from
extracellular matrix components such as
fibronectin and collagen. Ligand binding to
the extracellular domain of integrins
changes the protein's conformation,
clustering it at the cell membrane to initiate
signal transduction. Integrins lack kinase
activity; hence integrin-mediated signal
transduction is achieved through a variety of
intracellular protein kinases and adaptor
molecules, the main coordinator being
integrin-linked kinase.[30] As shown in the
picture to the right, cooperative An overview of integrin-mediated signal transduction, adapted from Hehlgens et
[30]
al. (2007).
integrin-RTK signalling determines the
timing of cellular survival, apoptosis,
proliferation, and differentiation.

Important differences exist between integrin signalling in circulating blood cells and non-circulating cells such as
epithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on
circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are only activated
in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at
the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are
non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to
underlying stromal cells that provide signals to maintain normal functioning.[31]

Toll gate
When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate
a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and
TRAM.[32] [33] [34] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1, and IKKi
that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses.
Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for
gene modulation.

Ligand-gated ion channel

A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell
membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell
of a neural synapse. The influx of ions that occurs in response to these channels opening induces action potentials,
such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening
of voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second
messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in
amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the
synapse.
Signal transduction 330

Intracellular
Further information: Intracellular receptor
Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within
their respective areas. The typical ligands for nuclear receptors are lipophilic hormones like the steroid hormones
testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must
pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the
nuclear membrane into the nucleus, enabling gene transcription and protein production.
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences,
located in the promoter region of the genes activated by the hormone-receptor complex. Due to them enabling gene
transcription, they are alternatively called inductors of gene expression. Activation of gene transcription is slower
than signals directly affecting existing proteins; therefore, the effects of hormones that use nucleic receptors are
long-term.
Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are
not well understood. Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding
domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the
receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance
differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior
to binding and providing structures for transactivation used for communication with the translational apparatus.
Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol; in the absence of steroids,
they cling together in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are
necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its
passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression
when their transactivation domain is hidden; activity can be enhanced by phosphorylation of serine residues at their
N-terminal as a result of another signal transduction pathway, a process called crosstalk.
Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized
ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through
the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in
the nucleus and are not accompanied by HSPs; they repress their gene by binding to their specific DNA sequence
when no ligand binds to them and vice versa.
Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like
receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich
repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates
NF-κB signaling, whereas others like NALP3 interact with inflammatory caspases and initiate processing of
particular cytokines like interleukin-1β.[35]
[36]
== Second messengers ==

First messengers are the intracellular chemical messengers (hormones, neurotransmitters, and panacrine/autocrine
agents) which reach the cell from from the extracellular fluid and bind to their specific receptors. Second messengers
are the substances which enter the cytoplasm and act within the cell to trigger a response. Second messengers
essentially serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular
signal transduction. Sordner (talk) 00:22, 7 December 2011 (UTC)
Signal transduction 331

Calcium
The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding to signaling
proteins that are then activated; it is then sequestered in the smooth endoplasmic reticulum and the mitochondria.
Two combined receptor/ion channel proteins control the transport of calcium: the InsP3-receptor that transports
calcium upon interaction with inositol triphosphate on its cytosolic side and the ryanodine receptor named after the
alkaloid ryanodine, similar to the InsP3 receptor but having a feedback mechanism that releases more calcium upon
binding with it. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its
free state concentration is very low and is mostly bound to organelle molecules like calreticulin when inactive.
Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings and
cell migration. The three main pathways that lead to its activation are GPCR pathways, RTK pathways and gated ion
channels; it regulates proteins either directly or by binding to an enzyme.

Lipophilics
Lipophilic second messenger molecules are derived from lipids residing in cellular membranes; enzymes stimulated
by activated receptors activate the lipids by modifying them. Examples include diacylglycerol and ceramide, the
former required for the activation of protein kinase C.

Nitric oxide
Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma
membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through
activation of soluble guanylyl cyclase, which when activated produces another second messenger, cGMP. NO can
also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are
reversible. It is toxic in high concentrations and causes damage during stroke, but is the cause of many other
functions like relaxation of blood vessels, apoptosis and erections.

Redox Signaling
In addition to nitric oxide, other electronically-activated species are also signal-transducing agents in a process called
redox signaling. Examples include superoxide, hydrogen peroxide, carbon monoxide, and hydrogen sulfide. Redox
signaling also includes active modulation of electonic flows in semiconductive macromolecules.

Cellular responses
Gene activations[37] and metabolism alterations[38] are examples of cellular responses to extracellular stimulation
that require signal transduction. Gene activation leads to further cellular effects, since the products of responding
genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can
activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to
physiological events like the increased uptake of glucose from the blood stream[38] and the migration of neutrophils
to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic
program.[39]
Mammalian cells require stimulation for cell division and survival; in the absence of growth factor, apoptosis ensues.
Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and
multicellular organisms; signal transduction pathways are perceived to be so central to biological processes that a
large number of diseases are attributed to their disregulation.
Signal transduction 332

Major pathways
Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect
second messengers and eventually result in altered cellular responses.
• MAPK/ERK pathway: A pathway that couples intracellular responses to the binding of growth factors to cell
surface receptors.  This pathway is very complex and includes many protein components.[40]   In many cell types,
activation of this pathway promotes cell division, and many forms of cancer are associated with aberrations in
it.[41]
• cAMP dependent pathway: In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent
protein kinase) (see picture), and thus, further effects mainly depend on cAMP-dependent protein kinase, which
vary based on the type of cell.
• IP3/DAG pathway: PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) yielding diacyl
glycerol (DAG) and inositol 1,4,5-triphosphate (IP3).  DAG remains bound to the membrane, and IP3 is released
as a soluble structure into the cytosol.  IP3 then diffuses through the cytosol to bind to IP3 receptors, particular
calcium channels in the endoplasmic reticulum (ER).  These channels are specific to calcium and only allow the
passage of calcium to move through.  This causes the cytosolic concentration of Calcium to increase, causing a
cascade of intracellular changes and activity.[42]   In addition, calcium and DAG together works to activate PKC,
which goes on to phosphorylate other molecules, leading to altered cellular activity.  End effects include taste,
manic depression, tumor promotion, etc.[42]

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Signal transduction 334

External links
• Netpath - A curated resource of signal transduction pathways in humans (http://www.netpath.org/)
• Signal Transduction - The Virtual Library of Biochemistry and Cell Biology (http://www.biochemweb.org/
signaling.shtml)
• TRANSPATH(R) (http://www.gene-regulation.com/cgi-bin/pub/databases/transpath/search.cgi) - A
database about signal transduction pathways
• Redox Signaling Molecules (http://www.energeticforum.com/health-fitness-nutrition/
8819-redox-signaling-molecules.html) - A public discussion.
• Redox Signaling Molecules (http://www.redoxsignalingmoleculesbook.com) - PDf download
• Science's STKE - Signal Transduction Knowledge Environment (http://stke.sciencemag.org/), from the journal
Science, published by AAAS.
• MeSH Signal+Transduction (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Signal+
Transduction)
• UCSD-Nature Signaling Gateway (http://www.signaling-gateway.org/), from Nature Publishing Group
• LitInspector (http://www.litinspector.org) - Signal transduction pathway mining in PubMed abstracts
• Huaxian Chen, et al. A Cell Based Immunocytochemical Assay For Monitoring Kinase Signaling Pathways And
Drug Efficacy (PDF) (http://www.licor.com./bio/PDF/AppNote_AnalBiochem.pdf) Analytical Biochemistry
338 (2005) 136-142
• www.Redoxsignaling.com (http://www.redoxsignaling.com)
• Signaling PAthway Database (http://www.grt.kyushu-u.ac.jp/spad/) - Kyushu University
• Cell cycle - Homo sapiens (human) (http://www.genome.jp/kegg/pathway/hsa/hsa04110.html) - KEGG
PATHWAY (http://www.genome.jp/kegg/pathway.html)
• Pathway Interaction Database (http://pid.nci.nih.gov/) - NCI
Diabetes mellitus 335

Diabetes mellitus
Diabetes mellitus
Classification and external resources

[1]
Universal blue circle symbol for diabetes.

ICD-10 [2] [3]

E10 –E14

ICD-9 [4]
250

MedlinePlus [5]
001214

eMedicine [6] [7]

med/546 emerg/134

MeSH [8]
C18.452.394.750

Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high
blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin
that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia
(increased thirst) and polyphagia (increased hunger).
There are three main types of diabetes:
• Type 1 diabetes: results from the body's failure to produce insulin, and presently requires the person to inject
insulin. (Also referred to as insulin-dependent diabetes mellitus, IDDM for short, and juvenile diabetes.)
• Type 2 diabetes: results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes
combined with an absolute insulin deficiency. (Formerly referred to as non-insulin-dependent diabetes mellitus,
NIDDM for short, and adult-onset diabetes.)
• Gestational diabetes: is when pregnant women, who have never had diabetes before, have a high blood glucose
level during pregnancy. It may precede development of type 2 DM.
Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion,
cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of
monogenic diabetes.
All forms of diabetes have been treatable since insulin became available in 1921, and type 2 diabetes may be
controlled with medications. Both type 1 and 2 are chronic conditions that usually cannot be cured. Pancreas
transplants have been tried with limited success in type 1 DM; gastric bypass surgery has been successful in many
Diabetes mellitus 336

with morbid obesity and type 2 DM. Gestational diabetes usually resolves after delivery. Diabetes without proper
treatments can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or
nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal
failure, retinal damage. Adequate treatment of diabetes is thus important, as well as blood pressure control and
lifestyle factors such as smoking cessation and maintaining a healthy body weight.
As of 2000 at least 171 million people worldwide have diabetes, or 2.8% of the population.[9] Type 2 diabetes is by
far the most common, affecting 90 to 95% of the U.S. diabetes population.[10]

Classification
Most cases of diabetes mellitus fall into three broad categories: type 1, type 2, and gestational diabetes. A few other
types are described. The term diabetes, without qualification, usually refers to diabetes mellitus. The rare disease
diabetes insipidus has similar symptoms as diabetes mellitus, but without disturbances in the sugar metabolism
(insipidus meaning "without taste" in Latin).

Comparison of type 1 and 2 diabetes

Feature Type 1 diabetes Type 2 diabetes

Onset [11] [11]

Sudden Gradual

Age at onset Mostly in adults

Any age
[11]
(mostly young)

Body habitus [11] [12] [11]

Thin or normal Often obese

Ketoacidosis [11] [11]

Common Rare

Autoantibodies [11] [11]

Usually present Absent

Endogenous insulin [11]

Low or absent Normal, decreased
[11]
or increased

Concordance [11] [11]

50% 90%
in identical twins

Prevalence Less prevalent More prevalent

- 90 to 95% of
[10]
  U.S. diabetics

The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes, juvenile diabetes,
and insulin-dependent diabetes mellitus (IDDM). Likewise, the term "type 2 diabetes" has replaced several former
terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes mellitus
(NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined
"type 3 diabetes" as: gestational diabetes,[13] insulin-resistant type 1 diabetes (or "double diabetes"), type 2 diabetes
which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "type 1.5"
diabetes).[14]

Type 1 diabetes
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the
pancreas leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or
idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, where beta cell loss is a T-cell
mediated autoimmune attack.[15] There is no known preventive measure against type 1 diabetes, which causes
approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise
Diabetes mellitus 337

healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal,
especially in the early stages. Type 1 diabetes can affect children or adults but was traditionally termed "juvenile
diabetes" because it represents a majority of the diabetes cases in children.
"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe
to dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent
diabetes. This term, however, has no biologic basis and should not be used.[16] There are many different reasons for
type 1 diabetes to be accompanied by irregular and unpredictable hyperglycemias, frequently with ketosis, and
sometimes serious hypoglycemias, including an impaired counterregulatory response to hypoglycemia, occult
infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (eg,
Addison's disease).[17] These phenomena are believed to occur no more frequently than in 1% to 2% of persons with
type 1 diabetes.[18]

Type 2 diabetes
Type 2 diabetes mellitus is characterized by insulin resistance which may be combined with relatively reduced
insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor.
However, the specific defects are not known. Diabetes mellitus due to a known defect are classified separately.
Type 2 diabetes is the most common type.
In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity. At this stage
hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce
glucose production by the liver.

Gestational diabetes
Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of
relatively inadequate insulin secretion and responsiveness. It occurs in about 2%–5% of all pregnancies and may
improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision
throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life.
Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to
the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and
skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory
distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death
may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may
be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress
or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
A 2008 study completed in the U.S. found that the number of American women entering pregnancy with preexisting
diabetes is increasing. In fact the rate of diabetes in expectant mothers has more than doubled in the past 6 years.[19]
This is particularly problematic as diabetes raises the risk of complications during pregnancy, as well as increasing
the potential that the children of diabetic mothers will also become diabetic in the future.
Diabetes mellitus 338

Other types
Pre-diabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not
high enough for a diagnosis of type 2 diabetes. Many people destined to develop type 2 diabetes spend many years in
a state of pre-diabetes which has been termed "America's largest healthcare epidemic."[20] :10–11
Latent autoimmune diabetes of adults is a condition in which Type 1 diabetes develops in adults. Adults with LADA
are frequently initially misdiagnosed as having Type 2 diabetes, based on age rather than etiology.
Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels
are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations
(autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been
genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes
(for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of
insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed).
Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic
entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World
Health Organization when the current taxonomy was introduced in 1999.[21]

Signs and symptoms

Hyperglycemia and osmosis

The classical symptoms of diabetes are polyuria (frequent urination),
polydipsia (increased thirst) and polyphagia (increased hunger).[22]
Symptoms may develop rapidly (weeks or months) in type 1 diabetes
while in type 2 diabetes they usually develop much more slowly and
may be subtle or absent.
Prolonged high blood glucose causes glucose absorption, which leads
to changes in the shape of the lenses of the eyes, resulting in vision
changes; sustained sensible glucose control usually returns the lens to
its original shape. Blurred vision is a common complaint leading to a
diabetes diagnosis; type 1 should always be suspected in cases of rapid
vision change, whereas with type 2 change is generally more gradual,
Overview of the most significant symptoms of
but should still be suspected .
diabetes.

Diabetic emergencies
People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation
characterized by the smell of acetone; a rapid, deep breathing known as Kussmaul breathing; nausea; vomiting and
abdominal pain; and altered states of consciousness.
A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and
is mainly the result of dehydration. Often, the patient has been drinking extreme amounts of sugar-containing drinks,
leading to a vicious circle in regard to the water loss.
Diabetes mellitus 339

Complications
All forms of diabetes increase the risk of long-term complications. These typically develop after many years
(10–20), but may be the first symptom in those who have otherwise not received a diagnosis before that time. The
major long-term complications relate to damage to blood vessels.
Diabetes doubles the risk of cardiovascular disease.[23] The main "macrovascular" diseases (related to atherosclerosis
of larger arteries) are ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular
disease.
Diabetes also causes "microvascular" complications—damage to the small blood vessels.[24] Diabetic retinopathy,
which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and
potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in
the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney
disease requiring dialysis. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly
causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation.
Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such
as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.

Other problems
A number of skin rashes can occur in diabetes that are collectively known as diabetic dermadromes.

Causes
The cause of diabetes depends on the type.
Type 1 diabetes is partly inherited and then triggered by certain infections, with some evidence pointing at
Coxsackie B4 virus. There is a genetic element in individual susceptibility to some of these triggers which has been
traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However,
even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental
trigger.
Type 2 diabetes is due primarily to lifestyle factors and genetics.[25]
Following is a comprehensive list of other causes of diabetes:[26]

• Genetic defects of β-cell Function • Endocrinopathies

• Maturity onset diabetes of the young (MODY) • Growth hormone excess (acromegaly)
• Mitochondrial DNA mutations • Cushing syndrome
• Genetic defects in insulin processing or insulin action • Hyperthyroidism
• Defects in proinsulin conversion • Pheochromocytoma
• Insulin gene mutations • Glucagonoma
• Insulin receptor mutations • Infections
• Exocrine Pancreatic Defects • Cytomegalovirus infection
• Chronic pancreatitis • Coxsackievirus B
• Pancreatectomy • Drugs
• Pancreatic neoplasia • Glucocorticoids
• Cystic fibrosis • Thyroid hormone
• Hemochromatosis • β-adrenergic agonists
• Fibrocalculous pancreatopathy
Diabetes mellitus 340

Pathophysiology
Insulin is the principal hormone that regulates uptake of glucose from
the blood into most cells (primarily muscle and fat cells, but not central
nervous system cells). Therefore deficiency of insulin or the
insensitivity of its receptors plays a central role in all forms of diabetes
mellitus.
Humans are capable of digesting some carbohydrates, in particular
those most common in food; starch, and some disaccharides such as
sucrose, are converted within a few hours to simpler forms most
notably the monosaccharide glucose, the principal carbohydrate energy The fluctuation of blood sugar (red) and the
source used by the body. The rest are passed on for processing by gut sugar-lowering hormone insulin (blue) in humans
flora largely in the colon. Insulin is released into the blood by beta during the course of a day with three meals. One
of the effects of a sugar-rich vs a starch-rich meal
cells (β-cells), found in the Islets of Langerhans in the pancreas, in
is highlighted.
response to rising levels of blood glucose, typically after eating. Insulin
is used by about two-thirds of the body's cells to absorb glucose from
the blood for use as fuel, for conversion to other needed molecules, or
for storage.

Insulin is also the principal control signal for conversion of glucose to

glycogen for internal storage in liver and muscle cells. Lowered
glucose levels result both in the reduced release of insulin from the
beta cells and in the reverse conversion of glycogen to glucose when
glucose levels fall. This is mainly controlled by the hormone glucagon
which acts in the opposite manner to insulin. Glucose thus forcibly Mechanism of insulin release in normal
produced from internal liver cell stores (as glycogen) re-enters the pancreatic beta cells. Insulin production is more
or less constant within the beta cells. Its release is
bloodstream; muscle cells lack the necessary export mechanism.
triggered by food, chiefly food containing
Normally liver cells do this when the level of insulin is low (which absorbable glucose.
normally correlates with low levels of blood glucose).

Higher insulin levels increase some anabolic ("building up") processes such as cell growth and duplication, protein
synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional
processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is
the trigger for entering or leaving ketosis (the fat burning metabolic phase).
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity
or resistance), or if the insulin itself is defective, then glucose will not have its usual effect so that glucose will not be
absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The
net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such
as acidosis.
When the glucose concentration in the blood is raised beyond its renal threshold (about 10 mmol/L, although this
may be altered in certain conditions, such as pregnancy), reabsorption of glucose in the proximal renal tubuli is
incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine
and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased
fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body
compartments, causing dehydration and increased thirst.
Diabetes mellitus 341

Diagnosis

2006 WHO Diabetes criteria[27]

Condition 2 hour glucose Fasting glucose

mmol/l(mg/dl) mmol/l(mg/dl)

Normal <7.8 (<140) <6.1 (<110)

Impaired fasting glycaemia <7.8 (<140) ≥ 6.1(≥110) & <7.0(<126)

Impaired glucose tolerance ≥7.8 (≥140) <7.0 (<126)

Diabetes mellitus ≥11.1 (≥200) ≥7.0 (≥126)

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any
one of the following:[21]
• Fasting plasma glucose level ≥ 7.0 mmol/L (126 mg/dL).
• Plasma glucose ≥ 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance
test.
• Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/L (200 mg/dL).
• Glycated hemoglobin (Hb A1C) ≥ 6.5%.[28]
A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the
above-listed methods on a different day. It is preferable to measure a fasting glucose level because of the ease of
measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to
complete and offers no prognostic advantage over the fasting test.[29] According to the current definition, two fasting
glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes mellitus.
People with fasting glucose levels from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) are considered to have impaired
fasting glucose. Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL
(11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these
two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus as
well as cardiovascular disease.[30]
Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from
any cause.[31]

Management
Diabetes mellitus is a chronic disease which cannot be cured except in very specific situations. Management
concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible, without causing
hypoglycemia. This can usually be accomplished with diet, exercise, and use of appropriate medications (insulin in
the case of type 1 diabetes, oral medications as well as possibly insulin in type 2 diabetes).
Patient education, understanding, and participation is vital since the complications of diabetes are far less common
and less severe in people who have well-managed blood sugar levels.[32] [33] The goal of treatment is an HbA1C
level of 6.5%, but should not be lower than that, and may be set higher.[34] Attention is also paid to other health
problems that may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels,
obesity, high blood pressure, and lack of regular exercise.[34]
Diabetes mellitus 342

Lifestyle
There are roles for patient education, dietetic support, sensible exercise, with the goal of keeping both short-term and
long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of
cardiovascular disease, lifestyle modifications are recommended to control blood pressure.[35]

Medications
Oral medications
Metformin is generally recommended as a first line treatment for type 2 diabetes as there is good evidence that it
decreases mortality.[36] Routine use of aspirin however has not been found to improve outcomes in uncomplicated
diabetes.[37]
Insulin
Type 1 diabetes is typically treated with a combinations of regular and NPH insulin, or synthetic insulin analogs.
When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially, while continuing oral
medications.[36] Doses of insulin are then increased to effect.[36]

Support
In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside
hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or
research projects. In other circumstances, general practitioners and specialists share care of a patient in a team
approach. Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, nursing specialists (e.g., DSNs
(Diabetic Specialist Nurse)), nurse practitioners, or certified diabetes educators, may jointly provide
multidisciplinary expertise.

Epidemiology
In 2000,
according to the
World Health
Organization, at
least 171 million
people
Prevalence of diabetes worldwide in 2000 (per 1000 inhabitants). World average was 2.8%.   no
worldwide suffer data  ≤ 7.5  7.5–15  15–22.5  22.5–30  30–37.5  37.5–45  45–52.5  52.5–60  60–67.5  67.5–75  75–82.5  ≥ 82.5
from diabetes, or
2.8% of the
population.[9] Its
incidence is
increasing
rapidly, and it is
estimated that by
2030, this Disability-adjusted life year for diabetes mellitus per 100,000 inhabitants in 2004.   no
number will data  <100  100-200  200-300  300-400  400-500  500-600  600-700  700-800  800-900  900-1000  1000-1500  >1500

almost double.[9]
Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed
countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients
Diabetes mellitus 343

will probably be found by 2030.[9] The increase in incidence of diabetes in developing countries follows the trend of
urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an
environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is
much speculation, some of it most compellingly presented.[9]
Prevalence in the United States
For at least 20 years, diabetes rates in North America have been increasing substantially. In 2010 nearly 26 million
people have diabetes in the United States alone, from those 7 million people remain undiagnosed. Another 57 million
people are estimated to have pre-diabetes.[38]
The Centers for Disease Control has termed the change an epidemic.[39] The National Diabetes Information
Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year. About 5%–10% of
diabetes cases in North America are type 1, with the rest being type 2. The fraction of type 1 in other parts of the
world differs. Most of this difference is not currently understood. The American Diabetes Association cite the 2003
assessment of the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease
Control and Prevention) that 1 in 3 Americans born after 2000 will develop diabetes in their lifetime.[40] [41]
According to the American Diabetes Association, approximately 18.3% (8.6 million) of Americans age 60 and older
have diabetes.[42] Diabetes mellitus prevalence increases with age, and the numbers of older persons with diabetes
are expected to grow as the elderly population increases in number. The National Health and Nutrition Examination
Survey (NHANES III) demonstrated that, in the population over 65 years old, 18% to 20% have diabetes, with 40%
having either diabetes or its precursor form of impaired glucose tolerance.[43]
Prevalence in Australia
Indigenous populations in first world countries have a higher prevalence and increasing incidence of diabetes than
their corresponding non-indigenous populations. In Australia the age-standardised prevalence of self-reported
diabetes in Indigenous Australians is almost 4 times that of non-indigenous Australians.[44] Preventative community
health programs such as Sugar Man (diabetes education) are showing some success in tackling this problem.

Etymology
The word “diabetes” (  /ˌdaɪ.əˈbiːtiːz/ or /ˌdaɪ.əˈbiːtɪs/) comes from Latin diabētēs, which in turn comes from
Ancient Greek διαβήτης (diabētēs) which literally means “a passer through; a siphon.”[45] Ancient Greek physician
Aretaeus of Cappadocia (fl. 1st century CE) used that word, with the intended meaning “excessive discharge of
urine,” as the name for the disease.[46] [47] Ultimately, the word comes from Greek διαβαίνειν (diabainein), meaning
“to pass through,”[45] which is composed of δια- (dia-), meaning “through” and βαίνειν (bainein), meaning “to
go”.[46] The word “diabetes” is first recorded in English, in the form diabete, in a medical text written around 1425.
The word “mellitus” (/mɪˈlaɪtəs/ or /ˈmɛlɪtəs/) comes from the classical Latin word mellītus, meaning “mellite”[48]
(i.e. sweetened with honey;[48] honey-sweet[49] ). The Latin word comes from mell-, which comes from mel,
meaning “honey;[48] [49] sweetness;[49] pleasant thing,[49] ” and the suffix -ītus,[48] whose meaning is the same as that
of the English suffix “-ite.”[50] It was Thomas Willis who in 1675 added “mellitus” to the word “diabetes” as a
designation for the disease, when he noticed that the urine of a diabetic had a sweet taste (glycosuria).[47] This sweet
taste had been noticed in urine by the ancient Greeks, Chinese, Egyptians, Indians, and Persians.

History
Diabetes is one of the oldest known diseases.[47] An Egyptian manuscript from c. 1550 BCE mentions the phrase
“the passing of too much urine.”[47] The great Indian physician Sushruta (fl. 6th century BCE)[47] identified the
disease and classified it as Medhumeha.[51] He further identified it with obesity and sedentary lifestyle, advising
exercises to help "cure" it.[51] The ancient Indians tested for diabetes by observing whether ants were attracted to a
person's urine, and called the ailment "sweet urine disease" (Madhumeha).
Diabetes mellitus 344

Concerning the sweetness of urine, it is to be noted that the Chinese, Japanese and Korean words for diabetes are
based on the same ideographs (糖尿病) which mean "sugar urine disease". It was in 1776 that Matthew Dobson
confirmed that the sweet taste comes from an excess of a kind of sugar in the urine and blood.[52]
The first complete clinical description of diabetes was given by the Ancient Greek physician Aretaeus of Cappadocia
(fl. 1st century CE), who noted the excessive amount of urine which passed through the kidneys and gave the disease
the name “diabetes.”[47]
Diabetes mellitus appears to have been a death sentence in the ancient era. Hippocrates makes no mention of it,
which may indicate that he felt the disease was incurable. Aretaeus did attempt to treat it but could not give a good
prognosis; he commented that "life (with diabetes) is short, disgusting and painful."[53]
In medieval Persia, Avicenna (980–1037) provided a detailed account on diabetes mellitus in The Canon of
Medicine, "describing the abnormal appetite and the collapse of sexual functions," and he documented the sweet
taste of diabetic urine. Like Aretaeus before him, Avicenna recognized a primary and secondary diabetes. He also
described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed,
which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern
times. Avicenna also "described diabetes insipidus very precisely for the first time", though it was later Johann Peter
Frank (1745–1821) who first differentiated between diabetes mellitus and diabetes insipidus.[54]
Although diabetes has been recognized since antiquity, and treatments of various efficacy have been known in
various regions since the Middle Ages, and in legend for much longer, pathogenesis of diabetes has only been
understood experimentally since about 1900.[55] The discovery of a role for the pancreas in diabetes is generally
ascribed to Joseph von Mering and Oskar Minkowski, who in 1889 found that dogs whose pancreas was removed
developed all the signs and symptoms of diabetes and died shortly afterwards.[56] In 1910, Sir Edward Albert
Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced
by the pancreas—he proposed calling this substance insulin, from the Latin insula, meaning island, in reference to
the insulin-producing islets of Langerhans in the pancreas.
The endocrine role of the pancreas in metabolism, and indeed the existence of insulin, was not further clarified until
1921, when Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski,
and went further to demonstrate they could reverse induced diabetes in dogs by giving them an extract from the
pancreatic islets of Langerhans of healthy dogs.[57] Banting, Best, and colleagues (especially the chemist Collip)
went on to purify the hormone insulin from bovine pancreases at the University of Toronto. This led to the
availability of an effective treatment—insulin injections—and the first patient was treated in 1922. For this, Banting
and laboratory director MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their
Prize money with others in the team who were not recognized, in particular Best and Collip. Banting and Best made
the patent available without charge and did not attempt to control commercial production. Insulin production and
therapy rapidly spread around the world, largely as a result of this decision. Banting is honored by World Diabetes
Day which is held on his birthday, November 14.
The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir
Harold Percival (Harry) Himsworth, and published in January 1936.[58]
Despite the availability of treatment, diabetes has remained a major cause of death. For instance, statistics reveal that
the cause-specific mortality rate during 1927 amounted to about 47.7 per 100,000 population in Malta.[59]
Other landmark discoveries include:[55]
• Identification of the first of the sulfonylureas in 1942
• Reintroduction of the use of biguanides for Type 2 diabetes in the late 1950s. The initial phenformin was
withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis and metformin
was first marketed in France in 1979, but not until 1994 in the US.
Diabetes mellitus 345

• The determination of the amino acid sequence of insulin (by Sir Frederick Sanger, for which he received a Nobel
Prize)
• The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson (gaining Yalow the
1977 Nobel Prize in Physiology or Medicine)[60]
• The three-dimensional structure of insulin (PDB 2INS [61])
• Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988
• Demonstration that intensive glycemic control in type 1 diabetes reduces chronic side effects more as glucose
levels approach 'normal' in a large longitudinal study,[62] and also in type 2 diabetics in other large studies
• Identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s
In 1980, U.S. biotech company Genentech developed biosynthetic human insulin. The insulin was isolated from
genetically altered bacteria (the bacteria contain the human gene for synthesizing synthetic human insulin), which
produce large quantities of insulin. The purified insulin is distributed to pharmacies for use by diabetes patients.
Initially, this development was not regarded by the medical profession as a clinically meaningful development.
However, by 1996, the advent of insulin analogues which had vastly improved absorption, distribution, metabolism,
and excretion (ADME) characteristics which were clinically meaningful based on this early biotechnology
development.

Society and culture

The 1990 "St. Vincent Declaration"[63] [64] was the result of international efforts to improve the care accorded to
those with diabetes. Doing so is important both in terms of quality of life and life expectancy but also
economically—expenses due to diabetes have been shown to be a major drain on health-and productivity-related
resources for healthcare systems and governments.
Several countries established more and less successful national diabetes programmes to improve treatment of the
disease.[65]
A study shows that diabetic patients with neuropathic symptoms such as numbness or tingling in feet or hands are
twice as likely to be unemployed as those without the symptoms.[66]

In other animals
In animals, diabetes is most commonly encountered in dogs and cats. Middle-aged animals are most commonly
affected. Female dogs are twice as likely to be affected as males, while according to some sources male cats are also
more prone than females. In both species, all breeds may be affected, but some small dog breeds are particularly
likely to develop diabetes, such as Miniature Poodles.[67] The symptoms may relate to fluid loss and polyuria, but the
course may also be insidious. Diabetic animals are more prone to infections. The long-term complications recognised
in humans are much rarer in animals. The principles of treatment (weight loss, oral antidiabetics, subcutaneous
insulin) and management of emergencies (e.g. ketoacidosis) are similar to those in humans.[67]
Diabetes mellitus 346

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[39] "CDC's Diabetes Program-News and Information-Press Releases-October 26, 2000" (http:/ / www. cdc. gov/ Diabetes/ news/ docs/ 010126.
htm). . Retrieved 2008-06-23.
[40] Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF (October 2003). "Lifetime risk for diabetes mellitus in the United
States". JAMA 290 (14): 1884–90. doi:10.1001/jama.290.14.1884. PMID 14532317.
[41] American Diabetes Association (2005). "Total Prevalence of Diabetes & Pre-diabetes" (http:/ / web. archive. org/ web/ 20060208032127/
http:/ / www. diabetes. org/ diabetes-statistics/ prevalence. jsp). Archived from the original (http:/ / www. diabetes. org/ diabetes-statistics/
prevalence. jsp) on 2006-02-08. . Retrieved 2006-03-17.
[42] "Seniors and Diabetes" (http:/ / www. dlife. com/ dLife/ do/ ShowContent/ daily_living/ seniors/ ). Elderly And Diabetes-Diabetes and
Seniors. LifeMed Media. 2006. . Retrieved 2007-05-14.
[43] Harris MI, Flegal KM, Cowie CC, et al. (April 1998). "Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in
U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994". Diabetes Care 21 (4): 518–24.
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[44] Australian Institute for Health and Welfare. "Diabetes, an overview" (http:/ / web. archive. org/ web/ 20080617222036/ http:/ / www. aihw.
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[45] Oxford English Dictionary. diabetes. Retrieved 2011-06-10.
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[47] Dallas, John (2011). "Royal College of Physicians of Edinburgh. Diabetes, Doctors and Dogs: An exhibition on Diabetes and Endocrinology
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in/ iae/ t07/ i4/ iaet07i4p243. pdf). National Informatics Centre (Government of India).
[52] Dobson, M. (1776). "Nature of the urine in diabetes". Medical Observations and Inquiries 5: 298–310.
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ISBN 1-85070-427-9.
[54] Nabipour, I. (2003). "Clinical Endocrinology in the Islamic Civilization in Iran". International Journal of Endocrinology and Metabolism 1:
43–45 [44–5].
[55] Patlak M (December 2002). "New weapons to combat an ancient disease: treating diabetes" (http:/ / www. fasebj. org/ content/ 16/ 14/ 1853.
2). The FASEB Journal 16 (14): 1853. PMID 12468446. .
[56] Von Mehring J, Minkowski O. (1890). "Diabetes mellitus nach pankreasexstirpation". Arch Exp Pathol Pharmakol 26 (5–6): 371–387.
doi:10.1007/BF01831214.
[57] Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (November 1991). "Pancreatic extracts in the treatment of diabetes mellitus:
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[58] Himsworth (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types". Lancet i (5864): 127–30.
doi:10.1016/S0140-6736(01)36134-2.
[59] Department of Health (Malta), 1897–1972:Annual Reports.
[60] Yalow RS, Berson SA (July 1960). "Immunoassay of endogenous plasma insulin in man". The Journal of Clinical Investigation 39 (7):
1157–75. doi:10.1172/JCI104130. PMC 441860. PMID 13846364.
[61] http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=2INS
[62] The Diabetes Control And Complications Trial Research Group (September 1993). "The effect of intensive treatment of diabetes on the
development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications
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Diabetes mellitus 348

[63] Theodore H. Tulchinsky, Elena A. Varavikova (2008). The New Public Health, Second Edition. New York: Academic Press. p. 200.
ISBN 0-12-370890-7.
[64] Piwernetz K, Home PD, Snorgaard O, Antsiferov M, Staehr-Johansen K, Krans M (May 1993). "Monitoring the targets of the St Vincent
Declaration and the implementation of quality management in diabetes care: the DIABCARE initiative. The DIABCARE Monitoring Group
of the St Vincent Declaration Steering Committee". Diabetic Medicine 10 (4): 371–7. doi:10.1111/j.1464-5491.1993.tb00083.x.
PMID 8508624.
[65] Dubois, HFW and Bankauskaite, V (2005). "Type 2 diabetes programmes in Europe" (http:/ / www. euro. who. int/ Document/ Obs/
EuroObserver7_3. pdf) (PDF). Euro Observer 7 (2): 5–6. .
[66] Stewart WF, Ricci JA, Chee E, Hirsch AG, Brandenburg NA (June 2007). "Lost productive time and costs due to diabetes and diabetic
neuropathic pain in the US workforce". J. Occup. Environ. Med. 49 (6): 672–9. doi:10.1097/JOM.0b013e318065b83a. PMID 17563611.
[67] "Diabetes mellitus" (http:/ / www. merckvetmanual. com/ mvm/ index. jsp?cfile=htm/ bc/ 40302. htm). Merck Veterinary Manual, 9th
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External links
• Diabetes (http://www.dmoz.org/Health/Conditions_and_Diseases/Endocrine_Disorders/Pancreas/Diabetes/)
at the Open Directory Project
• American Diabetes Association (http://www.diabetes.org/)
• IDF Diabetes Atlas (http://www.diabetesatlas.org/)
• International Diabetes Federation (http://www.idf.org/)
• National Diabetes Education Program (http://ndep.nih.gov/)
• Peers for Progress (http://www.peersforprogress.org/)
• World Diabetes Day (http://www.worlddiabetesday.org/)
 349

Informational Macromolecules
 350

DNA synthesis and repair

DNA replication
DNA replication is a biological process that occurs in all living
organisms and copies their DNA; it is the basis for biological
inheritance. The process starts with one double-stranded DNA
molecule and produces two identical copies of the molecule. Each
strand of the original double-stranded DNA molecule serves as
template for the production of the complementary strand, a process
referred to as semiconservative replication. Cellular proofreading and
error toe-checking mechanisms ensure near perfect fidelity for DNA
replication.[1] [2]

In a cell, DNA replication begins at specific locations in the genome,

called "origins".[3] Unwinding of DNA at the origin, and synthesis of
new strands, forms a replication fork. In addition to DNA polymerase,
the enzyme that synthesizes the new DNA by adding nucleotides
matched to the template strand, a number of other proteins are
associated with the fork and assist in the initiation and continuation of
DNA synthesis.

DNA replication can also be performed in vitro (artificially, outside a

cell). DNA polymerases, isolated from cells, and artificial DNA
primers are used to initiate DNA synthesis at known sequences in a
template molecule. The polymerase chain reaction (PCR), a common
laboratory technique, employs such artificial synthesis in a cyclic
manner to amplify a specific target DNA fragment from a pool of
DNA replication. The double helix is unwound
DNA.
and each strand acts as a template for the next
strand. Bases are matched to synthesize the new
partner strands.
DNA replication 351

DNA structure
DNA usually exists as a double-stranded structure, with both
strands coiled together to form the characteristic double-helix.
Each single strand of DNA is a chain of four types of nucleotides
having the bases: adenine, cytosine, guanine, and thymine. A
nucleotide is a mono-, di-, or triphosphate deoxyribonucleoside;
that is, a deoxyribose sugar is attached to one, two, or three
phosphates. Chemical interaction of these nucleotides forms
phosphodiester linkages, creating the phosphate-deoxyribose
backbone of the DNA double helix with the bases pointing inward.
Nucleotides (bases) are matched between strands through
hydrogen bonds to form base pairs. Adenine pairs with thymine,
and cytosine pairs with guanine.

DNA strands have a directionality, and the different ends of a

single strand are called the "3' (three-prime) end" and the "5'
(five-prime) end" with the direction of the naming going 5 prime
to the 3 prime region.The strands of the helix are anti-parallel with
one being 5 prime to 3 then the opposite strand 3 prime to 5 .
These terms refer to the carbon atom in deoxyribose to which the
next phosphate in the chain attaches. Directionality has
consequences in DNA synthesis, because DNA polymerase can
synthesize DNA in only one direction by adding nucleotides to the
3' end of a DNA strand.
The pairing of bases in DNA through hydrogen bonding means
that the information contained within each strand is redundant.
The nucleotides on a single strand can be used to reconstruct
nucleotides on a newly synthesized partner strand.[4] The chemical structure of DNA
DNA replication 352

DNA polymerase
DNA polymerases are a family of enzymes that carry out all forms of
DNA replication.[6] However, a DNA polymerase can only extend an
existing DNA strand paired with a template strand; it cannot begin the
synthesis of a new strand. To begin synthesis, a short fragment of
DNA or RNA, called a primer, must be created and paired with the
template DNA strand.

DNA polymerase then synthesizes a new strand of DNA by extending

the 3' end of an existing nucleotide chain, adding new nucleotides
matched to the template strand one at a time via the creation of
phosphodiester bonds. The energy for this process of DNA
polymerization comes from two of the three total phosphates attached
to each unincorporated base. (Free bases with their attached phosphate
groups are called nucleoside triphosphates.) When a nucleotide is
being added to a growing DNA strand, two of the phosphates are
removed and the energy produced creates a phosphodiester bond that
attaches the remaining phosphate to the growing chain. The energetics
of this process also help explain the directionality of synthesis - if
DNA were synthesized in the 3' to 5' direction, the energy for the
process would come from the 5' end of the growing strand rather than
from free nucleotides.

In general, DNA polymerases are extremely accurate, making less

than one mistake for every 107 nucleotides added.[7] Even so, some
DNA polymerases also have proofreading ability; they can remove
nucleotides from the end of a strand in order to correct mismatched
bases. If the 5' nucleotide needs to be removed during proofreading,
the triphosphate end is lost. Hence, the energy source that usually
provides energy to add a new nucleotide is also lost.
DNA polymerases adds nucleotides to the 5' end
[5]
of a strand of DNA. If a mismatch is
accidentally incorporated, the polymerase is
inhibited from further extension. Proofreading
removes the mismatched nucleotide and extension
continues.

Replication process

Origins
For a cell to divide, it must first replicate its DNA.[8] This process is initiated at particular points in the DNA, known
as "origins", which are targeted by proteins that separate the two strands and initiate DNA synthesis.[3] Origins
contain DNA sequences recognized by replication initiator proteins (e.g., dnaA in E. coli' and the Origin Recognition
Complex in yeast).[9] These initiator proteins recruit other proteins to separate the two strands and initiate replication
forks.
Initiator proteins recruit other proteins and form the pre-replication complex, which separate the DNA strands at the
origin and forms a bubble. Origins tend to be "AT-rich" (rich in adenine and thymine bases) to assist this process,
because A-T base pairs have two hydrogen bonds (rather than the three formed in a C-G pair)—in general, strands
rich in these nucleotides are easier to separate because a greater number of hydrogen bonds requires more energy to
break them.[10]
All known DNA replication systems require a free 3' OH group before synthesis can be initiated. Four distinct
mechanisms are have been described.
DNA replication 353

1. All cellular life forms and many DNA viruses, phages and plasmids use a primase to synthesize a short RNA
primer with a free 3′ OH group which is subsequently elongated by a DNA polymerase.
2. The retroelements (including retroviruses) employ a transfer RNA that primes DNA replication by providing a
free 3′ OH that is used for elongation by the reverse transcriptase.
3. In the adenoviruses and the φ29 family of bacteriophages, the 3' OH group is provided by the side chain of an
amino acid of the genome attached protein (the terminal protein) to which nucleotides are added by the DNA
polymerase to form a new strand.
4. In the single stranded DNA viruses - a group that includes the circoviruses, the geminiviruses, the parvoviruses
and others - and also the many phages and plasmids that use the rolling circle replication (RCR) mechanism, the
RCR endonuclease creates a nick the genome strand (single stranded viruses) or one of the DNA strands (plasmids).
The 5′ end of the nicked strand is transferred to a tyrosine residue on the nuclease and the free 3′ OH group is then
used by the DNA polymerase for new strand synthesis.
The best known of these mechanisms is that used by the cellular organisms. In these once the two strands are
separated, RNA primers are created on the template strands. To be more specific, the leading strand receives one
RNA primer per active origin of replication while the lagging strand receives several; these several fragments of
RNA primers found on the lagging strand of DNA are called Okazaki fragments, named after their discoverer. DNA
polymerase extends the leading strand in one continuous motion and the lagging strand in a discontinuous motion
(due to the Okazaki fragments). RNase removes the RNA fragments used to initiate replication by DNA polymerase,
and another DNA Polymerase enters to fill the gaps. When this is complete, a single nick on the leading strand and
several nicks on the lagging strand can be found. Ligase works to fill these nicks in, thus completing the newly
replicated DNA molecule.
The primase used in this process differs significantly between bacteria and archaea/eukaryotes. Bacteria use a
primase belonging to the DnaG protein superfamily which contains a catalytic domain of the TOPRIM fold type.
The TOPRIM fold contains an α/β core with four conserved strands in a Rossmann-like topology. This structure is
also found in the catalytic domains of topoisomerase Ia, topoisomerase II, the OLD-family nucleases and DNA
repair proteins related to the RecR protein.
The primase used by archaea and eukaryotes in contrast contains a highly derived version of the RNA recognition
motif (RRM). This primase is structurally similar to many viral RNA dependent RNA polymerases, reverse
transcriptases, cyclic nucleotide generating cyclases and DNA polymerases of the A/B/Y families that are involved
in DNA replication and repair. All these proteins share a catalytic mechanism of di-metal-ion-mediated nucleotide
transfer, whereby two acidic residues located at the end of the first strand and between the second and third strands
of the RRM-like unit respectively, chelate two divalent cations.
As DNA synthesis continues, the original DNA strands continue to unwind on each side of the bubble, forming a
replication fork with two prongs. In bacteria, which have a single origin of replication on their circular chromosome,
this process eventually creates a "theta structure" (resembling the Greek letter theta: θ). In contrast, eukaryotes have
longer linear chromosomes and initiate replication at multiple origins within these.
DNA replication 354

Replication fork
The replication fork is a structure that forms
within the nucleus during DNA replication.
It is created by helicases, which break the
hydrogen bonds holding the two DNA
strands together. The resulting structure has
two branching "prongs", each one made up
of a single strand of DNA. These two
strands serve as the template for the leading
and lagging strands, which will be created as
DNA polymerase matches complementary Many enzymes are involved in the DNA replication fork.
nucleotides to the templates; The templates
may be properly referred to as the leading strand template and the lagging strand template.

Leading strand
The leading strand is the template strand of the DNA double helix so that the replication fork moves along it in the 3'
to 5' direction. This allows the newly synthesized strand complementary to the original strand to be synthesized 5' to
3' in the same direction as the movement of the replication fork.
On the leading strand, a polymerase "reads" the DNA and adds nucleotides to it continuously. This polymerase is
DNA polymerase III (DNA Pol III) in prokaryotes and presumably Pol ε[11] [12] in yeasts. In human cells the leading
and lagging strands are synthesized by Pol α and Pol δ within the nucleus and Pol γ in the mitochondria. Pol ε can
substitute for Pol δ in special circumstances[13] .

Lagging strand
The lagging strand is the strand of the template DNA double helix that is oriented so that the replication fork moves
along it in a 5' to 3' manner. Because of its orientation, opposite to the working orientation of DNA polymerase III,
which moves on a template in a 3' to 5' manner, replication of the lagging strand is more complicated than that of the
leading strand.
On the lagging strand, primase "reads" the DNA and adds RNA to it in short, separated segments. In eukaryotes,
primase is intrinsic to Pol α.[14] DNA polymerase III or Pol δ lengthens the primed segments, forming Okazaki
fragments. Primer removal in eukaryotes is also performed by Pol δ.[15] In prokaryotes, DNA polymerase I "reads"
the fragments, removes the RNA using its flap endonuclease domain (RNA primers are removed by 5'-3'
exonuclease activity of polymerase I [weaver, 2005], and replaces the RNA nucleotides with DNA nucleotides (this
is necessary because RNA and DNA use slightly different kinds of nucleotides). DNA ligase joins the fragments
together.
DNA replication 355

Dynamics at the replication fork

As helicase unwinds DNA at the replication fork, the DNA ahead

is forced to rotate. This process results in a build-up of twists in
the DNA ahead.[16] This build-up would form a resistance that
would eventually halt the progress of the replication fork. DNA
Gyrase is an enzyme that temporarily breaks the strands of DNA,
relieving the tension caused by unwinding the two strands of the
DNA helix; DNA Gyrase achieves this by adding negative
supercoils to the DNA helix. [17]

Bare single-stranded DNA tends to fold back on itself and form

secondary structures; these structures can interfere with the
movement of DNA polymerase. To prevent this, single-strand
binding proteins bind to the DNA until a second strand is
synthesized, preventing secondary structure formation.[18]
The assembled human DNA clamp, a trimer of the
Clamp proteins form a sliding clamp around DNA, helping the
protein PCNA.
DNA polymerase maintain contact with its template, thereby
assisting with processivity. The inner face of the clamp enables
DNA to be threaded through it. Once the polymerase reaches the end of the template or detects double-stranded
DNA, the sliding clamp undergoes a conformational change that releases the DNA polymerase. Clamp-loading
proteins are used to initially load the clamp, recognizing the junction between template and RNA primers.

Regulation
Eukaryotes
Within eukaryotes, DNA replication is controlled within the context of the
cell cycle. As the cell grows and divides, it progresses through stages in the
cell cycle; DNA replication occurs during the S phase (synthesis phase). The
progress of the eukaryotic cell through the cycle is controlled by cell cycle
checkpoints. Progression through checkpoints is controlled through complex
interactions between various proteins, including cyclins and cyclin-dependent
kinases.[19]

The G1/S checkpoint (or restriction checkpoint) regulates whether eukaryotic

cells enter the process of DNA replication and subsequent division. Cells that The cell cycle of eukaryotic cells.
do not proceed through this checkpoint are remain in the G0 stage and do not
replicate their DNA.
Replication of chloroplast and mitochondrial genomes occurs independent of the cell cycle, through the process of
D-loop replication.
Bacteria
Most bacteria do not go through a well-defined cell cycle but instead continuously copy their DNA; during rapid
growth, this can result in the concurrent occurrences of multiple rounds of replication.[20] In E. coli, the
best-characterized bacteria, DNA replication is regulated through several mechanisms, including: the
hemimethylation and sequestering of the origin sequence, the ratio of ATP to ADP, and the levels of protein DnaA.
All these control the process of initiator proteins binding to the origin sequences.
Because E. coli methylates GATC DNA sequences, DNA synthesis results in hemimethylated sequences. This
hemimethylated DNA is recognized by the protein SeqA, which binds and sequesters the origin sequence; in
DNA replication 356

addition, dnaA (required for initiation of replication) binds less well to hemimethylated DNA. As a result, newly
replicated origins are prevented from immediately initiating another round of DNA replication.[21]
ATP builds up when the cell is in a rich medium, triggering DNA replication once the cell has reached a specific
size. ATP competes with ADP to bind to DnaA, and the DnaA-ATP complex is able to initiate replication. A certain
number of DnaA proteins are also required for DNA replication — each time the origin is copied, the number of
binding sites for DnaA doubles, requiring the synthesis of more DnaA to enable another initiation of replication.

Termination
Eukaryotes initiate DNA replication at multiple points in the chromosome, so replication forks meet and terminate at
many points in the chromosome; these are not known to be regulated in any particular way. Because eukaryotes have
linear chromosomes, DNA replication is unable to reach the very end of the chromosomes, but ends at the telomere
region of repetitive DNA close to the end. This shortens the telomere of the daughter DNA strand. This is a normal
process in somatic cells. As a result, cells can only divide a certain number of times before the DNA loss prevents
further division. (This is known as the Hayflick limit.) Within the germ cell line, which passes DNA to the next
generation, telomerase extends the repetitive sequences of the telomere region to prevent degradation. Telomerase
can become mistakenly active in somatic cells, sometimes leading to cancer formation.
Because bacteria have circular chromosomes, termination of replication occurs when the two replication forks meet
each other on the opposite end of the parental chromosome. E coli regulate this process through the use of
termination sequences that, when bound by the Tus protein, enable only one direction of replication fork to pass
through. As a result, the replication forks are constrained to always meet within the termination region of the
chromosome.[22]

Polymerase chain reaction

Researchers commonly replicate DNA in vitro using the polymerase chain reaction (PCR). PCR uses a pair of
primers to span a target region in template DNA, and then polymerizes partner strands in each direction from these
primers using a thermostable DNA polymerase. Repeating this process through multiple cycles produces
amplification of the targeted DNA region. At the start of each cycle, the mixture of template and primers is heated,
separating the newly synthesized molecule and template. Then, as the mixture cools, both of these become templates
for annealing of new primers, and the polymerase extends from these. As a result, the number of copies of the target
region doubles each round, increasing exponentially.[23]

References
[1] hczohzhohzohz Berg JM, Tymoczko JL, Stryer L, Clarke ND (2002). Biochemistry. W.H. Freeman and Company. ISBN 0-7167-3051-0.
Chapter 27: DNA Replication, Recombination, and Repair (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fc,kgi?rid=stryer. chapter. 3740)
[2] Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell. Garland Science. ISBN 0-8153-3218-1.
Chapter 5: DNA Replication, Repair, and Recombination (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mboc4. chapter. 747)
[3] Berg JM, Tymoczko JL, Stryer L, Clarke ND (2002). Biochemistry. W.H. Freeman and Company. ISBN 0-7167-3051-0. Chapter 27, Section
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[4] Alberts, B., et.al., Molecular Biology of the Cell, Garland Science, 4th ed., 2002, pp. 238-240 ISBN 0-8153-3218-1
[5] Allison, Lizabeth A. Fundamental Molecular Biology. Blackwell Publishing. 2007. p.112.
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coli replication origin, oriC". The EMBO Journal 16 (21): 6574–83. doi:10.1093/emboj/16.21.6574. PMC 1170261. PMID 9351837.
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[10] Lodish H, Berk A, Zipursky LS, Matsudaira P, Baltimore D, Darnell J (2000). Molecular Cell Biology. W. H. Freeman and Company.
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ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mcb. section. 3163#3179)
[11] Pursell, Z.F. et al. (2007). "Yeast DNA Polymerase ε Participates in Leading-Strand DNA Replication". Science 317 (5834): 127–130.
doi:10.1126/science.1144067. PMC 2233713. PMID 17615360.
[12] Scott D McCulloch; Thomas A Kunkel (01/2008). "The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis
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[13] Hansen, Barbara (2011). Biochemistry and Medical Genetics: Lecture Notes. Kaplan Medical. pp. 21.
[14] Elizabeth R. Barry; Stephen D. Bell (12/2006). "DNA Replication in the Archaea". Microbiology and Molecular Biology Reviews 70 (4):
876–887. doi:10.1128/MMBR.00029-06. PMC 1698513. PMID 17158702.
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doi:10.1371/journal.pbio.0040185. PMC 1470461. PMID 16719561.
[21] Slater S, Wold S, Lu M, Boye E, Skarstad K, Kleckner N (September 1995). "E. coli SeqA protein binds oriC in two different
methyl-modulated reactions appropriate to its roles in DNA replication initiation and origin sequestration". Cell 82 (6): 927–36.
doi:10.1016/0092-8674(95)90272-4. PMID 7553853.
[22] TA Brown (2002). Genomes. BIOS Scientific Publishers. ISBN 1-85996-228-9. 13.2.3. Termination of replication (http:/ / www. ncbi. nlm.
nih. gov/ books/ bv. fcgi?rid=genomes. section. 8121#8156)
[23] Saiki, RK; Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988). "Primer-directed enzymatic amplification
of DNA with a thermostable DNA polymerase" (http:/ / sunsite. berkeley. edu/ cgi-bin/ ebind2html/ pcr/ 009). Science 239 (4839): 487–91.
doi:10.1126/science.2448875. PMID 2448875. .
DNA repair 358

DNA repair
DNA repair refers to a collection of processes by which a cell
identifies and corrects damage to the DNA molecules that encode its
genome. In human cells, both normal metabolic activities and
environmental factors such as UV light and radiation can cause DNA
damage, resulting in as many as 1 million individual molecular lesions
per cell per day.[1] Many of these lesions cause structural damage to
the DNA molecule and can alter or eliminate the cell's ability to
transcribe the gene that the affected DNA encodes. Other lesions
induce potentially harmful mutations in the cell's genome, which affect
the survival of its daughter cells after it undergoes mitosis. As a
consequence, the DNA repair process is constantly active as it
responds to damage in the DNA structure. When normal repair
processes fail, and when cellular apoptosis does not occur, irreparable
DNA damage may occur, including double-strand breaks and DNA
crosslinkages.[2] [3]

The rate of DNA repair is dependent on many factors, including the DNA damage resulting in multiple broken
cell type, the age of the cell, and the extracellular environment. A cell chromosomes

that has accumulated a large amount of DNA damage, or one that no

longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
1. an irreversible state of dormancy, known as senescence
2. cell suicide, also known as apoptosis or programmed cell death
3. unregulated cell division, which can lead to the formation of a tumor that is cancerous
The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of
the organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA
damage repair and protection.[4] Failure to correct molecular lesions in cells that form gametes can introduce
mutations into the genomes of the offspring and thus influence the rate of evolution.

DNA damage
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000
to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genome's
approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor
genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation.
The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are
chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing
non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA,
DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is,
however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both
superstructures are vulnerable to the effects of DNA damage.
DNA repair 359

Sources of damage
DNA damage can be subdivided into two main types:
1. endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts
(spontaneous mutation), especially the process of oxidative deamination
1. also includes replication errors
2. exogenous damage caused by external agents such as
1. ultraviolet [UV 200-300 nm] radiation from the sun
2. other radiation frequencies, including x-rays and gamma rays
3. hydrolysis or thermal disruption
4. certain plant toxins
5. human-made mutagenic chemicals, especially aromatic compounds that act as DNA intercalating agents
6. cancer chemotherapy and radiotherapy
7. viruses [5]
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged
ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is
unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).

Types of damage
There are five main types of damage to DNA due to endogenous cellular processes:
1. oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from
reactive oxygen species,
2. alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine,
6-O-Methylguanine
3. hydrolysis of bases, such as deamination, depurination, and depyrimidination.
4. "bulky adduct formation" (i.e., benzo[a]pyrene diol epoxide-dG adduct)
5. mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a
newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Damage caused by exogenous agents comes in many forms. Some examples are:
1. UV-B light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers. This is
called direct DNA damage.
2. UV-A light creates mostly free radicals. The damage caused by free radicals is called indirect DNA damage.
3. Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.
Low-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional
errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.[6] [7] [8]
4. Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA
backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria,
which grow in hot springs at 40-80 °C.[9] [10] The rate of depurination (300 purine residues per genome per
generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an
adaptive response cannot be ruled out.
5. Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as
polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases,
oxidized bases, alkylated phosphotriesters and Crosslinking of DNA just to name a few.
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage.
Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.[11]
DNA repair 360

Nuclear versus mitochondrial DNA damage

In human cells, and eukaryotic cells in general, DNA is found in two cellular locations - inside the nucleus and
inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle
and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is
highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the
genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are
expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is
located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of
proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free
radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation,
create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the
toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of
eukaryotic cells.

Senescence and apoptosis

Senescence, an irreversible state in which the cell no longer divides, is a protective response to the shortening of the
chromosome ends. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo
partial degradation each time a cell undergoes division (see Hayflick limit).[12] In contrast, quiescence is a reversible
state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a
functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the
organism,[13] which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating
inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of
a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis
is considered to be part of a strategy of protection against cancer.[14]

DNA damage and mutation

It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA
damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single-
and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA
damages can be recognized by enzymes, and, thus, they can be correctly repaired if redundant information, such as
the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for
copying. If a cell retains DNA damage, transcription of a gene can be prevented, and, thus, translation into a protein
will also be blocked. Replication may also be blocked and/or the cell may die.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be
recognized by enzymes once the base change is present in both DNA strands, and, thus, a mutation cannot be
repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are
replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency
according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly
different from each other, DNA damages and mutations are related because DNA damages often cause errors of
DNA synthesis during replication or repair; these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in
non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other
hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to
cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are
deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells
will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at
DNA repair 361

the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism,
because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they
give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are
likely a prominent cause of aging.[15]

DNA repair mechanisms

Cells cannot function if DNA damage corrupts the integrity and accessibility of
essential information in the genome (but cells remain superficially functional when
so-called "non-essential" genes are missing or damaged). Depending on the type of
damage inflicted on the DNA's double helical structure, a variety of repair
strategies have evolved to restore lost information. If possible, cells use the
unmodified complementary strand of the DNA or the sister chromatid as a template
to recover the original information. Without access to a template, cells use an
error-prone recovery mechanism known as translesion synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix, and such alterations
can be detected by the cell. Once damage is localized, specific DNA repair
molecules bind at or near the site of damage, inducing other molecules to bind and
form a complex that enables the actual repair to take place.

Direct reversal
Cells are known to eliminate three types of damage to their DNA by chemically
reversing it. These mechanisms do not require a template, since the types of
damage they counteract can occur in only one of the four bases. Such direct
reversal mechanisms are specific to the type of damage incurred and do not involve
breakage of the phosphodiester backbone. The formation of pyrimidine dimers
upon irradiation with UV light results in an abnormal covalent bond between
adjacent pyrimidine bases. The photoreactivation process directly reverses this
damage by the action of the enzyme photolyase, whose activation is obligately
Single-strand and double-strand
dependent on energy absorbed from blue/UV light (300–500 nm wavelength) to
DNA damage
promote catalysis.[16] Another type of damage, methylation of guanine bases, is
directly reversed by the protein methyl guanine methyl transferase (MGMT), the
bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used
only once; that is, the reaction is stoichiometric rather than catalytic.[17] A generalized response to methylating
agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon
sustained exposure by upregulation of alkylation repair enzymes.[18] The third type of DNA damage reversed by
cells is certain methylation of the bases cytosine and adenine.
DNA repair 362

Single-strand damage
When only one of the two strands of a double helix has
a defect, the other strand can be used as a template to
guide the correction of the damaged strand. In order to
repair damage to one of the two paired molecules of
DNA, there exist a number of excision repair
mechanisms that remove the damaged nucleotide and
replace it with an undamaged nucleotide
complementary to that found in the undamaged DNA
strand.[17]

1. Base excision repair (BER), which repairs damage

to a single base caused by oxidation, alkylation,
hydrolysis, or deamination. The damaged base is
Structure of the base-excision repair enzyme uracil-DNA
glycosylase. The uracil residue is shown in yellow. removed by a DNA glycosylase. The "missing
tooth" is then recognized by an enzyme called AP
endonuclease, which cuts the Phosphodiester bond. The missing part is then resynthesized by a DNA polymerase,
and a DNA ligase performs the final nick-sealing step.
2. Nucleotide excision repair (NER), which recognizes bulky, helix-distorting lesions such as pyrimidine dimers and
6,4 photoproducts. A specialized form of NER known as transcription-coupled repair deploys NER enzymes to
genes that are being actively transcribed.
3. Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired
(but undamaged) nucleotides.

Double-strand breaks
Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell
because they can lead to genome rearrangements. Three mechanisms exist to repair double-strand breaks (DSBs):
non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous
recombination.[17] PVN Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the
same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next
mitosis or in some rare instances, mutate."[2] [3]
DNA repair 363

In NHEJ, DNA Ligase IV, a specialized DNA ligase that

forms a complex with the cofactor XRCC4, directly joins
the two ends.[19] To guide accurate repair, NHEJ relies on
short homologous sequences called microhomologies
present on the single-stranded tails of the DNA ends to be
joined. If these overhangs are compatible, repair is usually
accurate.[20] [21] [22] [23] NHEJ can also introduce mutations
during repair. Loss of damaged nucleotides at the break site
can lead to deletions, and joining of nonmatching termini
forms translocations. NHEJ is especially important before
the cell has replicated its DNA, since there is no template
available for repair by homologous recombination. There
are "backup" NHEJ pathways in higher eukaryotes.[24]
Besides its role as a genome caretaker, NHEJ is required for
joining hairpin-capped double-strand breaks induced during
V(D)J recombination, the process that generates diversity in
B-cell and T-cell receptors in the vertebrate immune
system.[25]
DNA ligase, shown above repairing chromosomal damage, is
Homologous recombination requires the presence of an an enzyme that joins broken nucleotides together by catalyzing
identical or nearly identical sequence to be used as a the formation of an internucleotide ester bond between the
template for repair of the break. The enzymatic machinery phosphate backbone and the deoxyribose nucleotides.

responsible for this repair process is nearly identical to the

machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to
be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a
template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or
unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.

Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of
supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered
DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are
immediately repaired by the enzymes that created them.
A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break
DNA repair in that organism. At least two copies of the genome, with random DNA breaks, can form DNA
fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions
through a moving D-loop that can continue extension until they find complementary partner strands. In the final step
there is crossover by means of RecA-dependent homologous recombination.[26]

Translesion synthesis
Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to
replicate past DNA lesions such as thymine dimers or AP sites.[27] It involves switching out regular DNA
polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family),
often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase
switching is thought to be mediated by, among other factors, the post-translational modification of the replication
processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert
wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at
inserting correct bases opposite specific types of damage. For example, Pol η mediates error-free bypass of lesions
induced by UV irradiation, whereas Pol ι introduces mutations at these sites. Pol η is known to add the first adenine
DNA repair 364

across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn
conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations
during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may
cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either
bypassing or repairing lesions at locations of stalled DNA replication. A bypass platform is provided to these
polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to
polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18
proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication.[28]
[29]
After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if
the TLS is error-free, as in the case of Pol η, yet if TLS results in a mismatch, a specialized polymerase is needed to
extend it; Pol ζ. Pol ζ is unique in that it can extend terminal mismatches, whereas more processive polymerases
cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive
polymerase to a TLS polymerase such as Pol ι to fix the lesion, then PCNA may switch to Pol ζ to extend the
mismatch, and last PCNA will switch to the processive polymerase to continue replication.

Global response to DNA damage

Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA
lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins,
carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts
stalling the replication forks, are among known stimulation signals for a global response to DNA damage.[30] The
global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of
macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction
of multiple genes, cell cycle arrest, and inhibition of cell division.

DNA damage checkpoints

After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the
cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M
boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and
ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,[31] whereas ATR
primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal
transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including
BRCA1, MDC1, and 53BP1 has also been identified.[32] These proteins seem to be required for transmitting the
checkpoint activation signal to downstream proteins.
P53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA
damage.[33] At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21
mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.

The prokaryotic SOS response

The SOS response is the term used to describe changes in gene expression in Escherichia coli and other bacteria in
response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA.
The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS
boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the
lexA and recA genes.[34] The SOS response is known to be widespread in the Bacteria domain, but it is mostly
absent in some bacterial phyla, like the Spirochetes.[35] The most common cellular signals activating the SOS
response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks,
which are processed by DNA helicase to separate the two DNA strands.[30] In the initiation step, RecA protein binds
DNA repair 365

to ssDNA in an ATP hydrolysis driven reaction creating RecA–ssDNA filaments. RecA–ssDNA filaments activate
LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation.
The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition
of cell division and an increase in levels of proteins responsible for damage processing.
In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a
high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably,
with different length and composition, but it is always highly conserved and one of the strongest short signals in the
genome.[35] The high information content of SOS boxes permits differential binding of LexA to different promoters
and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response.
The error-prone translesion polymerases, for example, UmuCD’2 (also called DNA polymerase V), are induced later
on as a last resort.[36] Once the DNA damage is repaired or bypassed using polymerases or through recombination,
the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases
cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene
expression.

Eukaryotic transcriptional responses to DNA damage

Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple
proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome
wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to
damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct
transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response
pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage
differently indicating an absence of a common global response. The probable explanation for this difference between
yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are
distributed among different organs that have evolved different sensitivities to DNA damage.[36]
In general global response to DNA damage involves expression of multiple genes responsible for postreplication
repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional
activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an
important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase
in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations.
Yeast Rev1 and human polymerase η are members of [Y family translesion DNA polymerases present during global
response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in
eukaryotes.[30]
DNA repair 366

DNA repair and aging

Pathological effects of poor DNA repair

Experimental animals with genetic deficiencies in DNA repair often
show decreased life span and increased cancer incidence.[15] For
example, mice deficient in the dominant NHEJ pathway and in
telomere maintenance mechanisms get lymphoma and infections more
often, and, as a consequence, have shorter lifespans than wild-type
mice.[37] In similar manner, mice deficient in a key repair and
transcription protein that unwinds DNA helices have premature onset
of aging-related diseases and consequent shortening of lifespan.[38]
However, not every DNA repair deficiency creates exactly the DNA repair rate is an important determinant of
predicted effects; mice deficient in the NER pathway exhibited cell pathology

shortened life span without correspondingly higher rates of

mutation.[39]

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the
cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair
functioning result in premature aging,[15] increased sensitivity to carcinogens, and correspondingly increased cancer
risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus
radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand
break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.[40]

Longevity and caloric restriction

A number of individual genes have been identified as influencing
variations in life span within a population of organisms. The effects of
these genes is strongly dependent on the environment, in particular, on
the organism's diet. Caloric restriction reproducibly results in extended
lifespan in a variety of organisms, likely via nutrient sensing pathways
and decreased metabolic rate. The molecular mechanisms by which
such restriction results in lengthened lifespan are as yet unclear (see[41]
for some discussion); however, the behavior of many genes known to
be involved in DNA repair is altered under conditions of caloric
restriction.

For example, increasing the gene dosage of the gene SIR-2, which
regulates DNA packaging in the nematode worm Caenorhabditis
elegans, can significantly extend lifespan.[42] The mammalian homolog
of SIR-2 is known to induce downstream DNA repair factors involved
Most life span influencing genes affect the rate of
in NHEJ, an activity that is especially promoted under conditions of
DNA damage
caloric restriction.[43] Caloric restriction has been closely linked to the
rate of base excision repair in the nuclear DNA of rodents,[44] although
similar effects have not been observed in mitochondrial DNA.[45]

It is interesting to note that the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers
dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under
conditions of caloric restriction.[46] This observation supports the pleiotropy theory of the biological origins of aging,
which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a
DNA repair 367

corresponding disadvantage late in life.

Medicine and DNA repair modulation

Hereditary DNA repair disorders

Defects in the NER mechanism are responsible for several genetic disorders, including:
• Xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and
premature aging
• Cockayne syndrome: hypersensitivity to UV and chemical agents
• Trichothiodystrophy: sensitive skin, brittle hair and nails
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental
neurons.
Other DNA repair disorders include:
• Werner's syndrome: premature aging and retarded growth
• Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
• Ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents
All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because their victims
appear elderly and suffer from aging-related diseases at an abnormally young age, while not manifesting all the
symptoms of old age.
Other diseases associated with reduced DNA repair function include Fanconi's anemia, hereditary breast cancer and
hereditary colon cancer.

DNA repair and cancer

Inherited mutations that affect DNA repair genes are strongly associated with high cancer risks in humans.
Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA
mismatch repair pathway. BRCA1 and BRCA2, two famous mutations conferring a hugely increased risk of breast
cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and
homologous recombination.
Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to
repair DNA damage, resulting in cell death. Cells that are most rapidly dividing - most typically cancer cells - are
preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as stem cells in the
bone marrow are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues
only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor)
or by biochemical means (exploiting a feature unique to cancer cells in the body).

DNA repair and evolution

The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among
bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have
correspondingly more complex repair mechanisms.[47] The ability of a large number of protein structural motifs to
catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during
evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[48]
The fossil record indicates that single-cell life began to proliferate on the planet at some point during the
Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became
the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic
DNA repair 368

form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich
atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of
potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA
repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.

Rate of evolutionary change

On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that results in a change
from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny.
Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential
to be passed on to the organism's offspring. The rate of evolution in a particular species (or, in a particular gene) is a
function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an
influence over the process of evolutionary change.[49]

References
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31 (6): 637–656. doi:10.1111/j.1574-6976.2007.00082.x. PMID 17883408.
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Mutation". Chem. Rev 106 (2): 406–419. doi:10.1021/cr0404951. PMID 16464012.
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DNA repair 370

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External links
• Roswell Park Cancer Institute DNA Repair Lectures (http://asajj.roswellpark.org/huberman/DNA_Repair/
DNA_Repair.htm)
• A comprehensive list of Human DNA Repair Genes (http://www.cgal.icnet.uk/DNA_Repair_Genes.html)
• 3D structures of some DNA repair enzymes (http://www.biochem.ucl.ac.uk/bsm/xtal/teach/repair/tibs3.
html)
• Human DNA repair diseases (http://www.scielo.br/scielo.php?pid=S0100-84551997000400032&
script=sci_arttext&tlng=en)
• DNA repair special interest group (http://tango01.cit.nih.gov/sig/home.taf?_function=main&
SIGInfo_SIGID=32)
• DNA Repair (http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/D/DNArepair.html)
• DNA Damage and DNA Repair (http://www.benbest.com/lifeext/aging.html#dna)
• Segmental Progeria (http://www.benbest.com/lifeext/aging.html#progeria)
• DNA-damage repair; the good, the bad, and the ugly (https://www.researchgate.net/publication/
5565866_DNA-damage_repair_the_good_the_bad_and_the_ugly)

Oncogenes
An oncogene is a gene that has the potential to cause cancer.[1] In tumor cells, they are often mutated or expressed at
high levels.[2] An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with
the initial and continuing conversion of normal cells into cancer cells.
Most normal cells undergo a programmed form of death (apoptosis). Activated oncogenes can cause those cells that
ought to die to survive and proliferate instead.[3] Most oncogenes require an additional step, such as mutations in
another gene, or environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of
oncogenes have been identified in human cancer. Many cancer drugs target the proteins encoded by oncogenes.[2] [4]
[5] [6]

Proto-oncogene
A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The
resultant protein may be termed an oncoprotein.[7] Proto-oncogenes code for proteins that help to regulate cell
growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic
signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a
tumor-inducing agent, an oncogene.[8] Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK.
The MYC gene is implicated in Burkitt's Lymphoma, which starts when a chromosomal translocation moves an
enhancer sequence within the vicinity of the myc gene. The myc gene codes for widely used transcription factors.
When the enhancer sequence is wrongly placed, these transcription factors are produced at much higher rates.
Another example of an oncogene is the Bcr-Abl gene found on the Philadelphia Chromosome, a piece of genetic
material seen in Chronic Myelogenous Leukemia caused by the translocation of pieces from chromosomes 9 and 22.
Bcr-Abl codes for a receptor tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.
Oncogenes 371

Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are
three basic activation types:
• A mutation within a proto-oncogene can cause a change in the protein structure, causing
• an increase in protein (enzyme) activity
• a loss of regulation
• An increase in protein concentration, caused by
• an increase of protein expression (through misregulation)
• an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell
• a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the
cell
• A chromosomal translocation (another type of chromosome abnormality), causing
• an increased gene expression in the wrong cell type or at wrong times
• the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the
bone marrow leads to adult leukemia
The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25 nucleotides in length
that control gene expression by downregulating them.[9] Mutations in such microRNAs (known as oncomirs) can
lead to activation of oncogenes.[10] Antisense messenger RNAs could theoretically be used to block the effects of
oncogenes.

Classification
There are several systems for classifying oncogenes,[11] [12] but there is not yet a widely accepted standard. They are
sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the
"normal" process of signal transduction). There are several categories that are commonly used:

Category Examples Description

Growth factors, or c-Sis Usually secreted by specialized cells to induce cell proliferation in themselves,
mitogens nearby cells, or distant cells. An oncogene may cause a cell to secrete growth
factors even though it does not normally do so. It will thereby induce its own
uncontrolled proliferation (autocrine loop), and proliferation of neighboring cells.
It may also cause production of growth hormones in other parts of the body.

Receptor tyrosine epidermal growth factor receptor
kinases (EGFR), platelet-derived growth
factor receptor (PDGFR), and vascular
endothelial growth factor receptor
(VEGFR), HER2/neu
Kinases add phosphate groups to other proteins to turn them on or off. Receptor
kinases add phosphate groups to receptor proteins at the surface of the cell (which
receive protein signals from outside the cell and transmit them to the inside of the
cell). Tyrosine kinases add phosphate groups to the amino acid tyrosine in the
target protein. They can cause cancer by turning the receptor permanently on
(constitutively), even without signals from outside the cell.

Cytoplasmic tyrosine Src-family, Syk-ZAP-70 family, and -

kinases BTK family of tyrosine kinases, the
Abl gene in CML - Philadelphia
chromosome

Cytoplasmic Raf kinase, and cyclin-dependent -

Serine/threonine kinases (through overexpression).
kinases and their
regulatory subunits
Oncogenes 372

Regulatory GTPases Ras protein Ras is a small GTPase that hydrolyses GTP into GDP and phosphate. Ras is
activated by growth factor signaling (i.e., EGF, TGFalpha) and acting like a
binary switch (on/off) in growth signaling pathways. Downstream effectors of
Ras include Raf, MEK, MEKK, MAPK, ERK, most of which in turn regulate
genes that mediate cell proliferation.

Transcription factors myc gene -They regulate transcription of genes that induce cell proliferation.

Conversion of proto-oncogenes
There are two mechanisms by which proto-oncogenes can be converted to cellular oncogenes:
Quantitative: Tumor formation is induced by an increase in the absolute number of proto-oncogene products or by
its production in inappropriate cell types.
Qualitative: Conversion from proto-oncogene to transforming gene (c-onc) with changes in the nucleotide sequence
that are responsible for the acquisition of the new properties.[13]

History
The first oncogene was discovered in 1970 and was termed src (pronounced sarc as in sarcoma). Src was in fact first
discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr G. Steve Martin of the University
of California, Berkeley demonstrated that the SRC was indeed the oncogene of the virus. The first nucleotide
sequence of v-src was sequenced 1980 by A.P. Czernilofsky et al. (Nature Vol 287, pp 198-203).
In 1976 Drs. Dominique Stehelin, J. Michael Bishop and Harold E. Varmus of the University of California, San
Francisco demonstrated that oncogenes were activated proto-oncogenes, found in many organisms including
humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in Physiology or Medicine in
1989.[14]

References
[1] Wilbur, Beth, editor. The World of the Cell, Becker, W.M., et al., 7th ed. San Francisco, CA; 2009.
[2] Kimball's Biology Pages. (http:/ / users. rcn. com/ jkimball. ma. ultranet/ BiologyPages/ O/ Oncogenes. html) "Oncogenes" Free full text
[3] The Nobel Prize in Physiology or Medicine 2002. (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 2002/ illpres/ implications.
html) Illustrated presentation.
[4] Croce CM (Jan 2008). "Oncogenes and cancer" (http:/ / content. nejm. org/ cgi/ content/ full/ 358/ 5/ 502). N Engl J Med. 358 (5): 502–11.
doi:10.1056/NEJMra072367. PMID 18234754. .
[5] Yokota J (Mar 2000). "Tumor progression and metastasis" (http:/ / carcin. oxfordjournals. org/ cgi/ content/ full/ 21/ 3/ 497). Carcinogenesis.
21 (3): 497–503. doi:10.1093/carcin/21.3.497. PMID 10688870. .
[6] The Nobel Prize in Physiology or Medicine 1989 (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1989/ press. html) to J. Michael
Bishop and Harold E. Varmus for their discovery of "the cellular origin of retroviral oncogenes".
[7] Chapter 20 - NEOPLASMS OF THE THYROID - in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins
Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
[8] Todd R, Wong DT (1999). "Oncogenes". Anticancer Res. 19 (6A): 4729–46. PMID 10697588.
[9] Negrini M, Ferracin M, Sabbioni S, Croce CM (Jun 2007). "MicroRNAs in human cancer: from research to therapy". J Cell Sci. 120 (Pt 11):
1833–40. doi:10.1242/jcs.03450. PMID 17515481.
[10] Esquela-Kerscher A, Slack FJ (Apr 2006). "Oncomirs - microRNAs with a role in cancer". Nat Rev Cancer 6 (4): 259–69.
doi:10.1038/nrc1840. PMID 16557279.
[11] THE Medical Biochemistry Page (http:/ / web. indstate. edu/ thcme/ mwking/ oncogene. html#classes)
[12] Classification of Oncogene Function (http:/ / www. qub. ac. uk/ cm/ pat/ education/ Carcinogenesis/ tsld014. htm)
[13] Emery, Alan E. H.; Mueller, Robert Francis; Young, Ian T.; Ian D., MD Young (2001). "Oncogene". Emery's elements of medical genetics.
Edinburgh: Churchill Livingstone. ISBN 0-443-07125-X.
[14] Nobel Prize in Physiology or Medicine for 1989 jointly to J. Michael Bishop and Harold E. Varmus for their discovery of "the cellular origin
of retroviral oncogenes". (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1989/ press. html) Press Release.
Oncogenes 373

External links
• Drosophila Oncogenes and Tumor Suppressors - The Interactive Fly (http://www.sdbonline.org/fly/aignfam/
tumorsup.htm)
• List of web sites - oncogenes tables (http://microb230.med.upenn.edu/protocols/cancergenes.html)
 374

RNA synthesis and processing

Transcription
Transcription is the process of creating a complementary RNA copy of a sequence of DNA.[1] Both RNA and DNA
are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and
forth from DNA to RNA by the action of the correct enzymes. During transcription, a DNA sequence is read by
RNA polymerase, which produces a complementary, antiparallel RNA strand. As opposed to DNA replication,
transcription results in an RNA complement that includes uracil (U) in all instances where thymine (T) would have
occurred in a DNA complement.
Transcription can be explained easily in 4 or 5 steps, each moving like a wave along the DNA.
1. RNA Polymerase unwinds/"unzips" the DNA by breaking the hydrogen bonds between complementary
nucleotides.
2. RNA Polymerase adds matching RNA nucleotides that are paired with complementary DNA bases.
3. RNA sugar-phosphate backbone forms with assistance from RNA polymerase.
4. Hydrogen bonds of the untwisted RNA+DNA helix break, freeing the newly synthesized RNA strand.
5. If the cell has a nucleus, the RNA is further processed (addition of a 3' poly-A tail and a 5' cap) and exits through
to the cytoplasm through the nuclear pore complex.
Transcription is the first step leading to gene expression. The stretch of DNA transcribed into an RNA molecule is
called a transcription unit and encodes at least one gene. If the gene transcribed encodes a protein, the result of
transcription is messenger RNA (mRNA), which will then be used to create that protein via the process of
translation. Alternatively, the transcribed gene may encode for either ribosomal RNA (rRNA) or transfer RNA
(tRNA), other components of the protein-assembly process, or other ribozymes.
A DNA transcription unit encoding for a protein contains not only the sequence that will eventually be directly
translated into the protein (the coding sequence) but also regulatory sequences that direct and regulate the synthesis
of that protein. The regulatory sequence before (upstream from) the coding sequence is called the five prime
untranslated region (5'UTR), and the sequence following (downstream from) the coding sequence is called the three
prime untranslated region (3'UTR).
Transcription has some proofreading mechanisms, but they are fewer and less effective than the controls for copying
DNA; therefore, transcription has a lower copying fidelity than DNA replication.[2]
As in DNA replication, DNA is read from 3' → 5' during transcription. Meanwhile, the complementary RNA is
created from the 5' → 3' direction. This means its 5' end is created first in base pairing. Although DNA is arranged as
two antiparallel strands in a double helix, only one of the two DNA strands, called the template strand, is used for
transcription. This is because RNA is only single-stranded, as opposed to double-stranded DNA. The other DNA
strand is called the coding (lagging) strand, because its sequence is the same as the newly created RNA transcript
(except for the substitution of uracil for thymine). The use of only the 3' → 5' strand eliminates the need for the
Okazaki fragments seen in DNA replication.
Transcription is divided into 5 stages: pre-initiation, initiation, promoter clearance, elongation and termination.
Transcription 375

Major steps

Pre-initiation
In eukaryotes, RNA polymerase, and therefore the initiation of transcription, requires the presence of a core
promoter sequence in the DNA. Promoters are regions of DNA that promote transcription and, in eukaryotes, are
found at -30, -75, and -90 base pairs upstream from the transcription start site (abbreviated to TSS). Core promoters
are sequences within the promoter that are essential for transcription initiation. RNA polymerase is able to bind to
core promoters in the presence of various specific transcription factors.
The most characterized type of core promoter in eukaryotes is a short DNA sequence known as a TATA box, found
25-30 base pairs upstream from the TSS. The TATA box, as a core promoter, is the binding site for a transcription
factor known as TATA-binding protein (TBP), which is itself a subunit of another transcription factor, called
Transcription Factor II D (TFIID). After TFIID binds to the TATA box via the TBP, five more transcription factors
and RNA polymerase combine around the TATA box in a series of stages to form a preinitiation complex. One
transcription factor, DNA helicase, has helicase activity and so is involved in the separating of opposing strands of
double-stranded DNA to provide access to a single-stranded DNA template. However, only a low, or basal, rate of
transcription is driven by the preinitiation complex alone. Other proteins known as activators and repressors, along
with any associated coactivators or corepressors, are responsible for modulating transcription rate.
Thus, preinitiation complex contains: 1. Core Promoter Sequence 2. Transcription Factors 3. DNA Helicase 4. RNA
Polymerase 5. Activators and Repressors The transcription preinitiation in archaea is, in essence, homologous to that
of eukaryotes, but is much less complex.[3] The archaeal preinitiation complex assembles at a TATA-box binding
site; however, in archaea, this complex is composed of only RNA polymerase II, TBP, and TFB (the archaeal
homologue of eukaryotic transcription factor II B (TFIIB)).[4] [5]

Initiation
In bacteria, transcription begins with
the binding of RNA polymerase to the
promoter in DNA. RNA polymerase is
a core enzyme consisting of five
subunits: 2 α subunits, 1 β subunit, 1 β'
subunit, and 1 ω subunit. At the start of
initiation, the core enzyme is
Simple diagram of transcription initiation. RNAP = RNA polymerase
associated with a sigma factor that aids
in finding the appropriate -35 and -10
base pairs downstream of promoter sequences.[6] When the sigma factor and RNA polymerase combine, they form a
holoenzyme.

Transcription initiation is more complex in eukaryotes. Eukaryotic RNA polymerase does not directly recognize the
core promoter sequences. Instead, a collection of proteins called transcription factors mediate the binding of RNA
polymerase and the initiation of transcription. Only after certain transcription factors are attached to the promoter
does the RNA polymerase bind to it. The completed assembly of transcription factors and RNA polymerase bind to
the promoter, forming a transcription initiation complex. Transcription in the archaea domain is similar to
transcription in eukaryotes.[7]
Transcription 376

Promoter clearance
After the first bond is synthesized, the RNA polymerase must clear the promoter. During this time there is a
tendency to release the RNA transcript and produce truncated transcripts. This is called abortive initiation and is
common for both eukaryotes and prokaryotes.[8] Abortive initiation continues to occur until the σ factor rearranges,
resulting in the transcription elongation complex (which gives a 35 bp moving footprint). The σ factor is released
before 80 nucleotides of mRNA are synthesized.[9] Once the transcript reaches approximately 23 nucleotides, it no
longer slips and elongation can occur. This, like most of the remainder of transcription, is an energy-dependent
process, consuming adenosine triphosphate (ATP).
Promoter clearance coincides with phosphorylation of serine 5 on the carboxy terminal domain of RNA Pol in
eukaryotes, which is phosphorylated by TFIIH.

Elongation
One strand of the DNA, the template
strand (or noncoding strand), is used as
a template for RNA synthesis. As
transcription proceeds, RNA
polymerase traverses the template Simple diagram of transcription elongation
strand and uses base pairing
complementarity with the DNA template to create an RNA copy. Although RNA polymerase traverses the template
strand from 3' → 5', the coding (non-template) strand and newly-formed RNA can also be used as reference points,
so transcription can be described as occurring 5' → 3'. This produces an RNA molecule from 5' → 3', an exact copy
of the coding strand (except that thymines are replaced with uracils, and the nucleotides are composed of a ribose
(5-carbon) sugar where DNA has deoxyribose (one less oxygen atom) in its sugar-phosphate backbone).

Unlike DNA replication, mRNA transcription can involve multiple RNA polymerases on a single DNA template and
multiple rounds of transcription (amplification of particular mRNA), so many mRNA molecules can be rapidly
produced from a single copy of a gene.
Elongation also involves a proofreading mechanism that can replace incorrectly incorporated bases. In eukaryotes,
this may correspond with short pauses during transcription that allow appropriate RNA editing factors to bind. These
pauses may be intrinsic to the RNA polymerase or due to chromatin structure.

Termination
Bacteria use two different strategies for
transcription termination. In
Rho-independent transcription
termination, RNA transcription stops
when the newly synthesized RNA
molecule forms a G-C-rich hairpin
loop followed by a run of Us. When Simple diagram of transcription termination
the hairpin forms, the mechanical
stress breaks the weak rU-dA bonds, now filling the DNA-RNA hybrid. This pulls the poly-U transcript out of the
active site of the RNA polymerase, in effect, terminating transcription. In the "Rho-dependent" type of termination, a
protein factor called "Rho" destabilizes the interaction between the template and the mRNA, thus releasing the newly
synthesized mRNA from the elongation complex.[10]

Transcription termination in eukaryotes is less understood but involves cleavage of the new transcript followed by
template-independent addition of As at its new 3' end, in a process called polyadenylation.[11]
Transcription 377

Measuring and detecting transcription

Transcription can be measured and detected in a variety of ways:
• Nuclear Run-on assay: measures the relative abundance of newly
formed transcripts
• RNase protection assay and ChIP-Chip of RNAP: detect active
transcription sites
• RT-PCR: measures the absolute abundance of total or nuclear RNA
levels, which may however differ from transcription rates
• DNA microarrays: measures the relative abundance of the global
total or nuclear RNA levels; however, these may differ from
transcription rates
• In situ hybridization: detects the presence of a transcript
• MS2 tagging: by incorporating RNA stem loops, such as MS2, into
a gene, these become incorporated into newly synthesized RNA.
The stem loops can then be detected using a fusion of GFP and the Electron micrograph of the ribosomal
MS2 coat protein, which has a high affinity, sequence-specific transcription process. The forming mRNA strands
are visible as branches from the main DNA
interaction with the MS2 stem loops. The recruitment of GFP to the
strand.
site of transcription is visualised as a single fluorescent spot. This
remarkable new approach has revealed that transcription occurs in discontinuous bursts, or pulses (see
Transcriptional bursting). With the notable exception of in situ techniques, most other methods provide cell
population averages, and are not capable of detecting this fundamental property of genes.[12]
• Northern blot: the traditional method, and until the advent of RNA-Seq, the most quantitative
• RNA-Seq: applies next-generation sequencing techniques to sequence whole transcriptomes, which allows the
measurement of relative abundance of RNA, as well as the detection of additional variations such as fusion genes,
post-translational edits and novel splice sites

Transcription factories
Active transcription units are clustered in the nucleus, in discrete sites called transcription factories or euchromatin.
Such sites can be visualized by allowing engaged polymerases to extend their transcripts in tagged precursors
(Br-UTP or Br-U) and immuno-labeling the tagged nascent RNA. Transcription factories can also be localized using
fluorescence in situ hybridization or marked by antibodies directed against polymerases. There are ~10,000 factories
in the nucleoplasm of a HeLa cell, among which are ~8,000 polymerase II factories and ~2,000 polymerase III
factories. Each polymerase II factory contains ~8 polymerases. As most active transcription units are associated with
only one polymerase, each factory usually contains ~8 different transcription units. These units might be associated
through promoters and/or enhancers, with loops forming a ‘cloud’ around the factor.
Transcription 378

History
A molecule that allows the genetic material to be realized as a protein was first hypothesized by François Jacob and
Jacques Monod. RNA synthesis by RNA polymerase was established in vitro by several laboratories by 1965;
however, the RNA synthesized by these enzymes had properties that suggested the existence of an additional factor
needed to terminate transcription correctly.
In 1972, Walter Fiers became the first person to actually prove the existence of the terminating enzyme.
Roger D. Kornberg won the 2006 Nobel Prize in Chemistry "for his studies of the molecular basis of eukaryotic
transcription".[13]

Reverse transcription
Some viruses (such as HIV, the cause of
AIDS), have the ability to transcribe RNA
into DNA. HIV has an RNA genome that is
duplicated into DNA. The resulting DNA
can be merged with the DNA genome of the
host cell. The main enzyme responsible for
synthesis of DNA from an RNA template is
called reverse transcriptase. In the case of
HIV, reverse transcriptase is responsible for
synthesizing a complementary DNA strand
(cDNA) to the viral RNA genome. An
associated enzyme, ribonuclease H, digests
the RNA strand, and reverse transcriptase
synthesises a complementary strand of DNA
to form a double helix DNA structure. This Scheme of reverse transcription
cDNA is integrated into the host cell's
genome via another enzyme (integrase) causing the host cell to generate viral proteins that reassemble into new viral
particles. In HIV, subsequent to this, the host cell undergoes programmed cell death, apoptosis of T cells.[14]
However, in other retroviruses, the host cell remains intact as the virus buds out of the cell.

Some eukaryotic cells contain an enzyme with reverse transcription activity called telomerase. Telomerase is a
reverse transcriptase that lengthens the ends of linear chromosomes. Telomerase carries an RNA template from
which it synthesizes DNA repeating sequence, or "junk" DNA. This repeated sequence of DNA is important
because, every time a linear chromosome is duplicated, it is shortened in length. With "junk" DNA at the ends of
chromosomes, the shortening eliminates some of the non-essential, repeated sequence rather than the
protein-encoding DNA sequence farther away from the chromosome end. Telomerase is often activated in cancer
cells to enable cancer cells to duplicate their genomes indefinitely without losing important protein-coding DNA
sequence. Activation of telomerase could be part of the process that allows cancer cells to become immortal.
However, the true in vivo significance of telomerase has still not been empirically proven.
Transcription 379

References
[1] MedicineNet.com. "Transcription definition" (http:/ / www. medterms. com/ script/ main/ art. asp?articlekey=5835). . Retrieved 11 October
2009.
[2] Berg J, Tymoczko JL, Stryer L (2006). Biochemistry (6th ed.). San Francisco: W. H. Freeman. ISBN 0716787245.
[3] Littlefield, O., Korkhin, Y., and Sigler, P.B. (1999). "The structural basis for the oriented assembly of a TBP/TFB/promoter complex". PNAS
96 (24): 13668–13673. doi:10.1073/pnas.96.24.13668. PMC 24122. PMID 10570130.
[4] Hausner, W; Thomm, M (2001). "Events during Initiation of Archaeal Transcription: Open Complex Formation and DNA-Protein
Interactions". Journal of Bacteriology 183 (10): 3025–3031. doi:10.1128/JB.183.10.3025-3031.2001. PMC 95201. PMID 11325929.
[5] Qureshi, SA; Bell, SD; Jackson, SP (1997). "Factor requirements for transcription in the archaeon Sulfolobus shibatae". EMBO Journal 16
(10): 2927–2936. doi:10.1093/emboj/16.10.2927. PMC 1169900. PMID 9184236.
[6] Raven, Peter H. (2011). Biology: ninth edition. New York: McGraw-Hill. pp. 278–301. ISBN 9780073532226.
[7] Mohamed Ouhammouch, Robert E. Dewhurst, Winfried Hausner, Michael Thomm, and E. Peter Geiduschek (2003). "Activation of archaeal
transcription by recruitment of the TATA-binding protein". Proceedings of the National Academy of Sciences of the United States of America
100 (9): 5097–5102. doi:10.1073/pnas.0837150100. PMC 154304. PMID 12692306.
[8] Goldman, R.; Ebright, H.; Nickels, E. (May 2009). "Direct detection of abortive RNA transcripts in vivo". Science 324 (5929): 927–928.
Bibcode 2009Sci...324..927G. doi:10.1126/science.1169237. ISSN 0036-8075. PMC 2718712. PMID 19443781.
[9] Dvir, A (Sep 2002). "Promoter escape by RNA polymerase II". Biochimica et Biophysica Acta 1577 (2): 208–223. ISSN 0006-3002.
PMID 12213653.
[10] Richardson J. Rho-dependent termination and ATPases in transcript termination. Biochimica et Biophysica Acta (BBA) - Gene Structure
and Expression. 2002;1577(2):251-260. Available at: http:/ / dx. doi. org/ 10. 1016/ S0167-4781(02)00456-6 [Accessed March 5, 2011].
[11] Lykke-Andersen S, Jensen TH. Overlapping pathways dictate termination of RNA polymerase II transcription. Biochimie.
2007;89(10):1177-82. Available at: http:/ / dx. doi. org/ 10. 1016/ j. biochi. 2007. 05. 007 [Accessed August 5, 2010].
[12] Raj, A. and van Oudenaarden, A. (2008). Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216-26.
[13] "Chemistry 2006" (http:/ / nobelprize. org/ nobel_prizes/ chemistry/ laureates/ 2006/ ). Nobel Foundation. . Retrieved 2007-03-29.
[14] Kolesnikova I. N. (2000 г.). "Some patterns of apoptosis mechanism during HIV-infection" (http:/ / www. dissercat. com/ content/
nekotorye-osobennosti-mekhanizmov-apoptoza-pri-vich-infektsii) (in ru). Dissertation. . Retrieved 2011-02-20.

External links
• Interactive Java simulation of transcription initiation. (http://cmol.nbi.dk/models/dynamtrans/dynamtrans.
html) From Center for Models of Life (http://cmol.nbi.dk/) at the Niels Bohr Institute.
• Interactive Java simulation of transcription interference--a game of promoter dominance in bacterial virus. (http:/
/cmol.nbi.dk/models/dna/rnap.html) From Center for Models of Life (http://cmol.nbi.dk/) at the Niels
Bohr Institute.
• Biology animations about this topic under Chapter 15 and Chapter 18 (http://highered.mcgraw-hill.com/sites/
dl/free/0072437316/120060/ravenanimation.html)
• Virtual Cell Animation Collection, Introducing Transcription (http://vcell.ndsu.nodak.edu/animations/
transcription/index.htm)
Regulation of gene expression 380

Regulation of gene expression

Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene
modulation.
For vocabulary, see Glossary of gene expression terms
Regulation of gene expression (or gene regulation) includes the
processes that cells and viruses use to regulate the way that the
information in genes is turned into gene products. Although a
functional gene product can be an RNA, the majority of known
mechanisms regulate protein coding genes. Any step of the gene's
expression may be modulated, from DNA-RNA transcription to the
post-translational modification of a protein.

Gene regulation is essential for viruses, prokaryotes and eukaryotes as

it increases the versatility and adaptability of an organism by allowing Diagram showing at which stages in the
the cell to express protein when needed. Although in 1951, Barbara DNA-mRNA-protein pathway expression can be
controlled
McClintock showed interaction between two genetic loci, Activator
(Ac) and Dissociator (Ds), the first discovery of a gene regulation
system is widely considered to be the identification in 1961 of the lac operon, discovered by Jacques Monod, in
which protein involved in lactose metabolism are expressed by E. coli only in the presence of lactose and absence of
glucose.

Furthermore, gene regulation drives the processes of cellular differentiation and morphogenesis, leading to the
creation of different cell types in multicellular organisms where the different types of cells may possess different
gene expression profiles though they all possess the same genome sequence.

Regulated stages of gene expression

Any step of gene expression may be modulated, from the DNA-RNA transcription step to post-translational
modification of a protein. The following is a list of stages where gene expression is regulated, the most extensively
utilised point is Transcription Initiation:
• Chromatin domains
• Transcription
• Post-transcriptional modification
• RNA transport
• Translation
• mRNA degradation
Regulation of gene expression 381

Modification of DNA
In eukaryotes, the accessibility of large regions of DNA can depend on its chromatin structure, which can be altered
as a result of histone modifications directed by DNA methylation, ncRNA, or DNA-binding protein. Hence these
modifications may up or down regulate the expression of gene. Certain of these modifications that regulate gene
expression are inheritable and are referred to as epigenetic regulation.

Chemical
Methylation of DNA is a common method of gene silencing. DNA is typically methylated by methyltransferase
enzymes on cytosine nucleotides in a CpG dinucleotide sequence (also called "CpG islands" when densely
clustered). Analysis of the pattern of methylation in a given region of DNA (which can be a promoter) can be
achieved through a method called bisulfite mapping. Methylated cytosine residues are unchanged by the treatment,
whereas unmethylated ones are changed to uracil. The differences are analyzed by DNA sequencing or by methods
developed to quantify SNPs, such as Pyrosequencing (Biotage) or MassArray (Sequenom), measuring the relative
amounts of C/T at the CG dinucleotide. Abnormal methylation patterns are thought to be involved in oncogenesis.

Structural
Transcription of DNA is dictated by its structure. In general, the density of its packing is indicative of the frequency
of transcription. Octameric protein complexes called nucleosomes are responsible for the amount of supercoiling of
DNA, and these complexes can be temporarily modified by processes such as phosphorylation or more permanently
modified by processes such as methylation. Such modifications are considered to be responsible for more or less
permanent changes in gene expression levels.
Histone acetylation is also an important process in transcription. Histone acetyltransferase enzymes (HATs) such as
CREB-binding protein also dissociate the DNA from the histone complex, allowing transcription to proceed. Often,
DNA methylation and histone deacetylation work together in gene silencing. The combination of the two seems to
be a signal for DNA to be packed more densely, lowering gene expression.

Regulation of transcription
Regulation of transcription controls when transcription occurs and how much RNA is created. Transcription of a
gene by RNA polymerase can be regulated by at least five mechanisms:
• Specificity factors alter the specificity of RNA polymerase for a given promoter or set of promoters, making it
more or less likely to bind to them (i.e., sigma factors used in prokaryotic transcription).
• Repressors bind to non-coding sequences on the DNA strand that are close to or overlapping the promoter
region, impeding RNA polymerase's progress along the strand, thus impeding the expression of the gene.
• General transcription factors position RNA polymerase at the start of a protein-coding sequence and then
release the polymerase to transcribe the mRNA.
• Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the
expression of the gene. Activators do this by increasing the attraction of RNA polymerase for the promoter,
through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.
• Enhancers are sites on the DNA helix that are bound to by activators in order to loop the DNA bringing a
specific promoter to the initiation complex. Enhancers are much more common in eukaryote than prokaryotes,
where only a few examples exist (to date).[1]
Regulation of gene expression 382

Post-transcriptional regulation
After the DNA is transcribed and mRNA is formed, there must be some sort of regulation on how much the mRNA
is translated into proteins. Cells do this by modulating the capping, splicing, addition of a Poly(A) Tail, the
sequence-specific nuclear export rates, and, in several contexts, sequestration of the RNA transcript. These processes
occur in eukaryotes but not in prokaryotes. This modulation is a result of a protein or transcript that, in turn, is
regulated and may have an affinity for certain sequences.

Regulation of translation
The translation of mRNA can also be controlled by a number of mechanisms, mostly at the level of initiation.
Recruitment of the small ribosomal subunit can indeed be modulated by mRNA secondary structure, antisense RNA
binding, or protein binding. In both prokaryotes and eukaryotes, a large number of RNA binding proteins exist,
which often are directed to their target sequence by the secondary structure of the transcript, which may change
depending on certain conditions, such as temperature or presence of a ligand (aptamer). Some transcripts act as
ribozymes and self-regulate their expression.

Examples of gene regulation

• Enzyme induction is a process in which a molecule (e.g., a drug) induces (i.e., initiates or enhances) the
expression of an enzyme.
• The induction of heat shock proteins in the fruit fly Drosophila melanogaster.
• The Lac operon is an interesting example of how gene expression can be regulated.
• Viruses, despite having only a few genes, possess mechanisms to regulate their gene expression, typically into an
early and late phase, using collinear systems regulated by anti-terminators (lambda phage) or splicing modulators
(HIV).

Developmental biology
A large number of studied regulatory systems come from developmental biology. Examples include:
• The colinearity of the Hox gene cluster with their nested antero-posterior patterning
• It has been speculated that pattern generation of the hand (digits - interdigits) The gradient of Sonic hedgehog
(secreted inducing factor) from the zone of polarizing activity in the limb, which creates a gradient of active Gli3,
which activates Gremlin, which inhibits BMPs also secreted in the limb, resulting in the formation of an
alternating pattern of activity as a result of this reaction-diffusion system.
• Somitogenesis is the creation of segments (somites) from a uniform tissue (Pre-somitic Mesoderm, PSM). They
are formed sequentially from anterior to posterior. This is achieved in amniotes possibly by means of two
opposing gradients, Retinoic acid in the anterior (wavefront) and Wnt and Fgf in the posterior, coupled to an
oscillating pattern (segmentation clock) composed of FGF + Notch and Wnt in antiphase.[2]
• Sex determination in the soma of a Drosophila requires the sensing of the ratio of autosomal genes to sex
chromosome-encoded genes, which results in the production of sexless splicing factor in females, resulting in the
female isoform of doublesex.[3]
Regulation of gene expression 383

Circuitry

Up-regulation and down-regulation

Up-regulation is a process that occurs within a cell triggered by a signal (originating internal or external to the cell),
which results in increased expression of one or more genes and as a result the protein(s) encoded by those genes. On
the converse, down-regulation is a process resulting in decreased gene and corresponding protein expression.
• Up-regulation occurs, for example, when a cell is deficient in some kind of receptor. In this case, more receptor
protein is synthesized and transported to the membrane of the cell and, thus, the sensitivity of the cell is brought
back to normal, reestablishing homeostasis.
• Down-regulation occurs, for example, when a cell is overstimulated by a neurotransmitter, hormone, or drug for a
prolonged period of time, and the expression of the receptor protein is decreased in order to protect the cell (see
also tachyphylaxis).

Inducible vs. repressible systems

Gene Regulation can be summarized by the response of the respective system:
• Inducible systems - An inducible system is off unless there is the presence of some molecule (called an inducer)
that allows for gene expression. The molecule is said to "induce expression". The manner by which this happens
is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.
• Repressible systems - A repressible system is on except in the presence of some molecule (called a corepressor)
that suppresses gene expression. The molecule is said to "repress expression". The manner by which this happens
is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.

Theoretical circuits
• Repressor/Inducer: an activation of a sensor results in the change of expression of a gene
• negative feedback: the gene product downregulates its own production directly or indirectly, which can result in
• keeping transcript levels constant/proportional to a factor
• inhibition of run-away reactions when coupled with a positive feedback loop
• creating an oscillator by taking advantage in the time delay of transcription and translation, given that the
mRNA and protein half-life is shorter
• positive feedback: the gene product upregulates its own production directly or indirectly, which can result in
• signal amplification
• bistable switches when two genes inhibit each other and both have positive feedback
• pattern generation

Methods
In general, most experiments investigating differential expression used whole cell extracts of RNA, called
steady-state levels, to determine which genes changed and by how much they did. These are, however, not
informative of where the regulation has occurred and may actually mask conflicting regulatory processess (see
post-transcriptional regulation), but it is still the most commonly analysed (QPCR and DNA microarray).
When studying gene expression, there are several methods to look at the various stages. In eukaryotes these include:
• The local chromatin environment of the region can be determined by ChIP-chip analysis by pulling down RNA
Polymerase II, Histone 3 modifications, Trithorax-group protein, Polycomb-group protein, or any other
DNA-binding element to which a good antibody is available.
• Epistatic interactions can be investigated by synthetic genetic array analysis
Regulation of gene expression 384

• Due to post-transcriptional regulation, transcription rates and total RNA levels differ significantly. To measure the
transcription rates nuclear run-on assays can be done and newer high-throughput methods are being developed,
using thiol labelling instead of radioactivity.[4]
• Only 5% of the RNA polymerised in the nucleus actually exists,[5] and not only introns, abortive products, and
non-sense transcripts are degradated. Therefore, the differences in nuclear and cytoplasmic levels can be see by
separating the two fractions by gentle lysis.[6]
• Alternative splicing can be analysed with a splicing array or with a tiling array (see DNA microarray).
• All in vivo RNA is complexed as RNPs. The quantity of transcripts bound to specific protein can be also analysed
by RIP-Chip. For example, DCP2 will give an indication of sequestered protein; ribosome-bound gives and
indication of transcripts active in transcription (although it should be noted that a more dated method, called
polysome fractionation, is still popular in some labs)
• Protein levels can be analysed by Mass spectrometry, which can be compared only to QPCR data, as microarray
data is relative and not absolute.
• RNA and protein degradation rates are measured by means of transcription inhibitors (actinomycin D or
α-amanitin) or translation inhibitors (Cycloheximide), respectively.

References
[1] Austin S, Dixon R (June 1992). "The prokaryotic enhancer binding protein NTRC has an ATPase activity which is phosphorylation and DNA
dependent". EMBO J. 11 (6): 2219–28. PMC 556689. PMID 1534752.
[2] Dequéant ML, Pourquié O. Segmental patterning of the vertebrate embryonic axis. Nat Rev Genet. 2008 May;9(5):370-82. PMID 18414404
[3] Gilbert SF (2003). Developmental biology, 7th ed., Sunderland, Mass: Sinauer Associates, 65–6. ISBN 0-87893-258-5.
[4] Cheadle C, Fan J, Cho-Chung YS, Werner T, Ray J, Do L, Gorospe M, Becker KG (2005). "Control of gene expression during T cell
activation: alternate regulation of mRNA transcription and mRNA stability". BMC Genomics 6: 75. doi:10.1186/1471-2164-6-75.
PMC 1156890. PMID 15907206.
[5] Jackson DA, Pombo A, Iborra F (2000). "The balance sheet for transcription: an analysis of nuclear RNA metabolism in mammalian cells"
(http:/ / www. fasebj. org/ cgi/ content/ abstract/ 14/ 2/ 242). FASEB J. 14 (2): 242–54. PMID 10657981. .
[6] Schwanekamp JA, Sartor MA, Karyala S, Halbleib D, Medvedovic M, Tomlinson CR (2006). "Genome-wide analyses show that nuclear and
cytoplasmic RNA levels are differentially affected by dioxin". Biochim. Biophys. Acta 1759 (8–9): 388–402.
doi:10.1016/j.bbaexp.2006.07.005. PMID 16962184.

Further reading
• Latchman, David S. (2005). Gene regulation: a eukaryotic perspective (http://books.google.com/
books?id=4x3ZzLNyfDsC). Psychology Press. ISBN 9780415365109.

External links
• Cellular Darwinism (http://www.scitopics.com/
Stochastic_gene_expression_and_cell_differentiation_during_embryo_development.html)
• MeSH Regulation of Gene Expression (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&
term=Regulation+of+Gene+Expression)
 385

Protein synthesis and modifications

Translation
In molecular biology and genetics, translation is the third stage of
protein biosynthesis (part of the overall process of gene expression). In
translation, messenger RNA (mRNA) produced by transcription is
decoded by the ribosome to produce a specific amino acid chain, or
polypeptide, that will later fold into an active protein. In Bacteria,
translation occurs in the cell's cytoplasm, where the large and small
subunits of the ribosome are located, and bind to the mRNA. In
Eukaryotes, translation occurs across the membrane of the endoplasmic
reticulum in a process called vectorial synthesis. The ribosome Diagram showing the translation of mRNA and
facilitates decoding by inducing the binding of tRNAs with the synthesis of proteins by a ribosome.
complementary anticodon sequences to that of the mRNA. The tRNAs
carry specific amino acids that are chained together into a polypeptide as the mRNA passes through and is "read" by
the ribosome in a fashion reminiscent to that of a stock ticker and ticker tape.

In many instances, the entire ribosome/mRNA complex will bind to the outer membrane of the rough endoplasmic
reticulum and release the nascent protein polypeptide inside for later vesicle transport and secretion outside of the
cell. Many types of transcribed RNA, such as transfer RNA, ribosomal RNA, and small nuclear RNA, do not
undergo translation into proteins.
Translation proceeds in four phases: activation, initiation, elongation and termination (all describing the growth of
the amino acid chain, or polypeptide that is the product of translation). Amino acids are brought to ribosomes and
assembled into proteins.
In activation, the correct amino acid is covalently bonded to the correct transfer RNA (tRNA). The amino acid is
joined by its carboxyl group to the 3' OH of the tRNA by an ester bond. When the tRNA has an amino acid linked to
it, it is termed "charged". Initiation involves the small subunit of the ribosome binding to the 5' end of mRNA with
the help of initiation factors (IF). Termination of the polypeptide happens when the A site of the ribosome faces a
stop codon (UAA, UAG, or UGA). No tRNA can recognize or bind to this codon. Instead, the stop codon induces
the binding of a release factor protein that prompts the disassembly of the entire ribosome/mRNA complex.
A number of antibiotics act by inhibiting translation; these include anisomycin, cycloheximide, chloramphenicol,
tetracycline, streptomycin, erythromycin, and puromycin, among others. Prokaryotic ribosomes have a different
structure from that of eukaryotic ribosomes, and thus antibiotics can specifically target bacterial infections without
any detriment to a eukaryotic host's cells.
Translation 386

Basic mechanisms
Further information: Prokaryotic translation and Eukaryotic translation
The basic process of protein production is addition of one amino acid
at a time to the end of a protein. This operation is performed by a
ribosome. The choice of amino acid type to add is determined by an
mRNA molecule. Each amino acid added is matched to a three
nucleotide subsequence of the mRNA. For each such triplet possible,
only one particular amino acid type is accepted. The successive amino
acids added to the chain are matched to successive nucletide triplets in
the mRNA. In this way the sequence of nucletides in the template
mRNA chain determines the sequence of amino acids in the generated
amino acid chain.[1]

The mRNA carries genetic information encoded as a ribonucleotide

sequence from the chromosomes to the ribosomes. The ribonucleotides Tertiary structure of tRNA. CCA tail in orange,
Acceptor stem in purple, D arm in red, Anticodon
are "read" by translational machinery in a sequence of nucleotide
arm in blue with Anticodon in black, T arm in
triplets called codons. Each of those triplets codes for a specific amino green.
acid.
The ribosome molecules translate this code to a specific sequence of amino acids. The ribosome is a multisubunit
structure containing rRNA and proteins. It is the "factory" where amino acids are assembled into proteins. tRNAs are
small noncoding RNA chains (74-93 nucleotides) that transport amino acids to the ribosome. tRNAs have a site for
amino acid attachment, and a site called an anticodon. The anticodon is an RNA triplet complementary to the mRNA
triplet that codes for their cargo amino acid.
Aminoacyl tRNA synthetase (an enzyme) catalyzes the bonding between specific tRNAs and the amino acids that
their anticodon sequences call for. The product of this reaction is an aminoacyl-tRNA molecule. This
aminoacyl-tRNA travels inside the ribosome, where mRNA codons are matched through complementary base
pairing to specific tRNA anticodons. The ribosome has three sites for tRNA to bind. They are the aminoacyl site
(abbreviated A), the peptidyl site (abbreviated P) and the exit site (abbreviated E). With respect to the mRNA, the
three sites are oriented 5’to 3’ E-P-A, because ribosomes move in a 3’ to 5’ fashion. The A site binds the incoming
tRNA with the complementary codon on the mRNA. The P site holds the tRNA with the growing polypeptide chain.
The E site holds the tRNA without its amino acid. When an aminoacyl-tRNA initially binds to its corresponding
codon on the mRNA, it is in the A site. Then, a peptide bond forms between the amino acid of the tRNA in the A site
and the amino acid of the charged tRNA in the P site. The growing polypeptide chain is transferred to the tRNA in
the A site. Translocation occurs, moving the tRNA in the P site, now without an amino acid, to the E site; the tRNA
that was in the A site, now charged with the polypeptide chain, is moved to the P site. The tRNA in the E site leaves
and another aminoacyl-tRNA enters the A site to repeat the process. [2]
After the new amino acid is added to the chain, the energy provided by the hydrolysis of a GTP bound to the
translocase EF-G (in prokaryotes) and eEF-2 (in eukaryotes) moves the ribosome down one codon towards the 3'
end. The energy required for translation of proteins is significant. For a protein containing n amino acids, the number
of high-energy Phosphate bonds required to translate it is 4n-1 . The rate of translation varies; it is significantly
higher in prokaryotic cells (up to 17-21 amino acid residues per second) than in eukaryotic cells (up to 6-9 amino
acid residues per second).[3]
Translation 387

Genetic code
Whereas other aspects such as the 3D structure, called tertiary structure, of protein can only be predicted using
sophisticated algorithms, the amino acid sequence, called primary structure, can be determined solely from the
nucleic acid sequence with the aid of a translation table.
This approach may not give the correct amino acid composition of the protein, in particular if unconventional amino
acids such as selenocysteine are incorporated into the protein, which is coded for by a conventional stop codon in
combination with a downstream hairpin (SElenoCysteine Insertion Sequence, or SECIS).
There are many computer programs capable of translating a DNA/RNA sequence into a protein sequence. Normally
this is performed using the Standard Genetic Code; many bioinformaticians have written at least one such program at
some point in their education. However, few programs can handle all the "special" cases, such as the use of the
alternative initiation codons. For instance, the rare alternative start codon CTG codes for Methionine when used as a
start codon, and for Leucine in all other positions.
Example: Condensed translation table for the Standard Genetic Code (from the NCBI Taxonomy webpage [4]).

AAs = FFLLSSSSYY**CC*WLLLLPPPPHHQQRRRRIIIMTTTTNNKKSSRRVVVVAAAADDEEGGGG
Starts = ---M---------------M---------------M----------------------------
Base1 = TTTTTTTTTTTTTTTTCCCCCCCCCCCCCCCCAAAAAAAAAAAAAAAAGGGGGGGGGGGGGGGG
Base2 = TTTTCCCCAAAAGGGGTTTTCCCCAAAAGGGGTTTTCCCCAAAAGGGGTTTTCCCCAAAAGGGG
Base3 = TCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAGTCAG

Translation tables
Even when working with ordinary Eukaryotic sequences such as the Yeast genome, it is often desired to be able to
use alternative translation tables—namely for translation of the mitochondrial genes. Currently the following
translation tables are defined by the NCBI Taxonomy Group [5] for the translation of the sequences in GenBank:

1: The Standard
2: The Vertebrate Mitochondrial Code
3: The Yeast Mitochondrial Code
4: The Mold, Protozoan, and Coelenterate Mitochondrial Code and the
Mycoplasma/Spiroplasma Code
5: The Invertebrate Mitochondrial Code
6: The Ciliate, Dasycladacean and Hexamita Nuclear Code
9: The Echinoderm and Flatworm Mitochondrial Code
10: The Euplotid Nuclear Codecbn dxh
11: The Bacterial and Plant Plastid Code
12: The Alternative Yeast Nuclear Code
13: The Ascidian Mitochondrial Code
14: The Alternative Flatworm Mitochondrial Code
15: Blepharisma Nuclear Code
16: Chlorophycean Mitochondrial Code
21: Trematode Mitochondrial Code
22: Scenedesmus obliquus mitochondrial Code
23: Thraustochytrium Mitochondrial Code

=
Translation 388

References
[1] Neill, Campbell (1996). Biology; Fourth edition. The Benjamin/Cummings Publishing Company. p. 309,310. ISBN 0-8053-1940-9.
[2] Griffiths, Anthony (2008). "9". Introduction to Genetic Analysis (9th ed.). New York: W.H. Freeman and Company. pp. 335-339.
ISBN 978-0-7167-6887-6.
[3] Ross JF, Orlowski M (February 1982). "Growth-rate-dependent adjustment of ribosome function in chemostat-grown cells of the fungus
Mucor racemosus". J. Bacteriol. 149 (2): 650–3. PMC 216554. PMID 6799491.
[4] http:/ / www. ncbi. nlm. nih. gov/ Taxonomy/ Utils/ wprintgc. cgi?mode=c
[5] http:/ / www. ncbi. nlm. nih. gov/ Taxonomy/

Further reading
• Champe, Pamela C; Harvey, Richard A; Ferrier, Denise R (2004). Lippincott's Illustrated Reviews: Biochemistry
(3rd ed.). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-2265-9.
• Cox, Michael; Nelson, David R.; Lehninger, Albert L (2005). Lehninger principles of biochemistry (4th ed.). San
Francisco...: W.H. Freeman. ISBN 0-7167-4339-6.
• Malys N, McCarthy JEG (2010). "Translation initiation: variations in the mechanism can be anticipated". Cellular
and Molecular Life Sciences 68 (6): 991–1003. doi:10.1007/s00018-010-0588-z. PMID 21076851.

External links
• Virtual Cell Animation Collection: Introducing Translation (http://vcell.ndsu.nodak.edu/animations/
translation/index.htm)
• mRNA to Amino Acid translator (http://www.bluetulip.org/discrepancy/aminotrans.php)
Posttranslational modification 389

Posttranslational modification
Posttranslational modification (PTM) is the chemical modification of a protein after its translation. It is one of the
later steps in protein biosynthesis, and thus gene expression, for many proteins.
A protein (also called a polypeptide) is a chain of
amino acids. During protein synthesis, 20 different
amino acids can be incorporated to become a protein.
After translation, the posttranslational modification of
amino acids extends the range of functions of the
protein by attaching it to other biochemical functional
groups (such as acetate, phosphate, various lipids and
carbohydrates), changing the chemical nature of an
amino acid (e.g. citrullination), or making structural
changes (e.g. formation of disulfide bridges).

Also, enzymes may remove amino acids from the

amino end of the protein, or cut the peptide chain in the
middle. For instance, the peptide hormone insulin is cut
twice after disulfide bonds are formed, and a propeptide
is removed from the middle of the chain; the resulting
protein consists of two polypeptide chains connected
by disulfide bonds. Also, most nascent polypeptides
start with the amino acid methionine because the "start"
codon on mRNA also codes for this amino acid. This
amino acid is usually taken off during post-translational
modification.
The bottom of this diagram shows the modification of primary
Other modifications, like phosphorylation, are part of
structure of insulin, as described.
common mechanisms for controlling the behavior of a
protein, for instance activating or inactivating an
enzyme.
Post-translational modification of proteins is detected by mass spectrometry or Eastern blotting.
Posttranslational modification 390

PTMs involving addition of functional groups

PTMs involving addition by an

enzyme in vivo

PTMs involving addition of hydrophobic

groups for membrane localization

• myristoylation, attachment of myristate, a C14

saturated acid
• palmitoylation, attachment of palmitate, a C16
saturated acid
• isoprenylation or prenylation, the addition of
an isoprenoid group (e.g. farnesol and
geranylgeraniol)
• farnesylation
• geranylgeranylation
• glypiation, glycosylphosphatidylinositol
(GPI) anchor formation via an amide bond to
C-terminal tail

PTMs involving addition of cofactors for

enhanced enzymatic activity

• lipoylation, attachment of a lipoate (C8)

functional group [1]
The genetic code diagram showing the amino acid residues as target of
• flavin moiety (FMN or FAD) may be
modification.
covalently attached
• heme C attachment via thioether bonds with cysteins
• phosphopantetheinylation, the addition of a 4'-phosphopantetheinyl moiety from coenzyme A, as in fatty acid,
polyketide, non-ribosomal peptide and leucine biosynthesis
• retinylidene Schiff base formation

PTMs involving unique modifications of translation factors

• diphthamide formation (on a histidine found in eEF2)
• ethanolamine phosphoglycerol attachment (on glutamte found in eEF1α)[2]
• hypusine formation (on conserved lysine of eIF5A (eukaryotic) and aIF5A (archeal))

PTMs involving addition of smaller chemical groups

• acylation, e.g. O-acylation (esters), N-acylation (amides), S-acylation (thioesters)
• acetylation, the addition of an acetyl group, either at the N-terminus [3] of the protein or at lysine residues.[4]
See also histone acetylation.[5] [6] The reverse is called deacetylation.
• formylation
• alkylation, the addition of an alkyl group, e.g. methyl, ethyl
• methylation the addition of a methyl group, usually at lysine or arginine residues. The reverse is called
demethylation.
• amide bond formation
Posttranslational modification 391

• amidation at C-terminus
• amino acid addition
• arginylation, a tRNA-mediation addition
• polyglutamylation, covalent linkage of glutamic acid residues to the N-terminus of tubulin and some other
proteins.[7] (See tubulin polyglutamylase)
• polyglycylation, covalent linkage of one to more than 40 glycine residues to the tubulin C-terminal tail
• gamma-carboxylation dependent on Vitamin K[8]
• glycosylation, the addition of a glycosyl group to either asparagine, hydroxylysine, serine, or threonine, resulting
in a glycoprotein. Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars.
• polysialylation, addition of polysialic acid, PSA, to NCAM
• ADP-ribosylation
• hydroxylation
• iodination (e.g. of thyroglobulin)
• oxidation
• phosphate ester (O-linked) or phosphoramidate (N-linked) formation
• phosphorylation, the addition of a phosphate group, usually to serine, threonine, and tyrosine (O-linked), or
histidine (N-linked)
• adenylylation, the addition of an adenylyl moiety, usually to tyrosine (O-linked), or histidine and lysine
(N-linked)
• pyroglutamate formation
• S-glutathionylation
• S-nitrosylation
• sulfation, the addition of a sulfate group to a tyrosine.
• selenoylation (co-translational incorporation of selenium in selenoproteins)

PTMs involving non-enzymatic additions in vivo

• glycation, the addition of a sugar molecule to a protein without the controlling action of an enzyme.

PTMs involving non-enzymatic additions in vitro

• biotinylation, acylation of conserved lysine residues with a biotin appendage
• pegylation

PTMs involving addition of other proteins or peptides

• ISGylation, the covalent linkage to the ISG15 protein (Interferon-Stimulated Gene 15)[9]
• SUMOylation, the covalent linkage to the SUMO protein (Small Ubiquitin-related MOdifier)[10]
• ubiquitination, the covalent linkage to the protein ubiquitin.
• Neddylation, the covalent linkage to Nedd
Posttranslational modification 392

PTMs involving changing the chemical nature of amino acids

• citrullination, or deimination, the conversion of arginine to citrulline
• deamidation, the conversion of glutamine to glutamic acid or asparagine to aspartic acid
• eliminylation, the conversion to an alkene by beta-elimination of phosphothreonine and phosphoserine, or
dehydration of threonine and serine, as well as by decarboxylation of cysteine [11]
• carbamylation, the conversion of lysine to homocitrulline [12]

PTMs involving structural changes

• disulfide bridges, the covalent linkage of two cysteine amino acids
• proteolytic cleavage, cleavage of a protein at a peptide bond
• racemization of proline by prolyl isomerase

Post-translational modification statistics

Recently statistics of each post-translational modification experimentally and putatively detected have been
compiled using proteome-wide information from the Swiss-Prot database.[13] These statistics can be found at http:/ /
selene.princeton.edu/PTMCuration/.

Case examples
• Cleavage and formation of disulfide bridges during the production of insulin
• PTM of histones as regulation of transcription: RNA polymerase control by chromatin structure
• PTM of RNA polymerase II as regulation of transcription
• Cleavage of polypeptide chains [14] as crucial for lectin specificity

External links
• List of posttranslational modifications in ExPASy [15]
• Statistics of each post-translational modification from the Swiss-Prot database [16]
• AutoMotif Server [17] - A Computational Protocol for Identification of Post-Translational Modifications in
Protein Sequences [18]
• Functional analyses for site-specific phosphorylation of a target protein in cells [19]
• Detection of Post-Translational Modifications after high-accuracy MSMS [20]

References
[1] Gramatikoff K. in Abgent Catalog (2004-5) p.263
[2] Whiteheart SW, Shenbagamurthi P, Chen L, et al. (1989). "Murine elongation factor 1 alpha (EF-1 alpha) is posttranslationally modified by
novel amide-linked ethanolamine-phosphoglycerol moieties. Addition of ethanolamine-phosphoglycerol to specific glutamic acid residues on
EF-1 alpha.". J. Biol. Chem. 264 (24): 14334–41. PMID 2569467.
[3] Polevoda B, Sherman F (2003). "N-terminal acetyltransferases and sequence requirements for N-terminal acetylation of eukaryotic proteins".
J Mol Biol 325 (4): 595–622. doi:10.1016/S0022-2836(02)01269-X. PMID 12507466.
[4] Yang XJ, Seto E (2008). "Lysine acetylation: codified crosstalk with other posttranslational modifications". Mol Cell 31 (4): 449–61.
doi:10.1016/j.molcel.2008.07.002. PMC 2551738. PMID 18722172.
[5] Bártová E, Krejcí J, Harnicarová A, Galiová G, Kozubek S (2008). "Histone modifications and nuclear architecture: a review". J Histochem
Cytochem 56 (8): 711–21. doi:10.1369/jhc.2008.951251. PMC 2443610. PMID 18474937.
[6] Glozak MA, Sengupta N, Zhang X, Seto E (2005). "Acetylation and deacetylation of non-histone proteins". Gene 363: 15–23.
doi:10.1016/j.gene.2005.09.010. PMID 16289629.
[7] Eddé B, Rossier J, Le Caer JP, Desbruyères E, Gros F, Denoulet P (1990). "Posttranslational glutamylation of alpha-tubulin". Science 247
(4938): 83–5. Bibcode 1990Sci...247...83E. doi:10.1126/science.1967194. PMID 1967194.
Posttranslational modification 393

[8] Walker CS, Shetty RP, Clark K, et al. (2001). "On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems.
Evidence for a gamma-glutamyl carboxylase in Drosophila". J. Biol. Chem. 276 (11): 7769–74. doi:10.1074/jbc.M009576200.
PMID 11110799.
[9] Malakhova, Oxana A.; Yan, Ming; Malakhov, Michael P.; Yuan, Youzhong; Ritchie, Kenneth J.; Kim, Keun Il; Peterson, Luke F.; Shuai, Ke;
and Dong-Er Zhang (2003). "Protein ISGylation modulates the JAK-STAT signaling pathway" (http:/ / www. genesdev. org/ cgi/ content/ full/
17/ 4/ 455). Genes & Development 17 (4): 455–60. doi:10.1101/gad.1056303. PMC 195994. PMID 12600939. .
[10] Van G. Wilson (Ed.) (2004). Sumoylation: Molecular Biology and Biochemistry (http:/ / www. horizonpress. com/ hsp/ books/ sumo. html).
Horizon Bioscience. ISBN 0-9545232-8-8.
[11] Brennan DF, Barford D (2009). "Eliminylation: a post-translational modification catalyzed by phosphothreonine lyases". Trends in
Biochemical Sciences 34 (3): 108–114. doi:10.1016/j.tibs.2008.11.005. PMID 19233656.
[12] Mydel P, et al. (2010). "Carbamylation-dependent activation of T cells: a novel mechanism in the pathogenesis of autoimmune arthritis.".
Journal of Immunology 184 (12): 6882–6890. doi:10.4049/ jimmunol.1000075. PMC 2925534. PMID 20488785.
[13] Khoury, George A.; Baliban, Richard C.; and Christodoulos A. Floudas (2011). "Proteome-wide post-translational modification statistics:
frequency analysis and curation of the swiss-prot database" (http:/ / www. nature. com/ srep/ 2011/ 110913/ srep00090/ full/ srep00090. html).
Scientific Reports 1 (90). doi:10.1038/srep00090. .
[14] http:/ / www. proteopedia. org/ wiki/ index. php/ 1tp8
[15] http:/ / www. uniprot. org/ docs/ ptmlist
[16] http:/ / selene. princeton. edu/ PTMCuration/
[17] http:/ / ams2. bioinfo. pl/
[18] http:/ / www. natureprotocols. com/ 2007/ 03/ 23/ automotif_server_a_computation. php
[19] http:/ / www. natureprotocols. com/ 2007/ 01/ 10/ functional_analyses_for_sitesp. php
[20] http:/ / www. detectorvision. com/ deltaMasses. html

Proteolysis
Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by
intramolecular digestion.

Purposes
Proteolysis is used by the cell for several purposes. They include:
• Removal of N-terminal methionine residues after translation.
• Removal of the signal sequence of peptides after their transport through a membrane
• Separation of viral proteins that were translated from a polycistronic mRNA
• Digestion of proteins from foods as a source of amino acids
• Conversion of predecessor-proteins (proenzymes, zymogens, prehormones) into their final structures.
• Degradation of unneeded or damaged proteins for example cyclins at different stages of the cell cycle.
Proteolysis is also used in research and diagnostic applications:
• In-gel digestion of proteins after separation by gel electrophoresis for the identification by mass spectrometry.
• Digestion of proteins in solution for proteome analysis by liquid chromatography-mass spectrometry (LC-MS).
Proteolysis 394

Examples
Examples of serine proteases include:
• trypsin
• chymotrypsin
• elastase
• papain

Venoms
Certain types of venom, such as those produced by venomous snakes, can also cause proteolysis. These venoms are,
in fact, complex digestive fluids that begin their work outside of the body. Proteolytic venoms cause a wide range of
toxic effects,[1] including effects that are:
• cytotoxic (cell-destroying)
• hemotoxic (blood-destroying)
• myotoxic (muscle-destroying)
• hemorrhagic (bleeding)

References
[1] Hayes WK. 2005. Research on Biological Roles and Variation of Snake Venoms. (http:/ / www. llu. edu/ llu/ grad/ natsci/ hayes/
research-c-venom. html?PHPSESSID=55842bf3eeb83dcdfec66c45b91925fc) Loma Linda University.

External links
• Proteolysis (http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=Proteolysis) at eMedicine
Dictionary
• Proteolysis MAP from Center on Proteolytic Pathways (http://www.proteolysis.org/)
Proteasome 395

Proteasome
Proteasomes are very large protein complexes inside all eukaryotes
and archaea, and in some bacteria.  In eukaryotes, they are located in
the nucleus and the cytoplasm.[1]   The main function of the
proteasome is to degrade unneeded or damaged proteins by proteolysis,
a chemical reaction that breaks peptide bonds.  Enzymes that carry out
such reactions are called proteases.  Proteasomes are part of a major
mechanism by which cells regulate the concentration of particular
proteins and degrade misfolded proteins.  The degradation process
yields peptides of about seven to eight amino acids long, which can
then be further degraded into amino acids and used in synthesizing new
proteins.[2]   Proteins are tagged for degradation with a small protein
called ubiquitin.  The tagging reaction is catalyzed by enzymes called
ubiquitin ligases.  Once a protein is tagged with a single ubiquitin
molecule, this is a signal to other ligases to attach additional ubiquitin
molecules.  The result is a polyubiquitin chain that is bound by the
proteasome, allowing it to degrade the tagged protein.[2]

In structure, the proteasome is a cylindrical complex containing a

"core" of four stacked rings around a central pore.  Each ring is
composed of seven individual proteins.  The inner two rings are made
of seven β subunits that contain three to seven protease active sites. 
These sites are located on the interior surface of the rings, so that the
target protein must enter the central pore before it is degraded.  The
outer two rings each contain seven α subunits whose function is to Cartoon representation of a proteasome. 
Its active sites are sheltered inside the
maintain a "gate" through which proteins enter the barrel.  These α
tube (blue).  The caps (red; in this case,
subunits are controlled by binding to "cap" structures or regulatory 11S regulatory particles) on the ends
particles that recognize polyubiquitin tags attached to protein regulate entry into the destruction
substrates and initiate the degradation process.  The overall system of chamber, where the protein is degraded.

ubiquitination and proteasomal degradation is known as the

ubiquitin-proteasome system.

The proteasomal degradation pathway is essential for many cellular

processes, including the cell cycle, the regulation of gene expression,
and responses to oxidative stress.  The importance of proteolytic
degradation inside cells and the role of ubiquitin in proteolytic
pathways was acknowledged in the award of the 2004 Nobel Prize in
Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose.[3]

Discovery
Before the discovery of the ubiquitin proteasome system, protein
degradation in cells was thought to rely mainly on lysosomes,
membrane-bound organelles with acidic and protease-filled interiors

Top view of the proteasome above.

Proteasome 396

that can degrade and then recycle exogenous proteins and aged or damaged organelles.[2]   However, work by Alfred
Goldberg in 1977 on ATP-dependent protein degradation in reticulocytes, which lack lysosomes, suggested the
presence of a second intracellular degradation mechanism.[4]   This was shown in 1978 to be composed of several
distinct protein chains, a novelty among proteases at the time.[5]   Later work on modification of histones led to the
identification of an unexpected covalent modification of the histone protein by a bond between a lysine side chain of
the histone and the C-terminal glycine residue of ubiquitin, a protein that had no known function.[6]   It was then
discovered that a previously identified protein associated with proteolytic degradation, known as ATP-dependent
proteolysis factor 1 (APF-1), was the same protein as ubiquitin.[7]   Later, the ATP-dependent proteolytic complex
that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S
proteasome.[8] [9]
Much of the early work leading up to the discovery of the ubiquitin proteasome system occurred in the late 1970s
and early 1980s at the Technion in the laboratory of Avram Hershko, where Aaron Ciechanover worked as a
graduate student.  Hershko's year-long sabbatical in the laboratory of Irwin Rose at the Fox Chase Cancer Center
provided key conceptual insights, though Rose later downplayed his role in the discovery.[10]   The three shared the
2004 Nobel Prize in Chemistry for their work in discovering this system.[3]
Although electron microscopy data revealing the stacked-ring structure of the proteasome became available in the
mid-1980s,[11]   the first structure of the proteasome core particle was not solved by X-ray crystallography until
1994.[12] As of 2006, no structure has been solved of the core particle in complex with the most common form of
regulatory cap.

Structure and organization

The proteasome subcomponents are often referred to by their
Svedberg sedimentation coefficient (denoted S).  The most
common form of the proteasome is known as the 26S proteasome,
which is about 2000 kilodaltons (kDa) in molecular mass and
contains one 20S core particle structure and two 19S regulatory
caps.  The core is hollow and provides an enclosed cavity in which
proteins are degraded; openings at the two ends of the core allow
the target protein to enter.  Each end of the core particle associates
with a 19S regulatory subunit that contains multiple ATPase active
sites and ubiquitin binding sites; it is this structure that recognizes
polyubiquitinated proteins and transfers them to the catalytic core. 
An alternative form of regulatory subunit called the 11S particle
can associate with the core in essentially the same manner as the
19S particle; the 11S may play a role in degradation of foreign
peptides such as those produced after infection by a virus.[13]

20S core particle A schematic diagram of the proteasome 20S core

particle viewed from one side.  The α subunits that
The number and diversity of subunits contained in the 20S core make up the outer two rings are shown in green, and
particle depends on the organism; the number of distinct and the β subunits that make up the inner two rings are
specialized subunits is larger in multicellular than unicellular shown in blue.

organisms and larger in eukaryotes than in prokaryotes.  All 20S

particles consist of four stacked heptameric ring structures that are
Proteasome 397

themselves composed of two different types of subunits; α

subunits are structural in nature, whereas β subunits are
predominantly catalytic.  The outer two rings in the stack consist
of seven α subunits each, which serve as docking domains for the
regulatory particles and the alpha subunits N-termini form a gate
that blocks unregulated access of substrates to the interior
cavity.[14] The inner two rings each consist of seven β subunits
and contain the protease active sites that perform the proteolysis
reactions.  The size of the proteasome is relatively conserved and
is about 150 angstroms (Å) by 115 Å.  The interior chamber is at
most 53 Å wide, though the entrance can be as narrow as 13 Å,
suggesting that substrate proteins must be at least partially
unfolded to enter.[15] Top view of the same schematic, illustrating the
seven-fold symmetry of the rings.
In archaea such as Thermoplasma acidophilum, all the α and all
the β subunits are identical, whereas eukaryotic proteasomes such
as those in yeast contain seven distinct types of each subunit.  In mammals, the β1, β2, and β5 subunits are catalytic;
although they share a common mechanism, they have three distinct substrate specificities considered
chymotrypsin-like, trypsin-like, and peptidyl-glutamyl peptide-hydrolyzing (PHGH).[16] Alternative β forms denoted
β1i, β2i, and β5i can be expressed in hematopoietic cells in response to exposure to pro-inflammatory signals such as
cytokines, in particular, interferon gamma.  The proteasome assembled with these alternative subunits is known as
the immunoproteasome, whose substrate specificity is altered relative to the normal proteasome.[15]

19S regulatory particle

The 19S particle in eukaryotes consists of 19 individual proteins and is divisible into two subassemblies, a 10-protein
base that binds directly to the α ring of the 20S core particle, and a 9-protein lid where polyubiquitin is bound.  Six
of the ten base proteins are ATPase subunits from the AAA Family, and an evolutionary homolog of these ATPases
exists in archaea, called PAN (Proteasome-Activating Nucleotidase).[17] The association of the 19S and 20S particles
requires the binding of ATP to the 19S ATPase subunits, and ATP hydrolysis is required for the assembled complex
to degrade folded and ubiquitinated proteins.  Note that only the step of substrate unfolding requires energy from
ATP hydrolysis, while ATP-binding alone can support all the other steps required for protein degradation (e.g.,
complex assembly, gate opening, translocation, and proteolysis).[18] [19] In fact, ATP binding to the ATPases by
itself supports the rapid degradation of unfolded proteins.  However, while ATP hydrolysis is required for unfolding
only, it is not yet clear whether this energy may be used in the coupling of some of these steps.[19] [20] As of 2011,
the atomic structure of the 26S proteasome has not been solved, despite massive efforts to do so. Nevertheless, it is
understood, in general, how the 19S associates with and regulates the 20S core particle.[14] [21] In fact, the 19S and
11S particles bind to the same sites in the α rings of the 20S core particle although, they each induce gate opening by
different mechanism.[14]

Regulation of the 20S by the 19S

The 19S regulatory particle is responsible for stimulating the 20S to degrade proteins.  A primary function of the 19S
regulatory ATPases is to open the gate in the 20S that blocks the entry of substrates into the degradation chamber.[22]
The mechanism by which the proteasomal ATPase open this gate has been recently elucidated.[14] 20S gate opening,
and thus substrate degradation, requires the C-termini of the proteasomal ATPases, which contains a specific motif
(i.e., HbYX motif).  The ATPases C-termini bind into pockets in the top of the 20S, and tether the ATPase complex
to the 20S proteolytic complex, thus joining the substrate unfolding equipment with the 20S degradation machinery. 
Binding of these C-termini into these 20S pockets by themselves stimulates opening of the gate in the 20S in much
Proteasome 398

the same way that a "key-in-a-lock" opens a door.[14] The precise mechanism by which this "key-in-a-lock"
mechanism functions has been structurally elucidated.[23]

11S regulatory particle

20S proteasomes can also associate with a second type of regulatory particle, the 11S regulatory particle, a
heptameric structure that does not contain any ATPases and can promote the degradation of short peptides but not of
complete proteins.  It is presumed that this is because the complex cannot unfold larger substrates.  This structure is
also known as PA28 or REG.  The mechanisms by which it binds to the core particle through the C-terminal tails of
its subunits and induces α-ring conformational changes to open the 20S gate suggest a similar mechanism for the
19S particle.[24] The expression of the 11S particle is induced by interferon gamma and is responsible, in conjunction
with the immunoproteasome β subunits, for the generation of peptides that bind to the major histocompatibility
complex.[13]

Assembly
The assembly of the proteasome is a complex process due to the number of subunits that must associate to form an
active complex.  The β subunits are synthesized with N-terminal "propeptides" that are post-translationally modified
during the assembly of the 20S particle to expose the proteolytic active site.  The 20S particle is assembled from two
half-proteasomes, each of which consists of a seven-membered pro-β ring attached to a seven-membered α ring.  The
association of the β rings of the two half-proteasomes triggers threonine-dependent autolysis of the propeptides to
expose the active site.  These β interactions are mediated mainly by salt bridges and hydrophobic interactions
between conserved alpha helices whose disruption by mutation damages the proteasome's ability to assemble.[25] The
assembly of the half-proteasomes, in turn, is initiated by the assembly of the α subunits into their heptameric ring,
forming a template for the association of the corresponding pro-β ring.  The assembly of α subunits has not been
characterized.[26]
In general, less is known about the assembly and maturation of the 19S regulatory particles.  They are believed to
assemble as two distinct subcomponents, the ATPase-containing base and the ubiquitin-recognizing lid.  The six
ATPases in the base may assemble in a pairwise manner mediated by coiled-coil interactions.[27] The order in which
the nineteen subunits of the regulatory particle are bound is a likely regulatory mechanism that prevents exposure of
the active site before assembly is complete.[21]
Proteasome 399

The protein degradation process

Ubiquitylation and targeting

Proteins are targeted for degradation by the proteasome
by covalent modification of a lysine residue that
requires the coordinated reactions of three enzymes.  In
the first step, a ubiquitin-activating enzyme (known as
E1) hydrolyzes ATP and adenylylates a ubiquitin
molecule.  This is then transferred to E1's active-site
cysteine residue in concert with the adenylylation of a
second ubiquitin.[28] This adenylylated ubiquitin is then
transferred to a cysteine of a second enzyme,
ubiquitin-conjugating enzyme (E2).  In the last step, a
Ribbon diagram of ubiquitin, the highly conserved protein that serves
member of a highly diverse class of enzymes known as as a molecular tag targeting proteins for degradation by the
ubiquitin ligases (E3) recognizes the specific protein to proteasome
be ubiquitinated and catalyzes the transfer of ubiquitin
from E2 to this target protein.  A target protein must be labeled with at least four ubiquitin monomers (in the form of
a polyubiquitin chain) before it is recognized by the proteasome lid.[29] It is therefore the E3 that confers substrate
specificity to this system.[30] The number of E1, E2, and E3 proteins expressed depends on the organism and cell
type, but there are many different E3 enzymes present in humans, indicating that there is a huge number of targets
for the ubiquitin proteasome system.

The mechanism by which a polyubiquitinated protein is targeted to the proteasome is not fully understood. 
Ubiquitin-receptor proteins have an N-terminal ubiquitin-like (UBL) domain and one or more ubiquitin-associated
(UBA) domains.  The UBL domains are recognized by the 19S proteasome caps and the UBA domains bind
ubiquitin via three-helix bundles.  These receptor proteins may escort polyubiquitinated proteins to the proteasome,
though the specifics of this interaction and its regulation are unclear.[31]
The ubiquitin protein itself is 76 amino acids long and was named due to its ubiquitous nature, as it has a highly
conserved sequence and is found in all known eukaryotic organisms.  The genes encoding ubiquitin in eukaryotes are
arranged in tandem repeats, possibly due to the heavy transcription demands on these genes to produce enough
ubiquitin for the cell.  It has been proposed that ubiquitin is the slowest-evolving protein identified to date.[32]

Unfolding and translocation

After a protein has been ubiquitinated, it is recognized
by the 19S regulatory particle in an ATP-dependent
binding step.[19] The substrate protein must then enter
the interior of the 20S particle to come in contact with
the proteolytic active sites.  Because the 20S particle's
central channel is narrow and gated by the N-terminal
tails of the α ring subunits, the substrates must be at
least partially unfolded before they enter the core.  The
passage of the unfolded substrate into the core is called The ubiquitination pathway
translocation and necessarily occurs after
deubiquitination.[19] However, the order in which substrates are deubiquitinated and unfolded is not yet clear.[33]
Proteasome 400

Which of these processes is the rate-limiting step in the overall proteolysis reaction depends on the specific substrate;
for some proteins, the unfolding process is rate-limiting, while deubiquitination is the slowest step for other
proteins.[18] The extent to which substrates must be unfolded before translocation is not known, but substantial
tertiary structure, and in particular nonlocal interactions such as disulfide bonds, are sufficient to inhibit
degradation.[34]
The gate formed by the α subunits prevents peptides longer than about four residues from entering the interior of the
20S particle.  The ATP molecules bound before the initial recognition step are hydrolyzed before translocation. 
While energy is needed for substrate unfolding, it is not required for translocation.[35] [36] The assembled 26S
proteasome can degrade unfolded proteins in the presence of a non-hydrolyzable ATP analog, but cannot degrade
folded proteins, indicating that energy from ATP hydrolysis is used for substrate unfolding.[35] Passage of the
unfolded substrate through the opened gate occurs via facilitated diffusion if the 19S cap is in the ATP-bound
state.[37]
The mechanism for unfolding of globular proteins is necessarily general, but somewhat dependent on the amino acid
sequence.  Long sequences of alternating glycine and alanine have been shown to inhibit substrate unfolding
decreasing the efficiency of proteasomal degradation; this results in the release of partially degraded byproducts,
possibly due to the decoupling of the ATP hydrolysis and unfolding steps.[38] Such glycine-alanine repeats are also
found in nature, for example in silk fibroin; in particular, certain Epstein-Barr virus gene products bearing this
sequence can stall the proteasome, helping the virus propagate by preventing antigen presentation on the major
histocompatibility complex.[39]

Proteolysis
The mechanism of proteolysis by the β subunits of the 20S core
particle is through a threonine-dependent nucleophilic attack.  This
mechanism may depend on an associated water molecule for
deprotonation of the reactive threonine hydroxyl.  Degradation
occurs within the central chamber formed by the association of the
two β rings and normally does not release partially degraded
products, instead reducing the substrate to short polypeptides
typically 7–9 residues long, though they can range from 4 to 25
residues depending on the organism and substrate.  The
biochemical mechanism that determines product length is not fully
characterized.[40] Although the three catalytic β subunits have a
common mechanism, they have slightly different substrate
specificities, which are considered chymotrypsin-like, trypsin-like,
and peptidyl-glutamyl peptide-hydrolyzing (PHGH)-like.  These
A cutaway view of the proteasome 20S core particle
variations in specificity are the result of interatomic contacts with
illustrating the locations of the active sites.  The α
subunits are represented as green spheres and the β local residues near the active sites of each subunit.  Each catalytic
subunits as protein backbones colored by individual β subunit also possesses a conserved lysine residue required for
polypeptide chain.  The small pink spheres represent proteolysis.[16]
the location of the active-site threonine residue in each
subunit.  Light blue chemical structures are the
Although the proteasome normally produces very short peptide
inhibitor bortezomib bound to the active sites.
fragments, in some cases these products are themselves
biologically active and functional molecules.  Certain transcription
factors regulating the expression of specific genes, including one component of the mammalian complex NF-κB, are
synthesized as inactive precursors whose ubiquitination and subsequent proteasomal degradation converts them to an
Proteasome 401

active form.  Such activity requires the proteasome to cleave the substrate protein internally: rather than processively
degrading it from one terminus.  It has been suggested that long loops on these proteins' surfaces serve as the
proteasomal substrates and enter the central cavity, while the majority of the protein remains outside.[41] Similar
effects have been observed in yeast proteins; this mechanism of selective degradation is known as regulated
ubiquitin/proteasome dependent processing (RUP).[42]

Ubiquitin-independent degradation
Although most proteasomal substrates must be ubiquitinated before being degraded, there are some exceptions to
this general rule, especially when the proteasome plays a normal role in the post-translational processing of the
protein.  The proteasomal activation of NF-κB by processing p105 into p50 via internal proteolysis is one major
example.[41] Some proteins that are hypothesized to be unstable due to intrinsically unstructured regions,[43] are
degraded in a ubiquitin-independent manner.  The most well-known example of a ubiquitin-independent proteasome
substrate is the enzyme ornithine decarboxylase.[39] Ubiquitin-independent mechanisms targeting key cell cycle
regulators such as p53 have also been reported, although p53 is also subject to ubiquitin-dependent degradation.[44]
Finally, structurally abnormal, misfolded, or highly oxidized proteins are also subject to ubiquitin-independent and
19S-independent degradation under conditions of cellular stress.[45]

Evolution
The 20S proteasome is both ubiquitous and essential in
eukaryotes.  Some prokaryotes, including many archaea and the
bacterial order Actinomycetales also share homologs of the 20S
proteasome, whereas most bacteria possess heat shock genes hslV
and hslU, whose gene products are a multimeric protease arranged
in a two-layered ring and an ATPase.[46] The hslV protein has
been hypothesized to resemble the likely ancestor of the 20S
proteasome.[47] In general, HslV is not essential in bacteria, and
not all bacteria possess it, whereas some protists possess both the
20S and the hslV systems.[46]

Sequence analysis suggests that the catalytic β subunits diverged

earlier in evolution than the predominantly structural α subunits. 
In bacteria that express a 20S proteasome, the β subunits have high The assembled complex of hslV (blue) and hslU (red)
from E. coli.  This complex of heat shock proteins is
sequence identity to archaeal and eukaryotic β subunits, whereas
thought to resemble the ancestor of the modern
the α sequence identity is much lower.  The presence of 20S proteasome.
proteasomes in bacteria may result from lateral gene transfer,
while the diversification of subunits among eukaryotes is ascribed to multiple gene duplication events.[46]

Cell cycle control

Cell cycle progression is controlled by ordered action of cyclin-dependent kinases (CDKs), activated by specific
cyclins that demarcate phases of the cell cycle.  Mitotic cyclins, which persist in the cell for only a few minutes, have
one of the shortest life spans of all intracellular proteins.[2] After a CDK-cyclin complex has performed its function,
the associated cyclin is polyubiquitinated and destroyed by the proteasome, which provides directionality for the cell
cycle.  In particular, exit from mitosis requires the proteasome-dependent dissociation of the regulatory component
cyclin B from the mitosis promoting factor complex.[48] In vertebrate cells, "slippage" through the mitotic
checkpoint leading to premature M phase exit can occur despite the delay of this exit by the spindle checkpoint.[49]
Proteasome 402

Earlier cell cycle checkpoints such as post-restriction point check between G1 phase and S phase similarly involve
proteasomal degradation of cyclin A, whose ubiquitination is promoted by the anaphase promoting complex (APC),
an E3 ubiquitin ligase.[50] The APC and the Skp1/Cul1/F-box protein complex (SCF complex) are the two key
regulators of cyclin degradation and checkpoint control; the SCF itself is regulated by the APC via ubiquitination of
the adaptor protein, Skp2, which prevents SCF activity before the G1-S transition.[51]
Individual components of the 19S particle have their own regulatory roles.  Gankyrin, a recently identified
oncoprotein, is one of the 19S subcomponents that also tightly binds the cyclin-dependent kinase CDK4 and plays a
key role in recognizing ubiquitinated p53, via its affinity for the ubiquitin ligase MDM2.  Gankyrin is anti-apoptotic
and has been shown to be overexpressed in some tumor cell types such as hepatocellular carcinoma.[52]

Regulation of plant growth

In plants, signaling by auxins, or phytohormones that order the direction and tropism of plant growth, induces the
targeting of a class of transcription factor repressors known as Aux/IAA proteins for proteasomal degradation. 
These proteins are ubiquitinated by SCFTIR1, or SCF in complex with the auxin receptor TIR1.  Degradation of
Aux/IAA proteins derepresses transcription factors in the auxin-response factor (ARF) family and induces
ARF-directed gene expression.[53] The cellular consequences of ARF activation depend on the plant type and
developmental stage, but are involved in directing growth in roots and leaf veins.  The specific response to ARF
derepression is thought to be mediated by specificity in the pairing of individual ARF and Aux/IAA proteins.[54]

Apoptosis
Both internal and external signals can lead to the induction of apoptosis, or programmed cell death.  The resulting
deconstruction of cellular components is primarily carried out by specialized proteases known as caspases, but the
proteasome also plays important and diverse roles in the apoptotic process.  The involvement of the proteasome in
this process is indicated by both the increase in protein ubiquitination, and of E1, E2, and E3 enzymes that is
observed well in advance of apoptosis,[28] [55] [56] During apoptosis, proteasomes localized to the nucleus have also
been observed to translocate to outer membrane blebs characteristic of apoptosis.[57]
Proteasome inhibition has different effects on apoptosis induction in different cell types.  In general, the proteasome
is not required for apoptosis, although inhibiting it is pro-apoptotic in most cell types that have been studied. 
Apoptosis is mediated through disrupting the regulated degradation of pro-growth cell cycle proteins.[58] However,
some cell lines — in particular, primary cultures of quiescent and differentiated cells such as thymocytes and
neurons — are prevented from undergoing apoptosis on exposure to proteasome inhibitors.  The mechanism for this
effect is not clear, but is hypothesized to be specific to cells in quiescent states, or to result from the differential
activity of the pro-apoptotic kinase JNK.[59] The ability of proteasome inhibitors to induce apoptosis in rapidly
dividing cells has been exploited in several recently developed chemotherapy agents such as bortezomib and
salinosporamide A.

Response to cellular stress

In response to cellular stresses – such as infection, heat shock, or oxidative damage – heat shock proteins that
identify misfolded or unfolded proteins and target them for proteasomal degradation are expressed.  Both Hsp27 and
Hsp90—chaperone proteins have been implicated in increasing the activity of the ubiquitin-proteasome system,
though they are not direct participants in the process.[60] Hsp70, on the other hand, binds exposed hydrophobic
patches on the surface of misfolded proteins and recruits E3 ubiquitin ligases such as CHIP to tag the proteins for
proteasomal degradation.[61] The CHIP protein (carboxyl terminus of Hsp70-interacting protein) is itself regulated
via inhibition of interactions between the E3 enzyme CHIP and its E2 binding partner.[62]
Similar mechanisms exist to promote the degradation of oxidatively damaged proteins via the proteasome system.  In
particular, proteasomes localized to the nucleus are regulated by PARP and actively degrade inappropriately
Proteasome 403

oxidized histones.[63] Oxidized proteins, which often form large amorphous aggregates in the cell, can be degraded
directly by the 20S core particle without the 19S regulatory cap and do not require ATP hydrolysis or tagging with
ubiquitin.[45] However, high levels of oxidative damage increases the degree of cross-linking between protein
fragments, rendering the aggregates resistant to proteolysis.  Larger numbers and sizes of such highly oxidized
aggregates are associated with aging.[64]
Dysregulation of the ubiquitin proteasome system may contribute to several neural diseases.  It may lead to brain
tumors such as astrocytomas.[65] In some of the late-onset neurodegenerative diseases that share aggregation of
misfolded proteins as a common feature, such as Parkinson's disease and Alzheimer's disease, large insoluble
aggregates of misfolded proteins can form and then result in neurotoxicity, through mechanisms that are not yet well
understood.  Decreased proteasome activity has been suggested as a cause of aggregation and Lewy body formation
in Parkinson's.[66] This hypothesis is supported by the observation that yeast models of Parkinson's are more
susceptible to toxicity from α-synuclein, the major protein component of Lewy bodies, under conditions of low
proteasome activity.[67] Impaired proteasomal activity may underlie cognitive disorders such as the autism spectrum
disorders, and muscle and nerve diseases such as inclusion body myopathy.[65]

Role in the immune system

The proteasome plays a straightforward but critical role in the function of the adaptive immune system.  Peptide
antigens are displayed by the major histocompatibility complex class I (MHC) proteins on the surface of
antigen-presenting cells.  These peptides are products of proteasomal degradation of proteins originated by the
invading pathogen.  Although constitutively expressed proteasomes can participate in this process, a specialized
complex composed of proteins whose expression is induced by interferon gamma produces peptides of the optimal
size and composition for MHC binding.  These proteins whose expression increases during the immune response
include the 11S regulatory particle, whose main known biological role is regulating the production of MHC ligands,
and specialized β subunits called β1i, β2i, and β5i with altered substrate specificity.  The complex formed with the
specialized β subunits is known as the immunoproteasome.[13] Another β5i variant subunit, β5t, is expressed in the
thymus, leading to a thymus-specific "thymoproteasome" whose function is as yet unclear.[68]
The strength of MHC class I ligand binding is dependent on the composition of the ligand C-terminus, as peptides
bind by hydrogen bonding and by close contacts with a region called the "B pocket" on the MHC surface.  Many
MHC class I alleles prefer hydrophobic C-terminal residues, and the immunoproteasome complex is more likely to
generate hydrophobic C-termini.[69]
Due to its role in generating the activated form of NF-κB, an anti-apoptotic and pro-inflammatory regulator of
cytokine expression, proteasomal activity has been linked to inflammatory and autoimmune diseases.  Increased
levels of proteasome activity correlate with disease activity and have been implicated in autoimmune diseases
including systemic lupus erythematosus and rheumatoid arthritis.[13]
The proteasome is also involved in Intracellular antibody-mediated proteolysis of antibody bound virions.  In this
neutralisation pathway, TRIM21 (a protein of the tripartite motif family) binds with immunoglobulin G to direct the
virion to the proteasome where it is degraded.[70]
Proteasome 404

Proteasome inhibitors
Chemical structure of bortezomib, a proteasome
inhibitor used in chemotherapy that is particularly
effective against multiple myeloma
Proteasome inhibitors have effective anti-tumor activity in cell
culture, inducing apoptosis by disrupting the regulated degradation
of pro-growth cell cycle proteins.[58] This approach of selectively
inducing apoptosis in tumor cells has proven effective in animal
models and human trials.  Bortezomib, a molecule developed by
Millennium Pharmaceuticals and marketed as Velcade, is the first
proteasome inhibitor to reach clinical use as a chemotherapy
agent.[71] Bortezomib is used in the treatment of multiple
myeloma.[72] Notably, multiple myeloma has been observed to
result in increased proteasome levels in blood serum that decrease
to normal levels in response to successful chemotherapy.[73]
Studies in animals have indicated that bortezomib may also have
clinically significant effects in pancreatic cancer.[74] [75]
Preclinical and early clinical studies have been started to examine
bortezomib's effectiveness in treating other B-cell-related
cancers,[76] particularly some types of non-Hodgkin's
lymphoma.[77]

The molecule ritonavir, marketed as Norvir, was developed as a

Bortezomib bound to the core particle in a yeast
proteasome.  The bortezomib molecule is in the center
colored by atom type (carbon = pink, nitrogen = blue,
oxygen = red, boron = yellow), surrounded by the local
protein surface.  The blue patch is the catalytic
threonine residue whose activity is blocked by the
presence of bortezomib.
of asthma.[81]
protease inhibitor and used to target HIV infection.  However, it
has been shown to inhibit proteasomes as well as free proteases; to
be specific, the chymotrypsin-like activity of the proteasome is
inhibited by ritonavir, while the trypsin-like activity is somewhat
enhanced.[78] Studies in animal models suggest that ritonavir may
have inhibitory effects on the growth of glioma cells.[79]
Proteasome inhibitors have also shown promise in treating
autoimmune diseases in animal models.  For example, studies in
mice bearing human skin grafts found a reduction in the size of
lesions from psoriasis after treatment with a proteasome
inhibitor.[80] Inhibitors also show positive effects in rodent models

Labeling and inhibition of the proteasome is also of interest in laboratory settings for both in vitro and in vivo study
of proteasomal activity in cells.  The most commonly used laboratory inhibitors are lactacystin, a natural product
synthesized by Streptomyces bacteria,[59] and peptide MG132.  Fluorescent inhibitors have also been developed to
specifically label the active sites of the assembled proteasome.[82]

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Proteasome 408

External links
• Glickman, Michael H.; Adir, Noam (2004). "The Proteasome and the Delicate Balance between Destruction and
Rescue". PLoS Biology 2 (1): e13. doi:10.1371/journal.pbio.0020013. PMC 314468. PMID 14737189.
• The Yeast 26S Proteasome with list of subunits and pictures (http://biochemie.web.med.uni-muenchen.de/
feldmann/proteasome_units.html)
• Ciechanover, A (2005). "Early work on the ubiquitin proteasome system, an interview with Aaron Ciechanover".
Cell Death and Differentiation 12 (9): 1167–77. doi:10.1038/sj.cdd.4401691. PMID 16094393.
• Hershko, A (2005). "Early work on the ubiquitin proteasome system, an interview with Avram Hershko". Cell
Death and Differentiation 12 (9): 1158–61. doi:10.1038/sj.cdd.4401709. PMID 16094391.
• Adams, J (2005). "Early work on the ubiquitin proteasome system, an interview with Irwin Rose". Cell Death and
Differentiation 12 (9): 1162–6. doi:10.1038/sj.cdd.4401700. PMID 16094392.
• Cvek, B; Dvorak, Z (2007). "Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes
with metals." (http://www.benthamdirect.org/pages/content.php?CPD/2007/00000013/00000030/0010B.
SGM). Current pharmaceutical design 13 (30): 3155–67. doi:10.2174/138161207782110390. PMID 17979756.
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Ucanlookitup, Ultra-Loser, Ultraviolet scissor flame, Umbrah, Unessacary cencorship, Unholydoom99, Unionhawk, Universalss, Unrulyevil, Urhixidur, Uruiamme, User27091, UtherSRG,
Article Sources and Contributors 411

Vandaliz3, Vanderz, Vanished 6551232, Vanished User 3388458, Vanished user 03, VanishedUser314159, Vary, Velella, Verbal, Verne Equinox, VernoWhitney, Vernon39, Victor.reznov,
Vilcxjo, Vinmax, Vinty, Violabiola, Viridian, Viriditas, Virtualphtn, Visor, Vkap, Voltronladiesman, Vortexrealm, Vpendse, Vsmith, Vssun, Vuo, W guice, WCFrancis, WCar1930,
WadeSimMiser, Waggers, Wahrmund, Walkerma, Walsh family, Walton One, Waqqasd, Warrior4321, Wars, Warut, Watcharakorn, WaterCommunicator, Waterairfirearth, Waterjuice,
WatermelonPotion, Waterwise, Wavelength, Wayne Hardman, Wayne Slam, Wayward, Wdfarmer, Weasel5i2, Wereon, Wesley, Weyes, Whatnotwhat, Whatnwas, White Wolf,
White.matthew.09, Whomp, Wiggdaddy, Wik, Wiki alf, Wikify567, Wikimann132, Wikimol, WikipedianMarlith, Wikipelli, Wikiwhoodi, Wiktionary4Prez!, Will Beback, Willard, William
Ashe, William Avery, William M. Connolley, Wimt, Windsor Help Desk, Winston365, Wizard191, Wknight94, WojPob, Wolf ODonnell, Woodcore, Woohookitty, WordyGirl90, Wtshymanski,
Wuebker04, Wyroba, X2Xnorris, XJamRastafire, Xaosflux, Xavier13, Xcryoftheafflictedx, Xerxesnine, Xezlec, Xfinnegan3x, Xiahou, Xiutwel, Xompanthy, Xrchz, Xyzaxis, Xyzzyplugh,
Yagagakhee, Yamaguchi先生, Yamamoto Ichiro, Yandman, Yath, YellowMonkey, Yonatan, Youssef1110, Yvwv, Yzmo, Zachalope, Zachnobob, Zaheermerali, Zeosurfer, Zeromaru, Zhen Lin,
ZimZalaBim, Zinnmann, Zombie621, Zondor, Zotel, Zpop101, Zurishaddai, Zven, Zzuuzz, Zé da Silva, Ævar Arnfjörð Bjarmason, Александър, 百家姓之四, 2548 anonymous edits

Nucleic acid  Source: http://en.wikipedia.org/w/index.php?oldid=462085002  Contributors: 168..., 2 of 8, A4, Abrech, Acelgoyobis, Adam Bishop, Addshore, Agathman, Alansohn, Alboyle,
Alex43223, Alexius08, Anclation, Andre Engels, Angela, Anthere, Antony-22, Antzervos, Aoi, Arakunem, Araucaria, Arbitrarily0, Armin Straub, Astronautics, AxelBoldt, Babyranks17,
Barticus88, Beethoven's DNA, Beetstra, Bensaccount, Bobchicken9, Bobo192, Bongwarrior, CDN99, CL, CLW, Cacycle, Can't sleep, clown will eat me, Careless hx, Ceyockey, Chanoyu,
ChaosR, Chillowack, ChrisCork, ChrisHodgesUK, Ciphers, Conversion script, Courcelles, Cpeditorial, Cyan, DARTH SIDIOUS 2, Daniel5127, DarkFalls, DerHexer, Desireader, Discospinster,
Dng267, Dposse, Dungodung, Dysprosia, EconoPhysicist, Ed Poor, Ellmist, Emw, Forluvoft, Frankenpuppy, Franz Bryan, FreplySpang, G3pro, Gaia Octavia Agrippa, GeeJo, Gentgeen,
GeorgeLouis, Giftlite, Gilliam, Gogo Dodo, GraemeL, Graft, Grunty Thraveswain, Gurch, Gwernol, Hede2000, Hellow yo, Hellowhy, Hephaestos, Hu, Hydrogen Iodide, I dream of horses, Inka
888, It Is Me Here, J Di, J.delanoy, JForget, JMBurke1791, James086, Jauhienij, Jhannah, Joanjoc, John Mackenzie Burke, John R Murray, JonMoulton, Josh Cherry, Josh Grosse, Julesd, K3f3rn,
Kablammo, Kalaiarasy, Kandar, Kbdank71, Keegan, Kierano, KimvdLinde, Kkmurray, Kpjas, Kyle 290, LAX, La goutte de pluie, Laurascudder, Leonard Vertighel, Lexor, Lfh, Liamdaly620,
Lir, Looie496, Luna Santin, LyXX, M80forYOU, Magog the Ogre 2, Marudubshinki, Maurice Carbonaro, Mav, Maxxicum, Mendaliv, Miaow Miaow, Mikegrant, Misza13, Mlouns, My76Strat,
Mygerardromance, Narayanese, Narsil, NellieBly, NewEnglandYankee, Ngourlie, Nirmos, Nk, Nposs, NuclearWarfare, Omicronpersei8, Onco p53, OrangeDog, Oxymoron83, P99am, Pakaran,
Petrb, Pgan002, Pharaoh of the Wizards, Philip Trueman, Piano non troppo, Pobregatita, Polypipe Wrangler, Popnose, Possum, Ppgardne, Ppntori, Preston.hussey, Pschemp, RJaguar3, Rcej,
Res2216firestar, Rifleman 82, Rjwilmsi, Ronhjones, SJP, Salamurai, Salvio giuliano, Scharks, Schmutz MDPI, Sciurinæ, Seba5618, Sgpsaros, ShellCoder, Shuipzv3, Simeon H, Sintaku,
SixPurpleFish, Smack, Smaug123, Snoyes, Sonicology, SpikeToronto, Squidonius, Stephen5406, Stewartadcock, Str1977, Strathallen, Tad Lincoln, Talon Artaine, Teles, The Thing That Should
Not Be, TheTito, Thehelpfulone, Thingg, Tide rolls, Tim1357, TimVickers, TimonyCrickets, Tommy2010, Trevor MacInnis, Tuganax, U.S.A.U.S.A.U.S.A., Ugen64, Uncle Dick, User A1,
VIOLENTRULER, Vary, Versus22, Violetriga, Vrenator, W3bj3d1, Waggers, Wayne Slam, Wikipedia addict101, Wimt, Wisdom89, Wysprgr2005, Xdenizen, Yachtsman1, Yk Yk Yk,
Yngvadottir, Yoenit, Ziusudra, 594 anonymous edits

RNA  Source: http://en.wikipedia.org/w/index.php?oldid=464368076  Contributors: 2013schwarzkopfn, 209.234.79.xxx, 28421u2232nfenfcenc, 4chanb, 7, 9Nak, A-giau, Aa battery2003,
Aaronatwpi, Abbhinand, Acroterion, AdamRetchless, Adenosine, AdjustShift, Agathman, Ahoerstemeier, Aitias, Alansohn, Ale jrb, Alethiophile, Alex43223, Alexbateman, Algumacoisaqq,
Alikhtarov, Allikendr1, Allstarecho, Alsager boy, Anclation, Andre Engels, Andrea105, Andres, Andycjp, Animeronin, Anoop2000, Anthony Appleyard, Anturiaethwr, Arcadian, Arlindos,
Arnesh, Aron.Foster, Arthena, Astronautics, AxelBoldt, BENWD33333, Bbrucebaker, Bdesham, Bear15987, Beethoven's DNA, Beland, Bensaccount, Bettia, Bilrand, Black88rabbit, Bmicomp,
Bobo192, Bongwarrior, Boppet, Bornhj, BrianHansen, Bryan Derksen, Butterball888, CART fan, CIreland, Cacycle, Calton, Can't sleep, clown will eat me, CardinalDan, Cflm001, Chaojoker,
ChazYork, Chino, Chrislk02, Closedmouth, Cmh, Codetiger, Courcelles, Crimsonfox, Crum375, Ctbolt, Cyc, DRosenbach, DVD R W, Daddyerinenoch, Daniel Olsen, Darth Smith, Dave101,
Davidmpye, Davish Krail, Gold Five, Davykamanzi, DeYoung9, Deadfishstyx, Debatebob, Delta G, Deor, Derek Ross, Derek.cashman, Dfrendewey, Diberri, Dino, Djaboube, DogcatcherDrew,
Dr.Kerr, Drbogdan, Drmed36, Drphilharmonic, Duncan.france, Duncharris, Dureo, EWikist, Edison, EdwardLane, Ekirth, El0i, Eleassar, Eleuther, Enviroboy, Eubulide, Eupedia, Evolver, Exir
Kamalabadi, Explicit, Fabrictramp, Fedra, Firien, Flauto Dolce, Forluvoft, Fæ, Gadfium, Gail, Gaius Cornelius, Gamaliel, GcSwRhIc, Gdarin, Giftlite, GkiwiPD, Glane23, Glenn, Goldfinger820,
Graft, Graham87, GrahamColm, GreatWhiteNortherner, Greengiant9875, Gsandi, Gtstricky, Guoguo12, HJ Mitchell, Hadal, Harold f, HaveAHappyJBDay, Hichris, Hu12, I dream of horses, II
MusLiM HyBRiD II, Ian.thomson, Ibbn, Icairns, Ihavewon, Indiealtphreak, Indosauros, Ipodamos, Ixfd64, J.delanoy, JMBurke1791, JMK, JNW, Jadeddissonance, JanDaMan, Jauhienij, Jay
Litman, Jcorry10, Jearbear34, Jebus989, Jh51681, Jleecole, Jmanigold, Jmcc150, John, John Mackenzie Burke, Johnuniq, Joker99352, JonMoulton, Jonemerson, Jonverve, Jorunn, Josh Cherry,
Jossi, Jtkiefer, Jules.lt, Jumbuck, Jusdafax, Kabewm, Ke6jjj, Keesiewonder, KeithTyler, King of the Court, KingTT, Kinu, KnowledgeOfSelf, Kuru, Kurzon, Kyoko, L Kensington, Lascorz,
Leuko, Lexor, Li-sung, Liamdaly620, Lir, LittleOldMe, Littlealien182, Logan, Longhair, Lozeldafan, MAKSIMYUSHKOV, MER-C, Macboots, Madurai1982, Magister Mathematicae, Magnus
Manske, Malcolm Farmer, Mandarax, MarcoTolo, Marj Tiefert, MarvPaule, Mashin6, Mastrnacho9, Mattman723, Maximaximax, MichaelHa, Mikael Häggström, Mike2vil, MirankerAD,
Misza13, Miyagawa, Mr d logan, MrZap, Munita Prasad, NHRHS2010, Narayanese, Natarajanganesan, Natseea, Neoguy999115, NerdyScienceDude, Neverquick, Nihiltres, Nimavojdani,
Northfox, Nposs, Oda Mari, Olleicua, Ollj, Onco p53, OttoMäkelä, P99am, PDH, Pascal666, Perfecto, Pgk, PhilKnight, PierreAbbat, Pinethicket, Ppgardne, Pschemp, PuzzletChung, Pvosta,
RMFan1, RadioFan2 (usurped), Rallyemax, Rcej, RexNL, Rich Farmbrough, Richard001, RickK, Rjwilmsi, Rnaactivation, Roadsoap, Rob.bastholm, Romanm, RoseAE, RoyBoy, Saflksahfdl,
Salvio giuliano, Sam Korn, Sannse, Sardaukar Blackfang, Sazzlysarah, Scarian, Scientizzle, Seaphoto, Selket, Sephirothjms, Shanel, Shizhao, Shoeofdeath, SimonP, SimpsonMA, Sjlegg,
Slowking Man, Smalljim, Smelissali, Sodium, Some jerk on the Internet, Speciate, Splette, Sponk, SpookyMulder, Spring, Squidonius, Sriram sh, Srlasky, Sunny876, Suruena, Sverdrup, Syeda
Hassan Rabia, TakuyaMurata, Tbhotch, Tegel, Tegiap, TestPilot, The Anome, The High Fin Sperm Whale, The Nut, The Thing That Should Not Be, The Wordsmith, Tide rolls, Tim bates,
TimVickers, Tinz, Tktktk, Toddst1, Touchstone42, Trampikey, TransControl, TreasuryTag, Tree Biting Conspiracy, Tresiden, Trusilver, Umirox, Unconcerned, Unmerklich, Usna, Uthbrian,
Veinor, Versus22, Vespristiano, Violetriga, Vishnava, Voloshinov, Vossman, Vrenator, Vsmith, W8TVI, WarthogDemon, Wavemaster447, Westcairo, WikHead, Wikieditor06, Wikipelli,
WillowW, Wknight94, Wmoss2, Woodsrock, Woohookitty, WriterHound, Xuul, Yahel Guhan, Yikrazuul, Yobol, Yurivict, Zack, Zashaw, Zntrip, Zoeb, Zotti6464, Zzuuzz, පසිඳු කාවින්ද, 俠刀行,
852 anonymous edits

DNA  Source: http://en.wikipedia.org/w/index.php?oldid=463729977  Contributors: (, (jarbarf), -Majestic-, 168.., 168..., 169, 17Drew, 2over0, 3dscience, 4u1e, 62.253.64.xxx, 7434be, 84user, A
D 13, A bit iffy, A-giau, AManWithNoPlan, Aaaxlp, Aatomic1, Academic Challenger, Acather96, Acer, Adam Bishop, Adambiswanger1, Adamstevenson, Adashiel, Adenosine, Adrian.benko,
Ahoerstemeier, Airconswitch, Aitias, Aj123456, Alai, Alan Au, Aldaron, Aldie, Alegoo92, Alexandremas, Alkivar, Alphachimp, Alzhaid, Amboo85, Anarchy on DNA, Ancheta Wis, Andonic,
Andre Engels, Andrew wilson, Andreww, Andrij Kursetsky, Andycjp, Anita1988, Anomalocaris, Antandrus, Ante Aikio, Anthere, Anthony, Anthony Appleyard, Antilived, Antony-22, Aquaplus,
Aquilla34, ArazZeynili, Arcadian, Ardyn, Argionember, ArielGold, Armored Ear, Artichoker, Artoasis, Asbestos, Ashnard, Astronautics, Astrowob, Atlant, Aude, AustralianRupert, Autonova,
Avala, Avicennasis, AxelBoldt, AySz88, AzaToth, B, BD2412, BMF81, Banus, BaronLarf, Bbatsell, Bci2, Bcorr, Ben Webber, Ben-Zin, BenBildstein, Bender235, Benjah-bmm27, Bensaccount,
Bernie Sanders' DNA, Bert Macklin, Bevo, Bhadani, Bhar100101, BiH, Bijee, BikA06, Bill Nelson's DNA, Billmcgn189, Biolinker, Biriwilg, Bjwebb, Bkell, Blastwizard, Bloger, Blondtraillite,
Bmtbomb, Bobblewik, Bobo192, Boghog, Bongwarrior, Borisblue, Bornhj, Brian0918, Brighterorange, Briland, Brim, Brockett, Bruce1ee, Bryan, Bryan Derksen, Bubba73, CWY2190, Cacycle,
Caerwine, Cainer91, Cal 1234, Calabe1992, Calaschysm, Can't sleep, clown will eat me, Canadaduane, Carbon-16, Carcharoth, Carlo.milanesi, Carlwev, Carstensen, Casliber, Cathalgarvey,
CatherineMunro, CattleGirl, Causa sui, Cburnett, Cerberus lord, Chaboura, Chanora, Chanting Fox, Chaojoker, Charm, Chick Bowen, Chill Pill Bill, Chino, Chodges, Chris 73, Chris84, Chuck
Grassley's DNA, Chuck02, Cinnamon colbert, Clivedelmonte, Cloakedyoshi, ClockworkSoul, CloudNine, Collins.mc, Colorajo, CommonsDelinker, Conversion script, Cool3, Coolawesome,
Coredesat, Cornacchia123, Cosmotron, Cradlelover123, Crazycomputers, Crowstar, Crusadeonilliteracy, CryptoDerk, Crzrussian, Cubskrazy29, CupOBeans, Curehd, Curps, Cyan, Cyclonenim,
Cyrius, D6, DARTH SIDIOUS 2, DIREKTOR, DJAX, DJRafe, DNA EDIT WAR, DNA is shyt, DVD R W, Daniel Olsen, Daniel987600, Danielkueh, Danny, Danny B-), Danski14, Darklilac,
Darth Panda, Davegrupp, David D., David Eppstein, Davidartois, Davidbspalding, Dawn Bard, Daycd, Db099221, Dbabbitt, Dbfirs, Dcoetzee, DeAceShooter, DeadEyeArrow, Delldot, Delta G,
Deltabeignet, DevastatorIIC, Diberri, Dicklyon, Diego Grez, Digger3000, DigitalGhost, Digitalme, Dina, Djm1279, Dlohcierekim's sock, Dmn, Dnacond, DocWatson42, Docjames, Doctor Faust,
Docu, Dogposter, DonSiano, Donarreiskoffer, Dr d12, Dr.Kerr, Drbogdan, Drphilharmonic, Drpickem, Ds2207, Dudewheresmywallet, Dullhunk, Duncan.france, Dungodung, Dysmorodrepanis,
E. Wayne, ERcheck, ESkog, Echo park00, Echuck215, EdJohnston, Eddycrai, Editing DNA, Edwy, Efbfweborg, Effeietsanders, Egil, ElTyrant, Elb2000, Eleassar777, EliasAlucard, ElinorD,
Ellmist, Eloquence, Emoticon, Empty Buffer, Emw, Ephemeronium, Epingchris, Erik Zachte, ErrantX, Escape Artist Swyer, Esurnir, Etanol, Ettrig, EurekaLott, Everyking, Evil Monkey,
Ewawer, Excirial, Execvator, FF2010, FOTEMEH, Fabhcún, Factual, Fagstein, Fastfission, Fconaway, Fcrick, Fernando S. Aldado, Ffirehorse, Figma, Figure, Firetrap9254, Fishingpal99,
Flavaflav1005, Florentino floro, Fnielsen, Forluvoft, Freakofnurture, FreplySpang, Friendly Neighbour, Frostyservant, Fruge, Fs, Fvasconcellos, G3pro, GAThrawn22, GHe, GODhack, GVnayR,
Gaara san, Gakrivas, Galoubet, Gary King, Gatortpk, Gazibara, GeeJo, Gene Nygaard, GeoMor, Giftiger wunsch, Giftlite, Gilisa, Gilliam, Gimmetrow, Gjuggler, Glen Hunt's DNA, Glenn,
Gmaxwell, GoEThe, Goatasaur, Gogo Dodo, GoldRingChip, Golnazfotohabadi, GordonWatts, GorillaWarfare, Gracenotes, Graeme Bartlett, GraemeL, Grafikm fr, Graft, Graham87,
GrahamColm, Grandegrandegrande, GregorB, Grover cleveland, Gurko, Gustav von Humpelschmumpel, Gutza, Gwsrinme, HJ Mitchell, Hadal, Hagerman, Hairchrm, Hairwheel, Hammersoft,
Hannes Röst, Harianto, HayleyJohnson21, Headbomb, Heathhunnicutt, Hephaestos, Heron, Hersfold, Hersfold tool account, Heyheyhack, Hockey21dude, Horatio, Hu, Hughdbrown,
Hurricanehink, Hut 8.5, Hvn0413, Hzh, I hate DNA, Ialsoagree, Iapetus, Icairns, Ilia Kr., Impamiizgraa, InShaneee, Inge-Lyubov, IronGargoyle, Isilanes, Isis07, Itub, Ixfd64, Izehar, JForget,
JHMM13, JWSchmidt, JWSurf, JZuehlke, Jacek Kendysz, Jackrm, JamesMLane, JamesMt1984, Janejellyroll, Jarhed, Javert, Jaxl, Jeka911, Jer ome, JeremyA, Jerzy, Jetsetpainter, Jh51681,
Jiddisch, Jim1138, Jimriz, Jimwong, Jlh29, Jls043, Jmcc150, Jnorton7558, JoanneB, Joconnol, Joeywallace9, Johanvs, John Mackenzie Burke, JohnArmagh, Johntex, Johnuniq, Jojit fb,
JonMoulton, Jonrunles, Jonverve, Jorge Stolfi, Jorvik, JoshuaZ, Josq, Jossi, Jrtayloriv, Jstech, Jujutacular, Julian Diamond, Jumbo Snails, Junes, Juneythomas, Jwrosenzweig, Kahlfin, Kapow,
Karrmann, Katyare, Kaushlendratripathi, Kazkaskazkasako, Kbh3rd, Kbrose, Keegan, Keepweek, Keilana, Kelly Martin, Kemyou, Kendrick7, KerryO77, Kevin B12, Kevmitch, Kghose,
Kholdstare99, Kierano, KimvdLinde, King of Hearts, KingTT, Kingturtle, Kitch, Knowledge Seeker, KnowledgeOfSelf, Koavf, KrakatoaKatie, Kums, Kungfuadam, Kuru, Kwamikagami,
Kwekubo, L Kensington, LA2, LFaraone, La goutte de pluie, Lascorz, Latka, Lavateraguy, Lee Daniel Crocker, Leevanjackson, Lemchesvej, Leptictidium, Lerdsuwa, Leuko, Lexor, Lfh,
Lhenslee, Lia Todua, LightFlare, Lightmouse, Lightspeedchick, Ligulem, LikeLakers2, Lincher, Lion Wilson, Lir, Llongland, Llull, Lockesdonkey, Logical2u, Loginbuddy, Looxix, Loren36,
Loris, Low-frequency internal, Luigi30, Luk, Lumos3, Luna Santin, Luuva, MER-C, MKoltnow, MONGO, MSGJ, Mac, Madeleine Price Ball, Madhero88, Magadan, Magister Mathematicae,
Magnus Manske, Majorly, Malcolm rowe, Malo, Mandarax, Mandyj61596, Mantissa128, Marcus.aerlous, Marj Tiefert, Martin.Budden, MarvPaule, Mashin6, Master dingley, Materialscientist,
Mattbr, Mattbrundage, Mattjblythe, Maurice Carbonaro, Mav, Max Baucus' DNA, Max Naylor, McDogm, Medessec, Medos2, Melaen, Melchoir, Mentalmaniac07, Mgiganteus1, Mgtoohey,
Mhking, Michael Devore, MichaelHa, Michaelas10, Michigan user, MidgleyDJ, Midnightblueowl, Midoriko, Mika293, Mike Rosoft, Mikker, Mikko Paananen, Minimac, Mintman16,
MisfitToys, Misza13, Mithent, Mjpieters, Mleefs7, Moink, Moorice, Mortene, Motley Crue Rocks, Mr Bungle, Mr Meow Meow, Mr Stephen, MrErku, Mstislavl, Mstroeck, Mulad, Munita
Article Sources and Contributors 412

Prasad, Muro de Aguas, Mwanner, Mxn, Nakon, Nanettea, Nanodance, Narayanese, Natalie Erin, Natarajanganesan, Nate1028, NatureA16, Nauseam, Nbauman, Neckro, Netkinetic, Netoholic,
Neutrality, Never give in, NewEnglandYankee, Nick Number, Nighthawk380, NighthawkJ, Nihiltres, Nirajrm, Nishkid64, Nitecrawler, Nitramrekcap, No Guru, NoIdeaNick, NochnoiDozor,
Nohat, Nono64, Northfox, NorwegianBlue, Nthornberry, NuclearWarfare, Nunh-huh, OBloodyHell, OOODDD, Obli, Oblivious, Ocaasi, Ocolon, OekelWm, Ojl, Omicronpersei8, Onco p53,
Opabinia regalis, Opelio, Orphan Wiki, Orrin Hatch's DNA, Orthologist, Ortolan88, Ouishoebean, Outriggr, OwenX, P99am, PDH, PFHLai, PaePae, Pakaran, Pascal666, Patrick0Moran,
Patrick2480, Patstuart, Paul Foxworthy, Paul venter, Paulinho28, Pcb21, Pde, Peak, Pedro, Perseus, Son of Zeus, Persian Poet Gal, Peter Isotalo, Peter K., Peter Winnberg, Pgan002, Philip
Trueman, PhilipO, Phoenix Hacker, Pierceno, PierreAbbat, Pifactorial, Pigman, Pigmietheclub, Pilotguy, Pkank, Pkirlin, Poor Yorick, Portugue6927, Potatoswatter, Prathfig, Preston47,
Prestonmag, Priscilla 95925, Pristontale111, Pro crast in a tor, Prodego, Psora, PsyMar, Psymier, Pumpkingrower05, Pyrospirit, Quebec99, Quickbeam, Qutezuce, Qxz, R'n'B, R. S. Shaw,
RDBrown, RJC, RJaguar3, RK, RSido, Ragesoss, Rajwiki123, RandomP, Randomblue, Raul654, Raven in Orbit, Ravidreams, Rdb, Rdsmith4, Red Director, Reddi, Rednblu, Redneckjimmy,
Redquark, Retired username, Rettetast, RexNL, Rezecib, Rich Farmbrough, RichG, Richard Durbin's DNA, Ricky81682, Rishi.bedi, Rjwilmsi, Roadnottaken, Robdurbar, RobertG, Rocastelo,
RoddyYoung, Rory096, Rotem Dan, Roy Brumback, RoyBoy, RoyLaurie, Royalguard11, Rr2wiki, RunOrDie, Russ47025, RxS, RyanGerbil10, Ryulong, S77914767, SCEhardt, STAN
SWANSON, SWAdair, Sabbre, Safwan40, Sakkura, Salix alba, SallyForth123, Sam Burne James, Samsara, Samuel, Samuel Blanning, SandyGeorgia, Sango123, Sangwine, Savidan, Scarce,
Sceptre, Schapel, Schutz, Sciencechick, Scincesociety, Sciurinæ, Scope creep, Scoterican, Sean William, SeanMack, Seans Potato Business, Seb az86556, SebastianHawes, Seldon1,
SemperBlotto, Sentausa, Serephine, Sgt. R.K. Blue, Shadowlynk, Shanes, ShaunL, Shekharsuman, Shizhao, Shmee47, Shoy, SimonD, Simultaneous, Sintaku, Sir.Loin, Sjjupadhyay, Sjollema,
Sloth monkey, Slrubenstein, Sly G, SmilesALot, Smithbrenon, Snowmanradio, Snowolf, Solipsist, Someone else, Sonett72, Sopoforic, Spaully, Spectrogram, Spiff, Splette, Spondoolicks,
Spongebobsqpants, SpuriousQ, Squidonius, Squirepants101, Statsone, Steel, Steinsky, Stemonitis, Stephenb, SteveHopson, Stevertigo, Stevietheman, Stewartadcock, Stuart7m, Stuhacking,
SupaStarGirl, Supreme Deliciousness, Supspirit, Susvolans, Sverdrup, Swid, Switchercat, Taco325i, Takometer, TakuyaMurata, Tariqabjotu, Tarret, Taulant23, Tavilis, Tazmaniacs, Tbhotch, Ted
Longstaffe, TeleComNasSprVen, Tellyaddict, TenOfAllTrades, Terraguy, Test100000, TestPilot, The Man in Question, The Rambling Man, The WikiWhippet, TheAlphaWolf, TheChrisD,
TheGrza, TheKMan, TheRanger, Theodolite, ThoHug, Thorwald, ThreeDaysGraceFan101, Thue, Tiddly Tom, Tide rolls, TigerShark, TimVickers, Timewatcher, Timir2, Timl2k4,
Timrollpickering, Timwi, Tobogganoggin, Toby Bartels, TobyWilson1992, Tom Allen, Tom Harkin's DNA, Tomgally, Toninu, Tony1, Tonyrenploki, Toto Azéro, Tpbradbury, Travelbird,
Trd300gt, Trent Lott's DNA, Triwbe, Troels Arvin, Tryptofish, Tstrobaugh, Tufflaw, Turnstep, Twilight Realm, Ty146Ty146, UBeR, Ucucha, Uluru345, Unconventional, Unint, Unukorno,
Usergreatpower, Username 772, Utcursch, Ute in DC, Uthbrian, Vaernnond, Vandelizer, Vanished user, Vary, Virtualphtn, Visium, Vividonset, VladimirKorablin, Vogel2014, Vsmith, Vyasa,
WAS 4.250, WAvegetarian, WHeimbigner, WJBscribe, Wafulz, WarthogDemon, Wavelength, WelshMatt, West Brom 4ever, Where, Whosasking, Whoutz, Why My Fleece?, Wik, Wiki alf,
Wiki emma johnson, Wikiborg, Wikipedia Administration, Will Beback Auto, William Pietri, WillowW, Wimt, Wizardist, Wkboonec, Wknight94, Wmahan, Wnt, Wobble, WolfmanSF,
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Protein  Source: http://en.wikipedia.org/w/index.php?oldid=462352893  Contributors: 0, 162.129.26.xxx, 168..., 200itlove, 8472, A K AnkushKumar, A-giau, AA, ABF, Aarktica, Aaron Schulz,
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Amino acid  Source: http://en.wikipedia.org/w/index.php?oldid=464057628  Contributors: 134.95.200.xxx, 1tennisstar15, 213.253.39.xxx, ABCD, Aardtek, Aboveleft, Access Denied,
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Article Sources and Contributors 413

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Properties of the twenty amino acids  Source: http://en.wikipedia.org/w/index.php?oldid=455045516  Contributors: Aa77zz, Arcadian, BenJWoodcroft, Benlisquare, BrentN, Cacycle,
Capricorn42, ChipperGuy, Chris Roy, Cpt ricard, DMacks, Dancojocari, Drphilharmonic, Edgar181, Eloil, Erechtheus, Flakinho, Gregogil, Gurch, Hichris, Itub, Jackroven, Keenan Pepper,
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Myoglobin  Source: http://en.wikipedia.org/w/index.php?oldid=457628794  Contributors: Adrian J. Hunter, Aitias, AndrewGNF, Anonymi, Antandrus, AnteaterZot, Arcadian, Atakdoug, Atlant,
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Hemoglobin  Source: http://en.wikipedia.org/w/index.php?oldid=464437569  Contributors: AWeenie, Abscissa, Achaemenes, AdrianaW, Ahoerstemeier, Aka ninja69, Alain.michalowicz,
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Article Sources and Contributors 414

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Biological membrane  Source: http://en.wikipedia.org/w/index.php?oldid=463308948  Contributors: 168..., Aceofhearts1968, Adashiel, Adrian J. Hunter, Aejohnst, Alan Liefting, Alansohn,
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Cell membrane  Source: http://en.wikipedia.org/w/index.php?oldid=464055323  Contributors: 168..., 1exec1, 6osama9, 7cg43m, ABF, AThing, Academic Challenger, Access Denied,
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Xeno, Xkfusionxk, Yancyfry jr, Yobol, Youssefsan, Yunshui, Zephyris, Zundark, Zzuuzz, ‫ﮐﺎﺷﻒ ﻋﻘﯿﻞ‬, 1429 anonymous edits

Polysaccharide  Source: http://en.wikipedia.org/w/index.php?oldid=461576748  Contributors: 0, 28421u2232nfenfcenc, 777sms, Alexius08, Androsyn, Andycjp, Anthonyhcole, Anypodetos,
Architpuri, Ardric47, Baldhur, BenFrantzDale, Bensaccount, Blue520, Bobo192, Boghog, Br77rino, Bryan Derksen, CanadianLinuxUser, Cfailde, Chemicus 234, Chimpex, Chuq, Cjb88,
Conversion script, CrazyChemGuy, Crl620, Da Joe, DaGizza, Dai mingjie, David Shear, Dhp1080, Discospinster, DocWatson42, Donarreiskoffer, Drthomasj, E. Fokker, El C, Ephemeronium,
Article Sources and Contributors 415

Eras-mus, Eric-Wester, Esoltas, Ettrig, Eubulides, EugeneZelenko, Farglator, Fieldday-sunday, Fragmaroom, Fredrik, G3pro, Gabix, Ghazer, Gits (Neo), Glennwells, Glycoform, GregorB,
Gscshoyru, Guillaume Ponchel, Gurch, Gwguffey, H Padleckas, Hadal, Hardrada, Harland1, HenkvD, HiDrNick, Hugo-cs, Hyalite, IRP, Imichigan2, Imoen, Insanephantom, Iohannes Animosus,
Iridos, Irvinefan, J.delanoy, Jatlas, Jazz man jeans, Jeff G., Jimrharvey, Kanags, Kandar, KangAK, Kaveish, Kenyon, Kirill Lokshin, Kleopatra, Kobeisbeast, Kostisl, Ks0stm, Kukini, Kupirijo,
Kuru, LachlanA, Lbthrice, Lir, MER-C, Magister Mathematicae, Marj Tiefert, Markgriz, Melintelinas, Mentifisto, Mikael Häggström, Mikemoral, Mobile Snail, Nephron, NickBush24, Nirmos,
Nonagonal Spider, Numbo3, OlaIsacsson, Orayzio, Owenozier, Oz Spinner, Paroxysm, Passw0rd, Persian Poet Gal, Pfortuny, Phgao, Piano non troppo, Ptr123, RaoInWiki, Res2216firestar,
Rfc1394, Rhys, Richard001, SamuelTheGhost, Sango123, Seancasey00, Securiger, SemperBlotto, Sentausa, Sietse Snel, Silence of the Yams, Sir Vicious, SpeedyGonsales, Stewartadcock,
Tenbaset, The MoUsY spell-checker, The number c, Theodore Kloba, Throwaway85, Tide rolls, TimVickers, Touchstone42, Tsemii, Versageek, Vuts, Wayne Slam, West.andrew.g,
WikipedianMarlith, Woohookitty, Yk Yk Yk, Zctglassman83, ~K, 284 anonymous edits

Overview of metabolism  Source: http://en.wikipedia.org/w/index.php?oldid=461664732  Contributors: - ), .:Ajvol:., A8UDI, AVand, Aaaaaactually, Aacac, Ababababa1, Acroterion, Adam
Hasheesh, AdjustShift, Adrian J. Hunter, Agentilini, Ahoerstemeier, Aitias, Alai, Alan Au, Alan Liefting, Alex.muller, Algumacoisaqq, Allstarecho, Alpha1337Saint, Amaher, Ampersand777,
Anaxial, AndreasJS, Androstachys, Anna Lincoln, Antandrus, Arcadian, Aremith, ArielGold, Arthena, AshLin, Ashleyisachild, BD2412, BarretBonden, Batmanand, Beetstra, Bensaccount,
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CattleGirl, Cheeserules214, Cheklevara, Citicat, Closedmouth, Colin, Colonies Chris, CommonsDelinker, Conversion script, Cryptographic hash, DARTH SIDIOUS 2, DMacks, DSRH,
Dabomb87, David D., Deanos, Der Spion, Diberri, Dipics, Discospinster, Docu, Dos Perros Estupidos, Drwickerson, Dto, Edderso, EdwardLane, El C, Element16, Ellenshuman, Emw, Enchanter,
Enigmaman, Epbr123, Ericoides, Etxrge, Excerpted31, Ezhuttukari, Fanghong, Fconaway, Femto, Fenteany, FireBrandon, Fredrik, Fvasconcellos, GNRY09, Gambori, Giftlite, Gjd001, Glenn,
Gmcfoley, Gohornets23, Gracenotes, Graham87, Gunnar Hendrich, H.kittredge, HJ Mitchell, Hallenrm, Harryboyles, Headbomb, HexaChord, Hordaland, Hubba, Hurriquake, IW.HG,
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Lightmouse, Lilac Soul, Linusgreen, Lir, Looxix, M.e, MK8, MPerel, Mac, Macowell, Madeleine Price Ball, Magnus Manske, Mahmudmasri, Marc Venot, Marek69, McSly, Mcat2, Mclal1pt1,
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Mygerardromance, NYKevin, NawlinWiki, NickBush24, NuclearWarfare, Nunquam Dormio, Onco p53, Opabinia regalis, Outriggr, OverlordQ, Oxymoron83, PDH, Patho, Pedrora, Petergans,
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edits

Glycolysis  Source: http://en.wikipedia.org/w/index.php?oldid=464400388  Contributors: - ), Abarry, Agpetern, Aka042, Albacore, Alex F., AlexCruise, Alhead, Alice.odin, Allstarecho, Alnokta,
AlphaEta, Alteripse, Andre Engels, Andres, Andrewpmk, Anetode, Arcadian, ArglebargleIV, Arthena, AubreyEllenShomo, AxelBoldt, Barticus88, Bensaccount, Bento00, Bogey97,
Bongwarrior, BorisTM, Brenont, Bryan Derksen, Bucketsofg, Buttholationszee, CBSB, CTZMSC3, Calvin 1998, Can't sleep, clown will eat me, CanisRufus, Cburnett, Ceyockey, Cheez277,
Choij, Clicketyclack, Colin, Conversion script, Ctbolt, Cyberman, D-rew, Darsie, David D., Daycd, Dburson, Delldot, Delta G, Demian12358, Dempsey1717, DevilsAdvocate, Diberri,
Dlamming, Dmdukes, Dnvrfantj, Dono, Drphilharmonic, Dude1818, Dullhunk, EconomicsGuy, Ekton, Element16, Elonka, Elronxenu, Enviroboy, Epbr123, Erianna, EricWesBrown, Etxrge,
Evergreen vsh007, Exor674, Fenteany, FreplySpang, Friginator, Fuzlyssa, Fvasconcellos, G00nsf, G3pro, Gaius Cornelius, Gcm, Geoking66, Giftlite, Gimboid13, Glane23, Graham87,
GraybeardBiochemist, Gtstricky, Gurch, Gurubrahma, Hadal, Harbinary, HexaChord, HoodedMan, Ibrmrn3000, Igotlotsaquarters, Ilphin, Isnow, Iwilcox, J. Finkelstein, J.delanoy, JDoorjam,
JForget, JHunterJ, JTN, JWSchmidt, JaGa, Jack the Stripper, Jack.schonbrun, Jag123, Jakob Theorell, Jauhienij, Jeff G., Jeffscott007, JeramieHicks, Jimhsu77479, Jmarchn, Jmauser, Joehall45,
JohnnyCalifornia, Jojit fb, Jonas094, Josh Cherry, Jotomicron, Jrockley, JuanitaJP, K. Hiippari, Kaarel, Kandar, KathrynLybarger, Khullah, Kirez, Kjaergaard, Kramtark, Krylonblue83,
Laportechicago, Larry_Sanger, Lentower, Lexivore, Lightmouse, Lilac Soul, Logan, Magister Mathematicae, Magnus Manske, Malcolm Farmer, Manticore, Marc Isaacs, Marcelo1229, Marj
Tiefert, Markacohen, Maximaximax, Meco, Meggar, Michall, MicroProf, Microbrain, Mifter, Miguel.mateo, Mikael Häggström, Mindmatrix, Miquonranger03, Mohawkjohn, Mpatel, Mplona,
Munkee, N5iln, Narayanese, Navdar, Naveen57, Niccus, NightFalcon90909, Northumbrian, Nuttcrakerr, Oatmeal batman, OccamzRazor, OliAtlason, Opabinia regalis, Pakaran, Paulwithap,
Pedvi, Pelirojopajaro, PhilANThropiSt, Pinethicket, PloniAlmoni, Plrk, Pmokeefe, Polypipe Wrangler, Popnose, Prav001, Pred7799, RainbowOfLight, Ravnoor, Recnilgiarc, Reedy, Registrar,
RetiredWikipedian789, Rhodekyll, Richard Arthur Norton (1958- ), Richard001, Righthing, Rjwilmsi, Roland Kaufmann, Ronhjones, Rozzychan, Ruzha, RyanGerbil10, Ryanreednro, SCEhardt,
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SouthernNights, Spamburgler, Spencerw, Speshuldusty, Stepa, Super tom2, Superdoggy, Svetlana Miljkovic, Swmmr1928, Szxd, Tekks, The Rambling Man, The Thing That Should Not Be,
Thehelpfulone, TicketMan, TimVickers, Tito4000, TsunadeSama, TutterMouse, Uhai, Una Smith, Use the force, Vin268, Wiki alf, Wikieditor06, Williamb, Wimt, Wknight94, Wolfinbm,
Yappy2bhere, YassineMrabet, Yerpo, Yraser, Yuorme, Z0OMD, Zargulon, Zephyris, Zoicon5, 535 anonymous edits

Gluconeogenesis  Source: http://en.wikipedia.org/w/index.php?oldid=463554773  Contributors: Accurizer, AhsenM, AlexCruise, Anand Karia, Arcadian, Avenged Eightfold, Axl, BVBede,
Barefootmatt, Bomac, Bubba hotep, CDN99, Calvero JP, Can't sleep, clown will eat me, Captain-n00dle, Chao, Clicketyclack, Crux, Dbrouse, Dcirovic, Diberri, Download, Drphilharmonic,
Edgar181, El C, Finlay McWalter, GraybeardBiochemist, Gökhan, Ibrmrn3000, Iknewwhereelectricitycomesfrom, Isnow, JaGa, Jag123, Jeppelbaum, Jmarchn, Jojhutton, Jyril, Kawta
maderchoud55, Kubanczyk, La goutte de pluie, Leptictidium, Lova Falk, Malljaja, Mcstrother, Michall, Michaplot, Mikael Häggström, Mikr18, Mjharrison, Molkhal, Neelix, Nerd, OverlordQ,
PL290, Pedrora, Pro crast in a tor, Richard001, Rod57, Rsabbatini, SCEhardt, Sandstein, Scoutersig, Seren-dipper, Shahriyar alavi, Skaaii, Someone87, TFOWR, Taral, TimVickers, Tristanb,
Turgonml, Una Smith, Unused0026, Uthbrian, Vojtech.dostal, Wafulz, Waves00, Wimjongman, Wolingfeng, Yale2013, Zanimum, 146 anonymous edits

Glycogen  Source: http://en.wikipedia.org/w/index.php?oldid=457697601  Contributors: 28421u2232nfenfcenc, AThing, Adamcieslicki, Agathoclea, Ahda, Ahltorp, Akamad, Akxcskier, Ale jrb,
Allstarecho, Alteripse, Arbitrarily0, Arcadian, Arthena, BRSM, Banus, Beetstra, Ben Thuronyi, Bencherlite, Bensaccount, Bhadani, BillFlis, Bomac, BorisTM, Bryan Derksen, Bunchofgrapes,
CDN99, Carbuncle, Cecilyen, Cederal, CeresVesta, Chem-awb, Chris Capoccia, CommonsDelinker, Copperman2011, Craigsjones, DanCAK, Darklilac, Darth Panda, Delta G, DocWatson42,
Drc79, Drphilharmonic, EJF, Edward, Enviroboy, Epbr123, Eric Shalov, Ettrig, Excirial, Fedir, Freestyle-69, GJeffery, Giftlite, Gilliam, Girlwithgreeneyes, GorillaWarfare, Hadal, Hbent, Hchoe,
Hongsy, Imoen, Jag123, Jambobambo, JamesAM, Jjayson, Jjron, Jmun7616, JorisvS, Jusdafax, JustAddPeter, Kanags, Kawta maderchoud556, Lewisskinner, Liaocyed, Lijealso, Looxix, MR
Deidra, Magnus Manske, Mattbrundage, McDogm, Michael Shields, Mikael Häggström, Mike Rosoft, Mj455972007, Mjharrison, Mmortal03, Narayanese, Ng.j, Nihiltres, Nirmos, Nutriveg,
Nxl256, Ohnoitsjamie, P.s. hua, PDH, Peter K., Physchim62, Pinethicket, Poktirity, Pro crast in a tor, Reconsider the static, Renato Caniatti, RexNL, Rfc1394, Richard001, Rjwilmsi, Ronhjones,
Rsabbatini, Sandstein, Securiger, Sethkatz, Shrimp wong, SietskeEN, Sir Vicious, Sjakkalle, Solidpoint, Sonjaaa, Spencerw, Stubblyhead, Taishaku, The sanch, Thegreenj, Tmcclell, Tminus65,
Tnxman307, Tonyle, Vedran12, Vrenator, WATerian, Whosasking, Wickey-nl, WikipedianMarlith, Wikiwooroo, WiseUmos, WriterHound, Ww, Xenonice, XxClayTheBossxX, XxNeXuSxX,
Zombiejesus, Zuma212, ~K, 이형주, 268 anonymous edits

Pentose phosphate pathway  Source: http://en.wikipedia.org/w/index.php?oldid=455031335  Contributors: -VL-, Adenosine, Anneli1, Arcadian, Bryan Derksen, Cepheus 5, Chtit draco,
CopperKettle, Dhorspool, Drphilharmonic, Edgar181, El C, Eras-mus, Eug, Fvasconcellos, Gabbe, GdenBesten, Ge Tianfang, Giftlite, GraybeardBiochemist, Horiavulpe, Isnow, Jag123, Jffre,
John Riemann Soong, Kazkaskazkasako, Kupirijo, Lrunge, Materialscientist, MiPe, Narayanese, Nina Gerlach, Nonagonal Spider, PatríciaR, Pcampeau, Pelirojopajaro, Shahriyar alavi,
Shoeofdeath, SkyMaja, Steinsky, Tagishsimon, Tahmmo, TimVickers, Time9, Xris0, Yikrazuul, 90 anonymous edits

Citric acid cycle  Source: http://en.wikipedia.org/w/index.php?oldid=464219279  Contributors: 1029x, 129.186.19.xxx, A bit iffy, AC+79 3888, AManWithNoPlan, Aa77zz, AdamRetchless,
Adenosine, AdultSwim, Alansohn, Alba, Aldaron, AlexanderPico, Andrea105, Animum, Antandrus, Arcadian, Arctic Night, Ashcraft, AxelBoldt, Basicsharingwatuknow!, Baxter9, Bdesham,
Bensaccount, Bernlomnty, Bluedustmite, Boghog, BorisTM, BrettAllen, Brian0918, Bryan Derksen, Butwhatdoiknow, CDN99, Cadsuane Melaidhrin, CaitlinG, Capricorn42, CardinalDan,
Castiron, Catbar, Charleschuck, Chibibrain, Christopher Parham, Christopherlin, ClamDip, Clicketyclack, ClockworkSoul, CoeurDeLion, Conversion script, Cquan, Craigy144, Crana, Curtholr,
Cyberman, DGG, DRHagen, DVirus101, Da Joe, DarkoV, Darsie, Davewho2, David D., Dawn Bard, Daycd, DeadEyeArrow, Delta G, Deor, Discospinster, Dj Capricorn, Djmccoul,
Dlrohrer2003, Dnvrfantj, Docboat, DrNixon, Drestros power, Drphilharmonic, Dryphi, Dwmyers, ESkog, Eleuther, Elronxenu, Enviroboy, Epingchris, Everyking, Eviternity, Freakmighty,
Ghettobrown, Giftlite, Gilliam, Gimboid13, GraybeardBiochemist, Gwernol, Gwib, H Padleckas, Haham hanuka, Imaninjapirate, Iridescent, Isfisk, J.delanoy, JForget, JG1440, Jackollie, Jag123,
Jesse Viviano, Jfdwolff, Jiang, Jiwhit01, Jlsmaddden, John D. Croft, John Lake, Johner, Jojit fb, Jose Ramos, Josh Cherry, JuanitaJP, Julianonions, Jyril, Kaidenet, Kandar, Katoa, Kawta
maderchoud, Kelovy, Kim Bruning, KoleTang, KrebsCycle, L Kensington, Lachoy11, Lexor, Lir, Luci Sandor, Luigifan, MER-C, Madeinsane, Magicxcian, Magnus Manske, Malljaja, Marek69,
Mark Patterson, Marqueed, Mav, MercuryBlue, Mgiganteus1, Michael Shields, Microbrain, MisterDub, Mkweise, Mohawkjohn, Mpatel, Mushin, Narayanese, Nbauman, Nchaimov, Nihiltres,
Nike tick, Nilmerg, Nomad2u001, Nucleusboy, ODoyle040, Oatmeal batman, Onco p53, OwenBlacker, Peak, Philip Trueman, Piano non troppo, Pion, Plasmic Physics, Pontificalibus,
ProfessorAM, Profoss, Pschemp, Qcomplex5, Rdphair, Rhino8, Rich Farmbrough, Richard001, Rjwilmsi, Rob Hooft, Ronhjones, Ryan Postlethwaite, Ryanreednro, SJP, Sardino, Sbfw,
ScAvenger lv, Scattered Lights, Scigatt, Seaphoto, Selket, Semper discens, Serein (renamed because of SUL), Shahriyar alavi, Shrimp wong, Shureg, Skeksys, SkyWalker, Slipstream, Snellios,
Sojoho09, Spaully, Spoladore, Stewartadcock, Student7, THEN WHO WAS PHONE?, Tarquin, Technopat, Thatother1dude, The Hybrid, Thegeneralguy, TimVickers, Tknight1011,
ToematoeAdmn, Tokhtuev, Trnoriega, Turmerick, Ugen64, Ultratomio, Vanderesch, VsevolodKrolikov, Weird Bird, Wik, WriterHound, YassineMrabet, YellowMonkey, Zarel, Zeeroid,
Zephyris, Ziga, 455 anonymous edits
Article Sources and Contributors 416

Oxidative phosphorylation  Source: http://en.wikipedia.org/w/index.php?oldid=454686404  Contributors: Abstraktn, Adenosine, Alan Liefting, Alnokta, Antelan, Anton Gutsunaev, Arcadian,
Art LaPella, AshLin, Bahar101, Bensaccount, Bobo192, Borgx, BorisTM, Brenont, Brighterorange, Bryan Derksen, Can't sleep, clown will eat me, Chris Rodgers, Clicketyclack,
CommonsDelinker, Conversion script, CopperKettle, Crazycomputers, Cst17, DJ Clayworth, DMacks, Danny, Davaith, David D., Dcirovic, Dj Capricorn, Drphilharmonic, Dwmyers, EerieNight,
El C, Epbr123, Eribro, Espresso Addict, Etxrge, Eubulides, Faramir333, Fvasconcellos, Gaius Cornelius, Graham87, GraybeardBiochemist, Habj, Harryboyles, Hodja Nasreddin, IKenny, IRP,
Ijustam, Imjustmatthew, J.delanoy, JWSchmidt, Jag123, Jamouse, Josh Cherry, Jpg, Julianonions, Jwollbold, Kakli, Kozuch, Laurip, LedgendGamer, Leonard^Bloom, Leptictidium,
Lesviolonsdautomne, Lilac Soul, MITBeaverRocks, Macowell, Marj Tiefert, Materialscientist, Maxim Gavrilyuk, Michael Devore, Mikael Häggström, Mwucherer, Narayanese, Nhandler,
Nono64, Nwbeeson, ParticleMan, Persian Poet Gal, Philgoetz, Piledhigheranddeeper, Pinkadelica, Plugs0, RDBrown, Rakwiki, Rich Farmbrough, Richard001, Richard0612, Rjwilmsi,
Semitallsmalls, Shahriyar alavi, Simpsons contributor, Slowpokeiv, Smokefoot, Smurrayinchester, Some jerk on the Internet, Some standardized rigour, StaticGull, Stepa, Stewartadcock,
StradivariusTV, Suruena, Tameeria, TimVickers, Treisijs, Ttownfeen, Ulisse0, Verticalstall, Wavelength, Wmpearl, WolfmanSF, WriterHound, Xp54321, Zephyris, 156 anonymous edits

Photosynthesis  Source: http://en.wikipedia.org/w/index.php?oldid=462428021  Contributors: (jarbarf), *drew, -- April, 1exec1, 28421u2232nfenfcenc, 678910, 9258fahsflkh917fas, @pple,
AJRM, ASKingquestions, ATMarsden, Abductive, Abu-Fool Danyal ibn Amir al-Makhiri, Academic Challenger, Accuruss, Adashiel, Adenosine, Agathman, Ahoerstemeier, Aidentbrown,
Aitias, Alan Liefting, Alansohn, Alexius08, Ali, Ali salter, Alksub, Amatulic, Amercer09, AmiDaniel, Amorymeltzer, Andris, AndyZ, Angam, Angela, Angr, AnonMoos, Anonymi, Ans,
Antandrus, AnthonyQBachler, Antony2, Apokryltaros, Aranea Mortem, Arcadian, Arjun01, Art LaPella, At09kg, Atrian, Aut1221, Avicennasis, AxelBoldt, B820, BGFMSM, Bailey654,
BanyanTree, Barras, Bateman1234, Bayerischermann, Bbatsell, Beetstra, Ben-Zin, Bencherlite, Bendzh, Bento00, Bergsten, Bertiethecat, Bfahome, Bhadani, Billare, Blahed768, Bluedeed,
Bobo192, Boghog, Boing! said Zebedee, Bonadea, Bongwarrior, Bookandcoffee, Bowlhover, Brainmachine, Bryan Derksen, Burnhamd, CERminator, CQJ, CWY2190, Cacycle, Calabe1992,
Call me Bubba, Caltas, CalumH93, Camw, Can't sleep, clown will eat me, CanadianLinuxUser, Canterbury Tail, CardinalDan, Cassius987, Causa sui, Cayte, Cbrown1023, Cdorman2, Celarnor,
CerealKiller, Ceyockey, Chamal N, Chao, Chasingsol, Cheesy Yeast, Chepry, Chirpy7, Chlor, Chodorkovskiy, ChrisHodgesUK, Chrislk02, Chun-hian, Cimex, Ciphergoth, Ckatz, Clicketyclack,
ClockworkSoul, ClockworkTroll, Closedmouth, Clubjuggle, Clyde10race, Cman12345657578, Cmdrjameson, Coching, Cohesion, Collegedegree, Color probe, ComCat, Commander,
CommonsDelinker, Condem, Consequencefree, Conversion script, Corrigen, Courcelles, Crazychinchilla, Crazytales, Creidieki, Crittens, Crystallina, CurtisSwain, Cyde, Cyrius, DARTH
SIDIOUS 2, DVD R W, DaGizza, Dacrycarpus, Daharde, Dandv, Daniel233, Daniel5127, DanielCD, Danny B-), Dar-Ape, Darekun, Darklich14, Darklilac, Dasyornis, Davewild, David D.,
David Wahler, DavidDidwin, DavidWBrooks, Daycd, Db099221, Dbenbenn, Dbrett480, Debresser, Decltype, Delfigolo, Delta G, Demi s96, Demiurge, Deor, DerHexer, Derekrhu, Devil42400,
Dfrg.msc, Dienamight, Dina, Dinsdalea, Dirty MF Harry, Discospinster, Dj Capricorn, Domminico, Doniago, Dori, DotComCairney, Dr. Mandellez, DrMtl, Drdaveng, Dreadstar, Dreg743,
Drphilharmonic, Dsinghs, Dullhunk, Dungodung, Dweller, Dwmyers, Długosz, EScribe, ESkog, Eaglestrike117, EarthPerson, EconoPhysicist, Ed, Edderso, Eddturtle, Eeekster, Eik Corell,
Eleassar, Elmer Clark, EncycloPetey, Epbr123, Epipelagic, EqualMusic, Eric Kvaalen, Etacar11, Ettrig, Etxrge, Eumeng.chong, Evercat, Everyking, Evil Monkey, Excirial, FF2010, Fahadsadah,
Faithlessthewonderboy, Feezo, Feniouk, Fenteany, Fermion, Fgbhrgthnrtgnb, FocalPoint, Fox6453, Fram, Freakofnurture, Fredrik, FreplySpang, Frymaster, Fullmetal123321, Funnybunny,
Funper, Fvw, GHe, GTBacchus, Gacha1, Gadfium, Gaff, Gaius Cornelius, Gary King, GeeJo, GeeOh, Gekedo, Gene Nygaard, Germen, Gggh, Ghewgill, Giftlite, Gigemag76, Gilderien, Gilliam,
Ginkgo100, Glenn, Goatman12, Govindjee, GregAsche, GregMinton, Gregturn, Grondemar, Gruzd, Guettarda, Guoguo12, Gwernol, HBNayr, HLHJ, Hadal, Haham hanuka, HalfShadow, Hans
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Rowsdower, Zarniwoot, Zedla, Zepheus, Zfr, ZooFari, Zvn, Zxoxm, రవిచంద్ర, 2154 anonymous edits

Fatty acid synthesis  Source: http://en.wikipedia.org/w/index.php?oldid=450714507  Contributors: AlexanderPico, Arcadian, AvicAWB, Azo bob, Bochyboch, Chodid, Clicketyclack,
Colinc719, Cow2001, Ctrlaltdelete200390, D6, Dcirovic, Drphilharmonic, Fizzyfifi, Giraffedata, GraybeardBiochemist, Hubba, Itub, Jaypg, John of Reading, Knopfkind, Kubanczyk, Leafyplant,
Luci Sandor, Mtuttle, NikeTenis, OG Clriley, Ojii-san, Panoramix303, Pro crast in a tor, RE73, RShorty30, Rjwilmsi, Skaaii, SkyMaja, Tommy2010, Yikrazuul, Zachlipton, 39 anonymous edits

Lipogenesis  Source: http://en.wikipedia.org/w/index.php?oldid=459445784  Contributors: Amog, Arcadian, Chodid, Colinc719, Ctrlaltdelete200390, Drphilharmonic, Ed7654, Gensanders,
Gökhan, Keenan Pepper, Ksero, Kubanczyk, Leptictidium, LittleT889, Paul August, Pelirojopajaro, Plico, RDBrown, Rich Farmbrough, Shrimp wong, Snellios, 61 anonymous edits

Acetyl-CoA carboxylase  Source: http://en.wikipedia.org/w/index.php?oldid=447826665  Contributors: Adeez, Alexhlau, Alnokta, Arcadian, Bfx0, Boghog, BorisTM, EagleFan, Edward,
Frietjes, GraybeardBiochemist, Im.a.lumberjack, J G Campbell, Jimhsu77479, Luuva, M gehrig2000, Mikael Häggström, Muhandes, Mushin, Nw.NPC, RainR, Rb1248, Reaper Eternal, Saxbryn,
Sbmehta, Shrimp wong, SimonP, Slaporte, The wub, Tom harrison, Waldroplab, WikHead, Woohookitty, Xris0, Yottie, 29 anonymous edits

Fatty acid degradation  Source: http://en.wikipedia.org/w/index.php?oldid=418315617  Contributors: Arcadian, Clicketyclack, Haripandit, Kubanczyk, Mikael Häggström, Nick Number, Rich
Farmbrough, Richard001, Synchronism, ThinkerThoughts, Walkerma, Wmpearl, WolfmanSF, Δ, 4 anonymous edits

Beta oxidation  Source: http://en.wikipedia.org/w/index.php?oldid=464183482  Contributors: -VL-, AC+79 3888, Abdull, Abrech, Arcadian, Aurista25, Beamoflaser, Bogdangiusca,
Bunnyhop11, C.Fred, Chibibrain, Christian75, Clicketyclack, ClockworkSoul, Coolstoryhansel, Darklilac, Dawhitfield, Dcirovic, Dmanagadze, Dono, Dr. Ambitious, Drocra, Drphilharmonic,
Eumeng.chong, Grafen, GraybeardBiochemist, Haripandit, HkCaGu, Hyalos, Jeyradan, Jstanley, Krylonblue83, Langthorne, Lecj77, Lemchesvej, LinkinPark, LoneSeeker, Magairlin, Mastee,
MauchoEagle, Meaganrock, Meph636, Mushin, NEUROtiker, Narfaniel, Natarajanganesan, Nitroblu, Oddity-, Paxse, Physchim62, RShorty30, Silkblackrose, Spongefrog, Stepa, Su-no-G,
Taskualads, TimVickers, Tomifly, V8rik, Velella, Vivekanand23, Vojtech.dostal, Wmpearl, Zerkalox, Zink53, Zoidbergness, 73 anonymous edits

Nitrogen fixation  Source: http://en.wikipedia.org/w/index.php?oldid=463457356  Contributors: 129.128.164.xxx, 2D, A2Kafir, Alansohn, Andrewlevy, Andyman1125, AnonGuy, Ashmoo,
Ashnard, Atubeileh, Auró, Avinashraut, Bakabaka, Beland, Bender235, Bendzh, Bkurl, Bob Burkhardt, Br77rino, Brian Crawford, Bryan Derksen, Butterflied, C S, Cacycle, Callior, CanisRufus,
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Article Sources and Contributors 417

XRK, Yersinia, Yobol, Zazil, Zombiejesus, 270 anonymous edits

Amino acid synthesis  Source: http://en.wikipedia.org/w/index.php?oldid=441364518  Contributors: Arcadian, Avs5221, Dan East, Diderot's dreams, Drphilharmonic, Edgar181, Elonka,
Giftlite, Keenan Pepper, Leptictidium, Littlealien182, Mirabellen, Nutriveg, Pedro-kun, Phlounder, Redheylin, Rockfang, Shrimp wong, Welsh, Wingedsubmariner, Woohookitty, Zephyris, 14
anonymous edits

Nucleotide  Source: http://en.wikipedia.org/w/index.php?oldid=464450294  Contributors: 2T, Access Denied, AdamRetchless, Adenosine, Adrian J. Hunter, Aliasd, Amorymeltzer, Andre
Engels, Andrejj, Antony-22, Arcadian, Baa, Banus, Bart133, Blakethegundork, Bobo192, Bomac, BorisTM, Bornhj, Breno, Brettyfxu, BrianKnez, Brona, Bryan Derksen, Buttonius, CWenger,
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edits

Urea cycle  Source: http://en.wikipedia.org/w/index.php?oldid=463357512  Contributors: 217.98.151.xxx, Andre Engels, Arcadian, AxelBoldt, BorisTM, Brighterorange, Brim, Bryan Derksen,
Cacycle, Ceyockey, Clicketyclack, Conversion script, Dennis Myts, Doprendek, Drphilharmonic, Dwmyers, Edgar181, Elano, Gaius Cornelius, Gludwiczak, GraybeardBiochemist, Hammaad,
Imz, Jfdwolff, JohnCD, Jugger90, La goutte de pluie, Linkminer, Materialscientist, MiPe, Mira.juanc, Nicke L, Nono64, Nuno Tavares, Onco p53, PDH, Paolo.dL, Patho, Pedrora, Physchim62,
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Wouterstomp, Yikrazuul, Zephyris, 72 anonymous edits

Hormone  Source: http://en.wikipedia.org/w/index.php?oldid=464316108  Contributors: 28421u2232nfenfcenc, 613 The Evil, 661kts, A2Kafir, A8UDI, AThing, Acdx, Adeez, Ahoerstemeier,
Alansohn, Ale And Quail, Aleenf1, Alexamies, Alison, Alteripse, Andre Engels, Andruxo, Arcadian, ArchonMagnus, Arthena, Artie p, B.wilson, Banus, Barney-12-3, Barrylb, Beetstra,
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gasboy, Ervance, Escape Orbit, Euryalus, Evolauxia, Ffsgoogle, Filippowiki, Foobar, Foxbat21, Fratrep, Freakofnurture, Free Bear, Fuzzform, G3pro, Gail, Giftlite, Gleng, Glenn, Godspet,
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Be, TheFearow, Thingg, Tide rolls, TimVickers, Tom Morris, Tommy2010, Toreau, Travelbird, Traxs7, Tristanb, Troop350, Turnaround3, Useight, Vala M, Vanderesch, Verklighet, Versus22,
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Wysprgr2005, X990, Xlilmelly32x, Xornok, Youandme, Youssefsan, Zannah, Zefr, Zelfverwijzing, Zfr, 598 anonymous edits

Signal transduction  Source: http://en.wikipedia.org/w/index.php?oldid=464481670  Contributors: 168..., 217.228.10.xxx, Adapter, Alberrosidus, Aliekens, Alisonchilla@yahoo.com, Andre
Engels, AndrewGNF, Andycjp, Arcadian, Arnero, Auntof6, AxelBoldt, Banus, Barbaking, Biochemza, Biologos, Bisc import, Boghog, Cacycle, CaesarAugustus7791, CanisRufus, Cessagian,
Charles Matthews, ChicXulub, Ciar, Clicketyclack, ClockworkSoul, CommonsDelinker, Conversion script, Cseoighe, DabMachine, Darkwind, David.Throop, Dcirovic, Deejoe, Derek Ross,
Dpryan, Droll, Drphilharmonic, Durova, Edgar181, Ekotkie, Eleassar, Emw, Erik Zachte, Erxnmedia, Fgibson30, Forluvoft, Freak in the bunnysuit, Freywa, GaryColemanFan, Genalipsis,
Gracejc25, Gracenotes, Graham87, Hedgehog33, Hideshi, Hodja Nasreddin, Holopoj, Howard McCay, Hypermagus, Itskkumaran, J.delanoy, JDspeeder1, JWSchmidt, Jagowins, Jfdwolff,
Jonkerz, K.murphy, Katemend, Kusma, LA2, Lapabc, Law, Lexor, LilHelpa, Locogato, Loren.wilton, MacDaid, MacGyverMagic, Magnus Manske, Malcolm Farmer, Mandolinface, Mangostar,
MarcoTolo, Master gopher, Mav, Mikael Häggström, Mikemoral, Minnsurfur2, Moisture, Motyka, Mr d logan, NawlinWiki, Nbauman, NickOsborn, NighthawkJ, Nina Gerlach, Nono64,
Ohconfucius, OldakQuill, Orange Suede Sofa, PFHLai, Pabloes, Peak, Peter Znamenskiy, Ph.eyes, Poccil, Pproctor, R. S. Shaw, REACHist, RainbowOfLight, RedWolf, Redheylin,
Remindmelater, Rich Farmbrough, Rjwilmsi, Rnakatsuji, Roadnottaken, Rocket000, Rokfaith, Sakkura, Samsara, Sapphic, ShoziKT, Sjiang11, Sjoerd de Vries, Skittleys, Slaporte, Slashme,
Someone else, Sordner, Spellcast, Suaudeau, Sue Larson, Suffusion of Yellow, Supten, TaintedCherub, Technopat, Tevildo, TimVickers, Tiny cookie ninja, Tristanb, Vaultdoor, Warkocur,
Whosasking, Williamb, Wisdom89, Woohookitty, Wynand.winterbach, Y4tell, Ychastnik APL, Yk Yk Yk, 185 anonymous edits

Diabetes mellitus  Source: http://en.wikipedia.org/w/index.php?oldid=462912618  Contributors: 01214410, 1297, 1ForTheMoney, 2 of 8, 28421u2232nfenfcenc, 4wajzkd02, A bit iffy, A.R.,
A455bcd9, A8UDI, ABF, AED, AGToth, AJCham, Aaron Kauppi, Aaron Simon, Abaute, Abellina, Adambigmac, AdultSwim, Aetkin, Afaprof01, Agapetos angel, Agateller, Ahoerstemeier,
Aitias, Al-khowarizmi, Alansohn, Alchav, AlcheMister, Aleenf1, Alex.tan, Alexander0884, Alexandria, Alexius08, Alexlinsker@gmail.com, AliaGemma, AlistairMcMillan, Alteripse,
Anarchist42, Anaxial, Andreas Toth, AndreasJS, Andres, Andrew73, AndrewHowse, Andrewpayneaqa, Andrewr47, Angela, AnimalMother, Animum, Aniten21, Anjik, Anlace, Ann Stouter,
Anna Frodesiak, Annalise, Annekcm, Anonymous251, Ant62493, Antandrus, AnthroGael, Antnoah, Antonio Lopez, AntonioMartin, Apeplinskie, Arcadian, Ardo191, Areyouinparis, ArielGold,
Arjun01, Arny, Artephius, Arthena, Arunjithp, Astanhope, AuburnPilot, Auntof6, Auslander99, AxelBoldt, Axl, Ayotte, Aytrus, Az1568, BF2MCplaya4life, BGOATDoughnut, Baa, Bachrach44,
Badgettrg, Bahruth, BaldMonkey, Barek, Barrymahon, Barticus88, Bavaro47, Bayerischermann, Baylink, Bcd760, BearGuard, Beetstra, Bellthorpe, Bender235, Benebenbike, Benny 142,
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BuckeyeRowe, BuickCenturyDriver, Burelom, Bücherwürmlein, C.brian.taylor@gmail.com, CDN99, CJGB, CO, CSyver, Calaka, Caltas, Calvin 1998, CambridgeBayWeather, Camw, Can't
sleep, clown will eat me, CanadianCaesar, Canderson7, Capricorn42, CaribDigita, Carrrrrnez, Cashpotato, Catgut, Cazarooni, Cbanks88, Cburnett, Ccacsmss, Cdrikari, Celarnor, Cenarium,
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JHMM13, JSR, JSpung, JWSchmidt, Jabaway, Jack007, Jackfork, Jackol, Jackrace, Jacob.jose, Jagged 85, Jahiegel, JakartaDean, Jalan z, Jamesday, Jamistic, Janejellyroll, Jasanchez, Jatlas,
Jauhienij, Javert, JavierMC, Jaxad0127, Jbmweb1, Jcarroll, Je.rrt, Jeendan, Jeepday, Jeeves, Jeff G., Jeff Nobles, Jeff3000, Jellyfishcom, JenC2, Jengod, Jere123 9, Jeremygentles, Jesanj,
Jfdwolff, Jgritz, Jitse Niesen, Jivecat, Jl1995, Jlanier, Jmadhura, Jmc wiki, Jmh649, Jmundo, Joanjoc, Job314, Joehall219, Joehall45, Joeybleach72, JohnMurphy, JonHarder, Jorian-Kell, Jorunn,
Josconklin, JosephBarillari, Josh Cherry, Jpala, Jpatokal, Jtdaugir, Juansempere, Julesd, JuliaHavey, Junglecat, Jwdietrich2, KJS77, KPH2293, Kaiba, Kaobear, Karada, Karenjc, Kartano,
Katalaveno, Katheryne S, Kbh3rd, Kehelm, Keilana, KeithBeltham, Kelly Martin, Kelp, Khukri, King of Hearts, Kingpin13, Kingskid 727, Kipala, Kirk.wolfe, Kiswanson, Kknd123,
Article Sources and Contributors 418

KnowledgeOfSelf, Knutties, Kochipoik, Koda2828, Kormerant, Koveras, Kowey, Kpjas, Krisandie, Krishnan2424, Kristinwt, Kristof vt, Krsont, Krylonblue83, Kukini, Kungfuadam, Kurykh,
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Mrchadsexington, Mrwick1, Mschel, Mschlindwein, Murrayhuntington, Mushroom, Mwanner, My Core Competency is Competency, Mykej, Mymommytime, N1RK4UDSK714, N2e,
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Zip0777, Ziphon, Zirland, Zsinj, Zzuuzz, ^demon, Ødipus sic, Александър, 2610 anonymous edits

DNA replication  Source: http://en.wikipedia.org/w/index.php?oldid=464453038  Contributors: 101louise101, AKaK, Access Denied, Adambro, Adenosine, Aesopos, Agathman, Ahoerstemeier,
Aitias, Alansohn, Alfio, Alphachimp, Alveolate, Andthendougsaid, Andy M. Wang, Arcadian, Archdevil75, Ariliand, Arthena, Arthmelow, Artman40, Ary29, Ashermadan, AxelBoldt,
Azcolvin429, BSoD, Baldhur, Before My Ken, Bender235, Bensaccount, Bio-queen, Biomedeng, Blanchardb, Blondtraillite, Bluerasberry, Bobo192, BokicaK, Bomac, Borgx, Bosborne21212,
Bowlhover, Bozartas, BradBeattie, Brianwatson94, Burner0718, CIreland, CTZMSC3, Calito00000001, CanadianLinuxUser, Canis Lupus, Captain Infinity, Catgut, Celarnor, Chasturn,
Chatmonregina, Chris Capoccia, Cless Alvein, ClockworkSoul, Cmdrjameson, CommonsDelinker, Conversion script, Cookatoo.ergo.ZooM, Coveman999, Crazysunshineboy, Cyktsui, Dac04,
Dan Gluck, Dantheman531, Dave Runger, David D., Debresser, Dennis Valeev, DerHexer, DividedByNegativeZero, Dr. Anton Funk PhD, DrMicro, Drphilharmonic, Dusanman1, Duxenaz,
Dysepsion, ERcheck, Edgar181, Edwy, Eganio, El C, Emw, Epbr123, Erick880, Exarion, Falconus, FangedFaerie, Faradayplank, Farosdaughter, Favonian, Fbv65edel, Fibonacci, Firelement85,
ForestDim, Freddy S., Freedomlinux, FriedMilk, GD, GLaDOS, Gail, Giftlite, Gobonobo, Golfandme, Graft, Gregoots, Guelphie, Guelphie85, Habj, Hadal, Harryboyles, Harsha112, Hello32020,
Heron, Hichris, Hu12, Iduggin, Ignacio Icke, Igoldste, Im emo tastic, Imjustmatthew, InvaderJim42, InverseHypercube, J.delanoy, JDCMAN, JForget, Jackhynes, Jadtnr1, JayZ, Jcwf, Jessi bob,
Jhinman, Jimhsu77479, JoanneB, Johnuniq, Jonemerson, Jossi, Jovianeye, Jpbowen, Jpeguero, JulianBlow, Julianonions, Jullag, Ka Faraq Gatri, Kaisershatner, Kakofonous, KnowledgeOfSelf,
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Carbonaro, Medfreak, Media1312, Megaman en m, Meno25, Mentifisto, Mesoderm, Mfedder, Mgiganteus1, MichaelHa, Midgrid, Mietchen, Mikael Häggström, Mike Rosoft, MishaPan, Monkey
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Now, Twooars, Tycho, Ucanlookitup, Ucphilsc, Vanderesch, Victor Blacus, Vojtech.dostal, Voyagerfan5761, Vsmith, WAvegetarian, Wangi, WaysToEscape, WebHamster, Whisky drinker,
Whiteniko, Whosyourjudas, Work permit, Wouterstomp, Wrlampe, Yashgaroth, Yerpo, Yukaxu, Zephyris, ZimZalaBim, Zrulli, 899 anonymous edits

DNA repair  Source: http://en.wikipedia.org/w/index.php?oldid=459966571  Contributors: ALargeElk, Abstraktn, Agathman, Alansohn, Aleenf1, Alextrevelian 006, Ali Raza, Alnokta,
Amazinglarry, Amboo85, Angela, Angusmclellan, Arcadian, Ariliand, Arup Acharjee, Asbhagwat, Asenine, Athf1234, Auk nambiar2002, Autrijus, Axl, Bavan Palasanthiran, Benbest,
Bernstein0275, Bhuvanesh aravind, Brian0918, Brighterorange, Bruno in Columbus, CaMpixx, Cadmium, Capricorn42, Chfosli, Ching-3, Christian75, Clementine2009, Clicketyclack, Cyktsui,
DO11.10, Dark Shikari, Dbabbitt, Deepa.kushwaha, Deli nk, DerHexer, Deville, Discospinster, Drphilharmonic, Duncharris, Ec5618, Edcolins, Edgar181, Eequor, El Mayimbe, Emvee, Emw,
Eugeneltc, Fenice, Firassalim, FisherQueen, Fnielsen, Foosh, ForestDim, Forluvoft, GVnayR, Gargaj, Gerriet42, Giftlite, Ginkgo100, Gnomehacker, Gogo Dodo, GrahamColm, HaHa AI, Hadal,
Harrison35, Harvestgalaxy, Headbomb, Herbee, Ikiroid, Itizen, Ixfd64, JDG, JWSchmidt, Jay Gatsby, Jimaginator, Jimktrains, JoergenB, Jon the Geek, JonHarder, Jonverve, Juliancolton,
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Oncogenes  Source: http://en.wikipedia.org/w/index.php?oldid=461936467  Contributors: Anabus, AndyZ, Arcadian, Axl, Banano03, Bform, Brim, Brodyt66, Bryan Derksen, Bubbachuck,
Charles Matthews, Chester Markel, Cometstyles, Conversion script, CopperKettle, CyrilleDunant, Czernilofsky, David cameron, Deepfreeze63, Dj Capricorn, Dr.alf, Dr.michael.benjamin,
Drphilharmonic, Ed Poor, Ejgx93, Electric goat, EnSamulili, EquationDoc, Gaius Cornelius, Graham87, Hakushu8, Headbomb, HorsePunchKid, Immunoboy, JWSchmidt, Jackhynes, Jaimeglz,
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XinaNicole, Yoni bhonker, Z3n0s, Zashaw, ‫ﻣﺎﻧﻲ‬, 103 anonymous edits

Transcription  Source: http://en.wikipedia.org/w/index.php?oldid=464437071  Contributors: 20Lukianto, A8UDI, ASDZXCQWE, AThing, Agathman, Ajdavis5, Alansohn, Alex-engraver,
Alohascott, Altzinn, Amorymeltzer, Anaxial, AnnaJune, Antandrus, Antony-22, Antorjal, Apers0n, Arcadian, Archer3, ArglebargleIV, BVBede, Batmanand, Bensaccount, Berkay0652,
Binksternet, Bloodpack, BokicaK, Bonás, Brettbarbaro, Brianwatson94, Brookie, BrotherGeorge, Bursting74, Cbailey7, Ceyockey, Cmcclean22, Cncplayer, CoeurDeLion, Corpx, Cvd5012,
DaDrought3, DanielCD, Danjel, Dcooper, Dhp4, Dpv, Drosilia, Drphilharmonic, Duncharris, E0steven, Ec5618, EnSamulili, Enviroboy, Epingchris, Evandrix, Fbv65edel, Feinoha, Fenoxielo,
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Grunt, Haham hanuka, Hede2000, Helixblue, Hilwhale, HoergerJ, Hpswimmer, Hughitt1, Hydrogen Iodide, Ifan160, Iknowyourider, Ilia Kr., Iridescent, JForget, JWSchmidt, Jacobso4, Jcdietz03,
Jcorry10, Jebus989, Jeffpkamp, JoanneB, John254, Johnuniq, Jullag, KDSKDS, Kaarel, Kazkaskazkasako, Khoikhoi, Kickassso, Kingpin13, Kku, Kshieh, Kubigula, Kukini, Kuru, Kzhr,
Lantonov, LeaHazel, Legendre17, Legolost, Lehtv, LeighClesterMolar, Lexor, Liam Skoda, Local hero, Lolzpvp, LostLucidity, MDG38, MarkSutton, Marshallsumter, Martin.Budden, Martyn
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Mms, MoogleDan, Mxn, NERIUM, Narayanese, Nburden, Neelix, Neur0X, Nick.wiebe, NightwolfAA2k5, Nishkid64, Noah Salzman, Nubiatech, Nuplex, Opabinia regalis, Opus118,
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Article Sources and Contributors 419

Rgocs, Riana, Ribrob, Richard001, Rida97, Rmky87, Rod57, Ronz, Rosieredfield, RyanGerbil10, S73v3n, SIMONCOHEN, SU Linguist, Sakkura, Sameerbau, Saurabh523, Scresawn, Seans
Potato Business, Segabud, Shanel, Sjakkalle, Sl, Smartse, Smelissali, Sophos II, Squidonius, Sriram sh, Srlasky, Staffwaterboy, Steinsky, Sydney3803, Tedtoal, Teethies563, Teply, TestPilot, The
Anome, The Flying Spaghetti Monster, The undertow, Thingg, This lousy T-shirt, Tide rolls, TimVickers, Timemutt, Tmh, Tomjc, Totophe64, Transitiveinstance, Tycho, Useight, Uthbrian,
Vanished user 39948282, Vidric, Vikky2904, Vojtech.dostal, WAS 4.250, WAvegetarian, Wayne Slam, WikHead, Woohookitty, Wouterstomp, Yerpo, Yided, Yvorez1274, Z.E.R.O., Zamftb,
Zashaw, Zephyris, Περίεργος, Александър, 635 anonymous edits

Regulation of gene expression  Source: http://en.wikipedia.org/w/index.php?oldid=463581999  Contributors: Aarre, Active contributor, Agathman, Ale jrb, AndreasJS, Annatyler23, Arcadian,
Arjayay, AxelBoldt, Ayush girish nagar, Bensaccount, Bluemonkey33, Boghog, Booyabazooka, Chenli, Chopin-Ate-Liszt!, Clicketyclack, DS Belgium, DanCAK, Darkwind, Diuturno,
Drphilharmonic, Eahd201, ElAmericano, Emmertjp, Fdardel, Fjarlq, Forluvoft, Froggermaster96, Gaius Cornelius, Garrett, Gomm, Gongoozler123, Greensburger, Hosszuka, Jasonmbechtel,
Jethero, Jfdwolff, Jgreally, JonHarder, Kembangraps, Kku, Lexor, Magnus Manske, Mahdim, Mamaberry11, Mauritsmaartendejong, Melaen, Mesoderm, Michael Hardy, Mike Storm, Mike2vil,
Mr mutwil, Mrs Often, Msks, Narayanese, Nassirys, Ngebendi, Nina Gerlach, Nono64, Onco p53, PDH, Pearle, Pengo, Ph.eyes, Quale, Rjwilmsi, Seans Potato Business, Serketan, Smartse,
Squidonius, SteveChervitzTrutane, Stevenfruitsmaak, TedE, Templatehater, TestPilot, Tevildo, Tomas e, Trusilver, Turan, Unscented, VoltairesBastard, Woohookitty, Wouterstomp, X!, ‫כל יכול‬,
121 anonymous edits

Translation  Source: http://en.wikipedia.org/w/index.php?oldid=462232674  Contributors: Agathman, Alansohn, Alexandre Vassalotti, Alnokta, Ammonfife, Antony-22, Antorjal, Appraiser,
Arcadian, Bensaccount, BernardP, Bioinformin, Bobmarley1987, Bomac, Brianwatson94, CanisRufus, Caulde, CharlesZ, Chewie, Chino, Closedmouth, Cookey118, Crum375, CrzyMke, Cunard,
DB au, Dan aka jack, Dexter prog, Donimo, Duja, Dzordzm, ESkog, Epbr123, Ettrig, Forluvoft, Fortunecookie289, Fotinakis, Franckperez, FrozenMan, G3pro, Gadfium, Gail, Gccwang, Giftlite,
Graft, Hackwrth, Haza-w, HilJackson, Ianian123, Immunize, Intropy, Irrbloss, JHMM13, JWSchmidt, James McNally, Jbhood, Josh Cherry, JuanitaJP, Kaarel, Kazulanth, Kazvorpal,
Kegs-cm13sx, Kim Bruning, Kostmo, Lando5, Lantonov, Lexor, Lgin, LukeGoodsell, M1ss1ontomars2k4, MBisanz, MBob, Marek69, Martin.Budden, Mephistophelian, Mesoderm, MichaK,
MichaelJanich, Mikael Häggström, Mobile Snail, Modulatum, Mohawkjohn, Mr. Know-It-All, Mrpark01, Neokamek, NewEnglandYankee, Nina Gerlach, Northfox, Nwbeeson, Oldekop,
Orionus, OtakuNOVAkun, PDH, PFHLai, Peak, Phe, Pro bug catcher, Psbsub, Pupunwiki, RDBrown, Rasmusw, Rjwilmsi, Rolando, Saippuakauppias, Salt Yeung, Sanbioinfo, Secundus
Zephyrus, Shadowelve11, SimonP, Sjdk13, SomethingCatchy, Sord halo, Squidonius, Stroppolo, Superdoggy, Sverdrup, Taoster, TenOfAllTrades, The Anome, Thisismikesother, Timemutt,
Timwi, TransControl, Trinit, Uncle-P, Unfortunate, Uraza, Vossman, Wavelength, Wickey-nl, Xiahou, YaacovCR, Yashgaroth, Yasingam, Yontally, ZayFoTT, Zephyris, 269 anonymous edits

Posttranslational modification  Source: http://en.wikipedia.org/w/index.php?oldid=452718420  Contributors: A876, Alon Gabbay, Amikake3, Aquaphobic, Arcadian, Arminius, Banus,
Bdekker, Bensaccount, Bromomir, Bryan Derksen, Bsadowski1, C31004, Ceyockey, Clicketyclack, Dcirovic, Dimethylformamide, Edgar181, Epingchris, GAThrawn22, Geobacter, Glane23,
Graft, Hodja Nasreddin, Jfdwolff, Jni, Jolivio, Jonkerz, Julesd, Kaarel, Kkmurray, Kosigrim, KuduIO, Kupirijo, La goutte de pluie, Lemchesvej, Madeleine Price Ball, Magnus Manske,
MarXidad, Mike Serfas, Minnsurfur2, PFHLai, Pgan002, Reinoutr, Rich Farmbrough, Rjwilmsi, Shuvaev, Silly shrimp, SimonP, Social tamarisk, Stewartadcock, Stillnotelf, Thewildtype,
Tuomas Hätinen, Vermiculus, WillowW, Wmpearl, Xwu, Yyadam7, Yyocean, Zephyris, 61 anonymous edits

Proteolysis  Source: http://en.wikipedia.org/w/index.php?oldid=433412130  Contributors: 217.228.14.xxx, Actarux, Algont, Almazi, Arcadian, Bryan Derksen, Champ0815, Clicketyclack,
Conversion script, Edward, EdwardLane, Habj, Hirokun, JohnOwens, Jotomicron, Jwinius, Kosigrim, Marj Tiefert, Martious, Maxamegalon2000, Michael Hardy, Nina Gerlach, Nono64,
PaddyM, PhD Dre, Rcej, Roadnottaken, SimonP, Stepa, Svartkell, WillowW, 21 anonymous edits

Proteasome  Source: http://en.wikipedia.org/w/index.php?oldid=461878424  Contributors: Aa77zz, AdamRetchless, Alai, Alansohn, Anthonyhcole, Ashanda, BCvek, Barticus88, Bender235,
Berkay0652, Biochemza, Biogvk, BloodIce, Bobblewik, Bobmarley1987, BostonBiochem, Brighterorange, Bryan Derksen, CBM, CDN99, Ceyockey, Chris Capoccia, ClockworkSoul,
Conversion script, Cyanoir, DeadEyeArrow, Dekisugi, Drphilharmonic, Editore99, Elb2000, Eleassar, Eubulides, Excirial, Fredrik, Fvasconcellos, Gacggt, Gaius Cornelius, Giftlite, Graham87,
GrahamColm, Grife, Hadal, Headbomb, Howard McCay, Hunter3316, Iayork, JPG-GR, JWSchmidt, Japanese Searobin, Kenmcl2, Kosigrim, Lexor, Lightmouse, LilHelpa, Lilious, Longhair,
Lucadino, Magnus Manske, Marj Tiefert, Martious, Maxxicum, Michael Devore, Michael Hardy, Michaelas10, Miguelferig, Naturespace, Neil916, NocturneNoir, NuclearWarfare, Oncogenes,
Opabinia regalis, Ph0987, Piledhigheranddeeper, Pspealman, Pustelnik, PuzzletChung, Quiddity, R'n'B, RDBrown, RGlasser, Reinoutr, Rich Farmbrough, Rjwilmsi, Rod57, Romanm, S3000,
Sangak, Sasata, Separa, Serephine, Shizhao, Smably, Smartse, Snowmanradio, Splette, Stone, TYelliot, Taw, Tbhotch, The ed17, ThinkerThoughts, ThomasO1989, TimVickers, Time9,
ToNToNi, Tomas.Persson, Treisijs, Tycho, Ucucha, Vanderesch, VasilievVV, Vojtech.dostal, Wavelength, Webridge, Weird Black Lady 4 U, WhatamIdoing, Wikipism, Will Beback Auto,
WillowW, Winchelsea, Wouterstomp, YUL89YYZ, 76 anonymous edits
Image Sources, Licenses and Contributors 420

Image Sources, Licenses and Contributors

Image:Sucrose-inkscape.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Sucrose-inkscape.svg  License: GNU Free Documentation License  Contributors: Don A. Carlson
Image:Fat triglyceride shorthand formula.PNG  Source: http://en.wikipedia.org/w/index.php?title=File:Fat_triglyceride_shorthand_formula.PNG  License: Public Domain  Contributors:
Wolfgang Schaefer
Image:AminoAcidball.svg  Source: http://en.wikipedia.org/w/index.php?title=File:AminoAcidball.svg  License: Public Domain  Contributors: Edgar181, TimVickers, Wutsje, YassineMrabet, 2
anonymous edits
Image:DNA chemical structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_chemical_structure.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported
 Contributors: Madprime, Wickey, 2 anonymous edits
Image:Beta-D-Glucose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-Glucose.svg  License: Public Domain  Contributors: Yikrazuul
Image:Saccharose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Saccharose.svg  License: Public Domain  Contributors: Booyabazooka, Calvero, Edgar181, 1 anonymous edits
Image:Cellulose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cellulose-2D-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Slashme
Image:1GZX Haemoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:1GZX_Haemoglobin.png  License: GNU Free Documentation License  Contributors: Original uploader
was Zephyris at en.wikipedia
Image:Amino acids 1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acids_1.png  License: GNU Free Documentation License  Contributors: Arria Belli,
CommonsDelinker, CommonsDelinkerHelper, Edgar181, Karelj, Matanya (usurped), OsamaK, 1 anonymous edits
Image:Schematic relationship between biochemistry, genetics and molecular biology.svg  Source:
http://en.wikipedia.org/w/index.php?title=File:Schematic_relationship_between_biochemistry,_genetics_and_molecular_biology.svg  License: Creative Commons Attribution-ShareAlike 3.0
Unported  Contributors: OldakQuill, PatríciaR
File:Wilson1900Fig2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Wilson1900Fig2.jpg  License: Public Domain  Contributors: Edmund Beecher Wilson
Image:Epithelial-cells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Epithelial-cells.jpg  License: GNU Free Documentation License  Contributors: Dbc334, Duesentrieb,
GeorgHH, Helix84, JWSchmidt, Martin H., ViperSnake151, 2 anonymous edits
Image:Cork Micrographia Hooke.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cork_Micrographia_Hooke.png  License: Public Domain  Contributors: Robert Hooke
Image:celltypes.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Celltypes.svg  License: Public Domain  Contributors: Science Primer (National Center for Biotechnology
Information). Vectorized by Mortadelo2005.
Image:Average prokaryote cell- en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Average_prokaryote_cell-_en.svg  License: Public Domain  Contributors: Mariana Ruiz
Villarreal, LadyofHats
Image:Animal cell structure en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Animal_cell_structure_en.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)
Image:Plant cell structure svg.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Plant_cell_structure_svg.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)
File:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: IP69.226.103.13
Image:Diagram human cell nucleus no text.png  Source: http://en.wikipedia.org/w/index.php?title=File:Diagram_human_cell_nucleus_no_text.png  License: Public Domain  Contributors:
Mariana Ruiz Villarreal LadyofHats. Original uploader was Peter Znamenskiy at en.wikipedia
Image:Endomembrane system diagram no text nucleus.png  Source: http://en.wikipedia.org/w/index.php?title=File:Endomembrane_system_diagram_no_text_nucleus.png  License: Public
domain  Contributors: Peter Znamenskiy at en.wikipedia
Image:Proteinsynthesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteinsynthesis.png  License: Public Domain  Contributors: Incnis Mrsi, Laikayiu, 1 anonymous edits
Image:PD-icon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:PD-icon.svg  License: Public Domain  Contributors: Alex.muller, Anomie, Anonymous Dissident, CBM, MBisanz,
Quadell, Rocket000, Strangerer, Timotheus Canens, 1 anonymous edits
File:Iceberg with hole near sanderson hope 2007-07-28 2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Iceberg_with_hole_near_sanderson_hope_2007-07-28_2.jpg  License:
Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors: Kim Hansen
File:3D model hydrogen bonds in water.svg  Source: http://en.wikipedia.org/w/index.php?title=File:3D_model_hydrogen_bonds_in_water.svg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: User Qwerter at Czech wikipedia: Qwerter. Transferred from cs.wikipedia; Transfer was stated to be made by User:sevela.p. Translated to english by by
Michal Maňas (User:snek01). Vectorized by Magasjukur2
File:Water droplet blue bg05.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Water_droplet_blue_bg05.jpg  License: GNU Free Documentation License  Contributors: Fir0002
File:SnowflakesWilsonBentley.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SnowflakesWilsonBentley.jpg  License: Public Domain  Contributors: Wilson Bentley
File:Spider web Luc Viatour.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Spider_web_Luc_Viatour.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors:
Luc Viatour
File:Capillarity.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Capillarity.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: MesserWoland
File:Label for dangerous goods - class 4.3.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Label_for_dangerous_goods_-_class_4.3.svg  License: Public Domain  Contributors:
w:User:MysidMysid
File:Earth's water distribution.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Earth's_water_distribution.svg  License: Public Domain  Contributors: USGS
File:The Earth seen from Apollo 17.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:The_Earth_seen_from_Apollo_17.jpg  License: Public Domain  Contributors: NASA. Photo
taken by either Harrison Schmitt or Ron Evans (of the Apollo 17 crew).
File:Water cycle.png  Source: http://en.wikipedia.org/w/index.php?title=File:Water_cycle.png  License: Public Domain  Contributors: USGS
File:Bay of Fundy High Tide.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bay_of_Fundy_High_Tide.jpg  License: GNU Free Documentation License  Contributors: Antaya,
Before My Ken, GeorgHH, Sam, Sanao, Shizhao
File:Bay of Fundy Low Tide.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bay_of_Fundy_Low_Tide.jpg  License: GNU Free Documentation License  Contributors: Antaya,
Before My Ken, GeorgHH, Sam, Sanao, Shizhao, Spiritia
File:Oasis in Lybia.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Oasis_in_Lybia.JPG  License: unknown  Contributors: -
File:Auto-and heterotrophs.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Auto-and_heterotrophs.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
Mikael Häggström
File:Blue Linckia Starfish.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Blue_Linckia_Starfish.JPG  License: Creative Commons Attribution-Sharealike 2.5  Contributors:
Richard Ling
File:Diatoms through the microscope.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Diatoms_through_the_microscope.jpg  License: Public Domain  Contributors: Prof. Gordon T.
Taylor, Stony Brook University
File:Longwood Gardens-Italian Garden.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Longwood_Gardens-Italian_Garden.jpg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: Original uploader was MikeParker at en.wikipedia
File:Field Trip- water sampling.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Field_Trip-_water_sampling.jpg  License: Creative Commons Attribution 3.0  Contributors: Original
uploader was Alloquep at en.wikipedia
File:SiphonTubes.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:SiphonTubes.JPG  License: Public Domain  Contributors: H2O-C, Honeplus, 1 anonymous edits
File:Humanitarian aid OCPA-2005-10-28-090517a.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Humanitarian_aid_OCPA-2005-10-28-090517a.jpg  License: Public Domain
 Contributors: Technical Sergeant Mike Buytas of the United States Air Force
File:Water quality.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Water_quality.jpg  License: Creative Commons Attribution 3.0  Contributors: Ionut Cojocaru
File:D-P005 Kein Trinkwasser.svg  Source: http://en.wikipedia.org/w/index.php?title=File:D-P005_Kein_Trinkwasser.svg  License: Public Domain  Contributors: Torsten Henning
File:MH-60S Helicopter dumps water onto Fire.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MH-60S_Helicopter_dumps_water_onto_Fire.jpg  License: Public Domain
 Contributors: Mass Communication Specialist 2nd Class Chris Fahey, U.S. Navy
Image Sources, Licenses and Contributors 421

File:Grand Anse Beach Grenada.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Grand_Anse_Beach_Grenada.jpg  License: Creative Commons Attribution 3.0  Contributors:
Varun Kapoor / Vkap
File:Water carrier.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Water_carrier.jpg  License: unknown  Contributors: Alan Liefting, Idleguy, Magog the Ogre, Siddhant
File:TapWater-china.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:TapWater-china.JPG  License: Creative Commons Attribution-ShareAlike 1.0 Generic  Contributors:
User:Shizhao
File:Usine Bret MG 1648.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Usine_Bret_MG_1648.jpg  License: Creative Commons Attribution-Sharealike 2.0  Contributors:
User:Rama
File:200407-sandouping-sanxiadaba-4.med.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:200407-sandouping-sanxiadaba-4.med.jpg  License: GNU Free Documentation License
 Contributors: Rehman, Saperaud, Shizhao, TomPreuss
File:Magnify-clip.png  Source: http://en.wikipedia.org/w/index.php?title=File:Magnify-clip.png  License: Public Domain  Contributors: User:Erasoft24
File:Cuisson des pates.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Cuisson_des_pates.jpg  License: GNU Free Documentation License  Contributors: Antoinel, Catfisheye, Man
vyi
File:Access to drinking water in third world.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Access_to_drinking_water_in_third_world.svg  License: Public Domain  Contributors:
Ephemeronium
File:Pre-mRNA-1ysv.png-tubes.png  Source: http://en.wikipedia.org/w/index.php?title=File:Pre-mRNA-1ysv.png-tubes.png  License: Creative Commons Attribution-Sharealike 3.0
 Contributors: Vossman
File:50S-subunit of the ribosome 3CC2.png  Source: http://en.wikipedia.org/w/index.php?title=File:50S-subunit_of_the_ribosome_3CC2.png  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: Yikrazuul
File:Piwi-siRNA-basepairing.png  Source: http://en.wikipedia.org/w/index.php?title=File:Piwi-siRNA-basepairing.png  License: GNU Free Documentation License  Contributors:
en:User:Narayanese
File:RNA chemical structure.GIF  Source: http://en.wikipedia.org/w/index.php?title=File:RNA_chemical_structure.GIF  License: GNU Free Documentation License  Contributors:
en:User:Narayanese
File:Ciliate telomerase RNA.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Ciliate_telomerase_RNA.JPG  License: Public domain  Contributors: Original uploader was
Narayanese at en.wikipedia
File:Full length hammerhead ribozyme.png  Source: http://en.wikipedia.org/w/index.php?title=File:Full_length_hammerhead_ribozyme.png  License: Creative Commons
Attribution-ShareAlike 3.0 Unported  Contributors: William G. Scott
File:Synthesis of Pseudouridine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Synthesis_of_Pseudouridine.svg  License: Public Domain  Contributors: Yikrazuul
File:DNA Structure+Key+Labelled.pn NoBB.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_Structure+Key+Labelled.pn_NoBB.png  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: Zephyris
File:ADN animation.gif  Source: http://en.wikipedia.org/w/index.php?title=File:ADN_animation.gif  License: Public Domain  Contributors: brian0918™
File:Speaker Icon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Speaker_Icon.svg  License: Public Domain  Contributors: Blast, G.Hagedorn, Mobius, 2 anonymous edits
File:DNA chemical structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_chemical_structure.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported
 Contributors: Madprime, Wickey, 2 anonymous edits
File:DNA orbit animated static thumb.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_orbit_animated_static_thumb.png  License: GNU Free Documentation License
 Contributors: 84user adapting file originally uploaded by Richard Wheeler (Zephyris) at en.wikipedia
File:DNA-ligand-by-Abalone.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA-ligand-by-Abalone.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
P99am
File:GC DNA base pair.svg  Source: http://en.wikipedia.org/w/index.php?title=File:GC_DNA_base_pair.svg  License: Public Domain  Contributors: Isilanes
File:AT DNA base pair.svg  Source: http://en.wikipedia.org/w/index.php?title=File:AT_DNA_base_pair.svg  License: Public Domain  Contributors: Isilanes
File:A-DNA, B-DNA and Z-DNA.png  Source: http://en.wikipedia.org/w/index.php?title=File:A-DNA,_B-DNA_and_Z-DNA.png  License: GNU Free Documentation License  Contributors:
Original uploader was Richard Wheeler (Zephyris) at en.wikipedia
File:Parallel telomere quadruple.png  Source: http://en.wikipedia.org/w/index.php?title=File:Parallel_telomere_quadruple.png  License: GNU Free Documentation License  Contributors:
Thomas Splettstoesser
File:Branch-dna.png  Source: http://en.wikipedia.org/w/index.php?title=File:Branch-dna.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Original uploader was Peter
K. at en.wikipedia
File:Multi-branch-dna.png  Source: http://en.wikipedia.org/w/index.php?title=File:Multi-branch-dna.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: . Original
uploader was Peter K. at en.wikipedia
File:Cytosin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Cytosin.svg  License: Public Domain  Contributors: NEUROtiker
File:5-Methylcytosine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:5-Methylcytosine.svg  License: Public Domain  Contributors: Yikrazuul (talk)
File:Thymin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Thymin.svg  License: Public Domain  Contributors: NEUROtiker
File:Benzopyrene DNA adduct 1JDG.png  Source: http://en.wikipedia.org/w/index.php?title=File:Benzopyrene_DNA_adduct_1JDG.png  License: GNU Free Documentation License
 Contributors: Benjah-bmm27, Bstlee, 1 anonymous edits
File:T7 RNA polymerase.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:T7_RNA_polymerase.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
User:Splette
File:DNA replication en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_replication_en.svg  License: Public Domain  Contributors: LadyofHats Mariana Ruiz
Image:Nucleosome1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleosome1.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Splette
File:Lambda repressor 1LMB.png  Source: http://en.wikipedia.org/w/index.php?title=File:Lambda_repressor_1LMB.png  License: GNU Free Documentation License  Contributors: Original
uploader was Zephyris at en.wikipedia
File:EcoRV 1RVA.png  Source: http://en.wikipedia.org/w/index.php?title=File:EcoRV_1RVA.png  License: GNU Free Documentation License  Contributors: Original uploader was Zephyris at
en.wikipedia
File:Holliday Junction cropped.png  Source: http://en.wikipedia.org/w/index.php?title=File:Holliday_Junction_cropped.png  License: GNU Free Documentation License  Contributors: Original
uploader was TimVickers at en.wikipedia
File:Holliday junction coloured.png  Source: http://en.wikipedia.org/w/index.php?title=File:Holliday_junction_coloured.png  License: GNU Free Documentation License  Contributors:
Original uploader was Zephyris at en.wikipedia
File:Chromosomal Recombination.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosomal_Recombination.svg  License: Creative Commons Attribution 2.5  Contributors:
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File:DNA nanostructures.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_nanostructures.png  License: Creative Commons Attribution 2.5  Contributors: (Images were kindly
provided by Thomas H. LaBean and Hao Yan.)
File:Maclyn McCarty with Francis Crick and James D Watson - 10.1371 journal.pbio.0030341.g001-O.jpg  Source:
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Attribution 2.5  Contributors: Marjorie McCarty
File:Myoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:Myoglobin.png  License: Public Domain  Contributors: →AzaToth
File:Peptide-Figure-Revised.png  Source: http://en.wikipedia.org/w/index.php?title=File:Peptide-Figure-Revised.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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File:Peptide group resonance.png  Source: http://en.wikipedia.org/w/index.php?title=File:Peptide_group_resonance.png  License: GNU Free Documentation License  Contributors: Original
uploader was WillowW at en.wikipedia
Image:Ribosome mRNA translation en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Ribosome_mRNA_translation_en.svg  License: Public Domain  Contributors: LadyofHats
File:Genetic code.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Genetic_code.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Madprime
Image Sources, Licenses and Contributors 422

File:Chaperonin-1AON.png  Source: http://en.wikipedia.org/w/index.php?title=File:Chaperonin-1AON.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: P99am
File:Proteinviews-1tim.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteinviews-1tim.png  License: GNU Free Documentation License  Contributors: Opabinia regalis
File:Protein Composite.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Protein_Composite.jpg  License: Creative Commons Attribution-Sharealike 2.0  Contributors: en:User:Gareth
White
File:Hexokinase ball and stick model, with substrates to scale copy.png  Source:
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at en.wikipedia
File:Mouse-cholera-antibody-1f4x.png  Source: http://en.wikipedia.org/w/index.php?title=File:Mouse-cholera-antibody-1f4x.png  License: GNU Free Documentation License  Contributors:
Opabinia regalis
File:Localisations02eng.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Localisations02eng.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Jeremy
Simpson and Rainer Pepperkok
Image:Amino Acids.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_Acids.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Dancojocari
Image:Lysine fisher struct num.png  Source: http://en.wikipedia.org/w/index.php?title=File:Lysine_fisher_struct_num.png  License: GNU Free Documentation License  Contributors:
User:Ppfk
Image:D+L-Alanine.gif  Source: http://en.wikipedia.org/w/index.php?title=File:D+L-Alanine.gif  License: Public Domain  Contributors: Ayacop, Edgar181, Jahobr, SharkD, 2 anonymous edits
Image:Amino acid zwitterions.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acid_zwitterions.png  License: GNU Free Documentation License  Contributors: TimVickers
Image:Protein-primary-structure.png  Source: http://en.wikipedia.org/w/index.php?title=File:Protein-primary-structure.png  License: Public Domain  Contributors: National Human Genome
Research Institute (NHGRI)
Image:L-selenocysteine-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-selenocysteine-2D-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27
Image:Beta alanine comparison.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta_alanine_comparison.png  License: GNU Free Documentation License  Contributors:
Dr.saptarshi, Edgar181, 1 anonymous edits
Image:Strecker Amino Acid Synthesis Scheme.png  Source: http://en.wikipedia.org/w/index.php?title=File:Strecker_Amino_Acid_Synthesis_Scheme.png  License: Public Domain
 Contributors: ~K
Image:Peptidformationball.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Peptidformationball.svg  License: Public Domain  Contributors: Karol007, Marek Mazurkiewicz,
PatríciaR, Rocket000, YassineMrabet, 2 anonymous edits
File:Amino acid catabolism.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acid_catabolism.png  License: Creative Commons Zero  Contributors: Mikael Häggström
Image:Molecular_structures_of_the_21_proteinogenic_amino_acids.svg  Source:
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image:L-alanine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-alanine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, EugeneZelenko,
Sunridin
image:L-arginine-skeletal-(tall).png  Source: http://en.wikipedia.org/w/index.php?title=File:L-arginine-skeletal-(tall).png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181,
Photohound, 1 anonymous edits
image:L-asparagine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-asparagine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181,
Photohound
image:L-aspartic-acid-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-aspartic-acid-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181,
Photohound
image:L-cysteine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-cysteine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181,
EugeneZelenko, Sunridin
image:L-glutamic-acid-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-glutamic-acid-skeletal.png  License: Public Domain  Contributors: Arrowsmaster, Benjah-bmm27,
Edgar181
image:L-glutamine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-glutamine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181
image:Glycine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Glycine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, DMacks, EugeneZelenko
image:L-histidine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-histidine-skeletal.png  License: Public Domain  Contributors: Ayacop, Benjah-bmm27, Bryan Derksen,
Cwbm (commons), Edgar181, Stepa, 1 anonymous edits
image:L-isoleucine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-isoleucine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181,
Photohound
image:L-leucine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-leucine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Panoramix303, 1
anonymous edits
image:L-lysine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-lysine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Cwbm (commons), Edgar181,
Marek Mazurkiewicz
image:L-methionine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-methionine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, EugeneZelenko
image:L-phenylalanine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-phenylalanine-skeletal.png  License: Public Domain  Contributors: Arrowsmaster,
Benjah-bmm27, EugeneZelenko, Sevela.p
image:L-proline-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-proline-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Fryed-peach
image:L-serine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-serine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, EugeneZelenko
image:L-threonine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-threonine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Photohound
image:L-tryptophan-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-tryptophan-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Cwbm (commons),
Edgar181, It Is Me Here, Mrgreen71
image:L-tyrosine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-tyrosine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Photohound
image:L-valine-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-valine-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Sunridin
image:L-selenocysteine-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-selenocysteine-2D-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27
image:Pyrrolysine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Pyrrolysine.svg  License: Public Domain  Contributors: Yikrazuul
file:Myoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:Myoglobin.png  License: Public Domain  Contributors: →AzaToth
file:PBB_GE_MB_204179_at_tn.png  Source: http://en.wikipedia.org/w/index.php?title=File:PBB_GE_MB_204179_at_tn.png  License: GNU Free Documentation License  Contributors: -
Image:Myoglobindiffraction.png  Source: http://en.wikipedia.org/w/index.php?title=File:Myoglobindiffraction.png  License: Public Domain  Contributors: Cdang, Karelj, Madmedea,
Mahahahaneapneap, Maksim
Image:Heme b.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Heme_b.svg  License: Public Domain  Contributors: Yikrazuul
Image:Hemoglobin t-r state ani.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Hemoglobin_t-r_state_ani.gif  License: GNU Free Documentation License  Contributors:
en:User:BerserkerBen
Image:Hb saturation curve.png  Source: http://en.wikipedia.org/w/index.php?title=File:Hb_saturation_curve.png  License: GNU Free Documentation License  Contributors: User:Diberri
File:Postnatal genetics en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Postnatal_genetics_en.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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Image:Sickle cell hemoglobin shortened.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sickle_cell_hemoglobin_shortened.png  License: Public Domain  Contributors: Madeleine
Price Ball, Materialscientist, 1 anonymous edits
Image:Nur04505.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Nur04505.jpg  License: Public Domain  Contributors: Achim Raschka, Eugene van der Pijll, Liné1, Mithril,
Royalbroil, Telim tor, TomCatX, 1 anonymous edits
Image Sources, Licenses and Contributors 423

Image:Mars Hubble.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mars_Hubble.jpg  License: Public domain  Contributors: NASA and The Hubble Heritage Team (STScI/AURA)
Image:Heart of Steel (Hemoglobin).jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Heart_of_Steel_(Hemoglobin).jpg  License: GNU Free Documentation License  Contributors:
Photographer: Julian Voss-Andreae; Uploaded to en-wiki by en:User:Julianva; Uploaded to Commons by User:Brainmachine
Image:Enzyme catalysis delta delta G.png  Source: http://en.wikipedia.org/w/index.php?title=File:Enzyme_catalysis_delta_delta_G.png  License: Creative Commons Attribution-ShareAlike
3.0 Unported  Contributors: Original uploader was Zephyris at en.wikipedia
Image:Induced fit diagram.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Induced_fit_diagram.svg  License: Public Domain  Contributors: Created by TimVickers, w:vector
graphicsvectorized by Fvasconcellos
Image:Enzyme catalysis uniform+differential binding.png  Source: http://en.wikipedia.org/w/index.php?title=File:Enzyme_catalysis_uniform+differential_binding.png  License: Creative
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Image:Lysozyme transition state.png  Source: http://en.wikipedia.org/w/index.php?title=File:Lysozyme_transition_state.png  License: GNU Free Documentation License  Contributors:
Original uploader was Zephyris at en.wikipedia
Image:Inter vs intramolecular reaction rates.png  Source: http://en.wikipedia.org/w/index.php?title=File:Inter_vs_intramolecular_reaction_rates.png  License: GNU Free Documentation
License  Contributors: Original uploader was Zephyris at en.wikipedia
Image:Serine protease catalysis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Serine_protease_catalysis.png  License: GNU Free Documentation License  Contributors: Original
uploader was Zephyris at en.wikipedia
Image:Carboxypeptidase catalysis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Carboxypeptidase_catalysis.png  License: GNU Free Documentation License  Contributors:
Original uploader was Zephyris at en.wikipedia
Image:EcDHFR raytraced.png  Source: http://en.wikipedia.org/w/index.php?title=File:EcDHFR_raytraced.png  License: Public Domain  Contributors: TimVickers
Image:KinEnzymo(en).svg  Source: http://en.wikipedia.org/w/index.php?title=File:KinEnzymo(en).svg  License: Public Domain  Contributors: TimVickers, YassineMrabet, Михајло
Анђелковић
Image:Enzyme progress curve.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Enzyme_progress_curve.svg  License: Copyrighted free use  Contributors: en:User:Poccil, Based on
public domain JPG by TimVickers.
Image:Michaelis-Menten saturation curve of an enzyme reaction.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Michaelis-Menten_saturation_curve_of_an_enzyme_reaction.svg
 License: Public Domain  Contributors: fullofstars
Image:Mechanism plus rates.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Mechanism_plus_rates.svg  License: Public Domain  Contributors: Atropos235, TimVickers
Image:Lineweaver-Burke plot.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Lineweaver-Burke_plot.svg  License: GNU Free Documentation License  Contributors: Original
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Image:Random order ternary mechanism.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Random_order_ternary_mechanism.svg  License: Public Domain  Contributors:
Fvasconcellos, TimVickers
Image:Ping pong.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Ping_pong.svg  License: Public Domain  Contributors: TimVickers
Image:Allosteric v by S curve.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Allosteric_v_by_S_curve.svg  License: Copyrighted free use  Contributors: by TimVickers.
Image:Burst phase.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Burst_phase.svg  License: Public Domain  Contributors: Original bitmap version by TimVickers, SVG version
traced over it in Inkscape by Qef.
Image:Reversible inhibition.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Reversible_inhibition.svg  License: Public Domain  Contributors: User Poccil on en.wikipedia
Image:Activation2 updated.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Activation2_updated.svg  License: GNU Free Documentation License  Contributors: Originally uploaded
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File:Common lipids lmaps.png  Source: http://en.wikipedia.org/w/index.php?title=File:Common_lipids_lmaps.png  License: GNU Free Documentation License  Contributors: Eoin Fahy
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File:Phosphatidyl-Ethanolamine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Phosphatidyl-Ethanolamine.png  License: Public Domain  Contributors: Original uploader was
Jag123 at en.wikipedia
File:Sphingomyelin-horizontal-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sphingomyelin-horizontal-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, 1 anonymous edits
File:Kdo2-lipidA.png  Source: http://en.wikipedia.org/w/index.php?title=File:Kdo2-lipidA.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: en:User:Lmaps and
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File:Phospholipids aqueous solution structures.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Phospholipids_aqueous_solution_structures.svg  License: Public Domain
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Image:2r9r opm.gif  Source: http://en.wikipedia.org/w/index.php?title=File:2r9r_opm.gif  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Andrei Lomize
Image:Cell membrane detailed diagram 4.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Cell_membrane_detailed_diagram_4.svg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: derivative work: Dhatfield (talk) Cell_membrane_detailed_diagram_3.svg: *derivative work: Dhatfield (talk) Cell_membrane_detailed_diagram.svg:
LadyofHats Mariana Ruiz
Image:Fluid Mosaic.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Fluid_Mosaic.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Jerome
Walker
Image:Alpha Intercalated Cell Cartoon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha_Intercalated_Cell_Cartoon.svg  License: Creative Commons Attribution 3.0
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Image:Membrane lipids.png  Source: http://en.wikipedia.org/w/index.php?title=File:Membrane_lipids.png  License: Public Domain  Contributors: BorisTM, Gwernol, WOSlinker, 2
anonymous edits
Image:Lactose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Lactose.svg  License: Public Domain  Contributors: Calvero.
Image:D-glucose color coded.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose_color_coded.png  License: Public Domain  Contributors: Original uploader was
ClockworkSoul at en.wikipedia
Image:Alpha-D-glucopyranose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-glucopyranose-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, Wickey-nl
Image:Beta-D-glucopyranose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-glucopyranose-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, Wickey-nl
Image:Glucose Fisher to Haworth.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_Fisher_to_Haworth.gif  License: GNU Free Documentation License  Contributors:
Wikimuzg
Image:sucrose 3Dprojection.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sucrose_3Dprojection.png  License: Public Domain  Contributors: glycoform
Image:amylose 3Dprojection.corrected.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amylose_3Dprojection.corrected.png  License: Public Domain  Contributors: glycoform
Image:starchy-foods..jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Starchy-foods..jpg  License: Public Domain  Contributors: Bestiasonica, Kilom691, Knutux,
Nachcommonsverschieber, 3 anonymous edits
Image:Cellulose-Ibeta-from-xtal-2002-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cellulose-Ibeta-from-xtal-2002-3D-balls.png  License: Public Domain
 Contributors: Ben Mills
File:Glycogen structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_structure.svg  License: Public Domain  Contributors: Mikael Häggström
File:Glycogen spacefilling model.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_spacefilling_model.jpg  License: Public Domain  Contributors: CeresVesta
File:ATP-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:ATP-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27, Daniel78, 1 anonymous edits
File:Trimyristin-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:Trimyristin-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27
File:Glucose Fisher to Haworth.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_Fisher_to_Haworth.gif  License: GNU Free Documentation License  Contributors:
Wikimuzg
File:Acetyl-CoA-2D.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Acetyl-CoA-2D.svg  License: Public Domain  Contributors: User:Bryan Derksen
Image Sources, Licenses and Contributors 424

File:1GZX Haemoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:1GZX_Haemoglobin.png  License: GNU Free Documentation License  Contributors: Original uploader
was Zephyris at en.wikipedia
File:Catabolism schematic.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Catabolism_schematic.svg  License: Public Domain  Contributors: Tim Vickers, vectorized by
File:Plagiomnium affine laminazellen.jpeg  Source: http://en.wikipedia.org/w/index.php?title=File:Plagiomnium_affine_laminazellen.jpeg  License: GNU Free Documentation License
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File:Sterol synthesis.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Sterol_synthesis.svg  License: Public Domain  Contributors: , original by Tim Vickers
File:Insulin glucose metabolism ZP.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Insulin_glucose_metabolism_ZP.svg  License: Public Domain  Contributors: Original uploader
was XcepticZP at en.wikipedia
File:Tree of life int.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Tree_of_life_int.svg  License: Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors: myself,
based on TimVickers's work.
File:A thaliana metabolic network.png  Source: http://en.wikipedia.org/w/index.php?title=File:A_thaliana_metabolic_network.png  License: Public Domain  Contributors: Original uploader
was TimVickers at en.wikipedia
File:SantoriosMeal.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SantoriosMeal.jpg  License: Public Domain  Contributors: Original uploader was Wetman at en.wikipedia
File:Glycolysis.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycolysis.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: WYassineMrabetTalk ✉
File:D-glucose wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose_wpmp.png  License: Public Domain  Contributors: Richard Wheeler (Zephyris)
File:biochem reaction arrow foward NNNN horiz med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_foward_NNNN_horiz_med.png  License: GNU
Free Documentation License  Contributors: Richard Wheeler (Zephyris)
File:Pyruvate2 wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Pyruvate2_wpmp.png  License: Public Domain  Contributors: Pyruvat.svg: NEUROtiker derivative work:
Iwilcox (talk)
Image:Glycolysis.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycolysis.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Tekks (talk). Original
uploader was Tekks at en.wikipedia
image:D-glucose wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose_wpmp.png  License: Public Domain  Contributors: Richard Wheeler (Zephyris)
image:Alpha-D-glucose-6-phosphate wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-glucose-6-phosphate_wpmp.png  License: Public Domain  Contributors:
Richard Wheeler (Zephyris)
image:Biochem_reaction_arrow_foward_YYNN_horiz_med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_foward_YYNN_horiz_med.png  License:
GNU Free Documentation License  Contributors: Richard Wheeler (Zephyris)
image:Beta-D-fructose-6-phosphate wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-fructose-6-phosphate_wpmp.png  License: Public Domain  Contributors:
Richard Wheeler (Zephyris)
image:Biochem_reaction_arrow_reversible_NNNN_horiz_med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_reversible_NNNN_horiz_med.png
 License: GNU Free Documentation License  Contributors: Richard Wheeler (Zephyris)
image:beta-D-fructose-1,6-bisphosphate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-fructose-1,6-bisphosphate_wpmp.png  License: Public Domain
 Contributors: Richard Wheeler (Zephyris)
image:D-glyceraldehyde-3-phosphate wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glyceraldehyde-3-phosphate_wpmp.png  License: Public Domain  Contributors:
Richard Wheeler (Zephyris)
image:glycerone-phosphate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Glycerone-phosphate_wpmp.png  License: Public Domain  Contributors: Richard Wheeler
(Zephyris)
image:1,3-bisphospho-D-glycerate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:1,3-bisphospho-D-glycerate_wpmp.png  License: GNU Free Documentation License
 Contributors: Richard Wheeler (Zephyris)
image:Biochem_reaction_arrow_reversible_YYYY_horiz_med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_reversible_YYYY_horiz_med.png
 License: GNU Free Documentation License  Contributors: Richard Wheeler (Zephyris)
image:3-phospho-D-glycerate_trulyglycerate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:3-phospho-D-glycerate_trulyglycerate_wpmp.png  License: Public Domain
 Contributors: 3-phospho-D-glycerate_wpmp.png: Richard Wheeler (Zephyris) derivative work: Iwilcox (talk)
image:2-phospho-D-glycerate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:2-phospho-D-glycerate_wpmp.png  License: Public Domain  Contributors: Richard Wheeler
(Zephyris)
image:phosphoenolpyruvate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Phosphoenolpyruvate_wpmp.png  License: Public Domain  Contributors: Richard Wheeler
(Zephyris)
image:Biochem_reaction_arrow_reversible_NYYN_horiz_med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_reversible_NYYN_horiz_med.png
 License: GNU Free Documentation License  Contributors: Richard Wheeler (Zephyris)
image:pyruvate_wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Pyruvate_wpmp.png  License: Public Domain  Contributors: Richard Wheeler (Zephyris)
Image:Glycolysis free energy changes.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycolysis_free_energy_changes.svg  License: Creative Commons Attribution-Sharealike 3.0
 Contributors: Popnose
File:Hexokinase B 1IG8 wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Hexokinase_B_1IG8_wpmp.png  License: Creative Commons Attribution-ShareAlike 3.0 Unported
 Contributors: Original uploader was Zephyris at en.wikipedia
File:Phosphofructokinase 6PFK wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Phosphofructokinase_6PFK_wpmp.png  License: GNU Free Documentation License
 Contributors: Original uploader was Zephyris at en.wikipedia
File:Pyruvate Kinase 1A3W wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Pyruvate_Kinase_1A3W_wpmp.png  License: GNU Free Documentation License  Contributors:
Original uploader was Zephyris at en.wikipedia
File:Gluconeogenesis pathway.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gluconeogenesis_pathway.png  License: Creative Commons Attribution-Sharealike 3.0
 Contributors: Unused0026 at en.wikipedia
Image:Glykogen.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glykogen.svg  License: Public Domain  Contributors: NEUROtiker
File:Glycogen phosphorylase2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_phosphorylase2.png  License: Public Domain  Contributors: Jmun7616
Image:Pentose Phosphate Pathway.png  Source: http://en.wikipedia.org/w/index.php?title=File:Pentose_Phosphate_Pathway.png  License: Creative Commons Attribution-Sharealike 3.0
 Contributors: GdenBesten
Image:Ox Pentose phosphate pathway.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Ox_Pentose_phosphate_pathway.svg  License: Public Domain  Contributors: Yikrazuul
Image:PPP (en).svg  Source: http://en.wikipedia.org/w/index.php?title=File:PPP_(en).svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Mike Jones
Image:Citric acid cycle with aconitate 2.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Citric_acid_cycle_with_aconitate_2.svg  License: Creative Commons Attribution-Sharealike
3.0  Contributors: Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins
Image:TCACycle_WP78.png  Source: http://en.wikipedia.org/w/index.php?title=File:TCACycle_WP78.png  License: Creative Commons Attribution 3.0  Contributors: Alexander Pico, Thomas
Kelder, Martijn van Iersel, Kristina Hanspers, Kdahlquist, Nick Fidelman
Image:Mitochondrial electron transport chain—Etc4.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Mitochondrial_electron_transport_chain—Etc4.svg  License: Public Domain
 Contributors: Fvasconcellos 22:35, 9 September 2007 (UTC)
Image:Ubiquinone–ubiquinol conversion.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Ubiquinone–ubiquinol_conversion.svg  License: Public Domain  Contributors:
Fvasconcellos 03:07, 12 September 2007 (UTC)
Image:Complex I.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Complex_I.svg  License: Public Domain  Contributors: Fvasconcellos 23:51, 9 September 2007 (UTC)
Image:Complex II.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Complex_II.svg  License: Public Domain  Contributors: Fvasconcellos 22:14, 29 September 2007 (UTC)
Image:Complex III reaction.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Complex_III_reaction.svg  License: Public Domain  Contributors: Fvasconcellos 02:19, 19 September
2007 (UTC)
File:Complex IV.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Complex_IV.svg  License: Public Domain  Contributors: Fvasconcellos 01:21, 10 October 2007 (UTC)
Image Sources, Licenses and Contributors 425

Image:ATPsyn.gif  Source: http://en.wikipedia.org/w/index.php?title=File:ATPsyn.gif  License: Public Domain  Contributors: Original uploader was TimVickers at en.wikipedia
File:Seawifs global biosphere.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Seawifs_global_biosphere.jpg  License: unknown  Contributors: Luis Fernández García, Tano4595,
TheDJ, Túrelio, Yikrazuul, 1 anonymous edits
File:Photosynthesis equation.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Photosynthesis_equation.svg  License: Public Domain  Contributors: ZooFari
File:Photosynthesis.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Photosynthesis.gif  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:At09kg
File:Simple photosynthesis overview.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Simple_photosynthesis_overview.svg  License: Creative Commons Attribution-Share Alike
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File:Chloroplast.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chloroplast.svg  License: Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors: SuperManu
File:Thylakoid membrane.png  Source: http://en.wikipedia.org/w/index.php?title=File:Thylakoid_membrane.png  License: Public Domain  Contributors: Original uploader was Tameeria at
en.wikipedia
File:Z-scheme.png  Source: http://en.wikipedia.org/w/index.php?title=File:Z-scheme.png  License: GNU Free Documentation License  Contributors: w:User:Bensaccount
File:Calvin-cycle4.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Calvin-cycle4.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Mike Jones
File:HatchSlackpathway2.svg  Source: http://en.wikipedia.org/w/index.php?title=File:HatchSlackpathway2.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors:
HatchSlackpathway.svg: *HatchSlackpathway.png: Adenosine derivative work: Jamouse derivative work: Adenosine (talk)
File:Leaf 1 web.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Leaf_1_web.jpg  License: Public Domain  Contributors: Ies, Ranveig, Red devil 666, Rocket000, WeFt,
Überraschungsbilder
File:Saturated Fatty Acid Synthesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Saturated_Fatty_Acid_Synthesis.png  License: Creative Commons Zero  Contributors:
Bochyboch
Image:Acety-CoA ACP transacylase.png  Source: http://en.wikipedia.org/w/index.php?title=File:Acety-CoA_ACP_transacylase.png  License: Creative Commons Zero  Contributors:
Bochyboch
Image:Malonyl-CoA ACP transacylase.png  Source: http://en.wikipedia.org/w/index.php?title=File:Malonyl-CoA_ACP_transacylase.png  License: Creative Commons Zero  Contributors:
Bochyboch
Image:3-ketoactl-ACP synthetase.png  Source: http://en.wikipedia.org/w/index.php?title=File:3-ketoactl-ACP_synthetase.png  License: Creative Commons Zero  Contributors: Bochyboch
Image:3-ketoacyl-ACP reductase.png  Source: http://en.wikipedia.org/w/index.php?title=File:3-ketoacyl-ACP_reductase.png  License: Creative Commons Zero  Contributors: Bochyboch
Image:3-hydroxyacyl-ACP dehydrase.png  Source: http://en.wikipedia.org/w/index.php?title=File:3-hydroxyacyl-ACP_dehydrase.png  License: Creative Commons Zero  Contributors:
Bochyboch
Image:Enoyl-ACP reductase.png  Source: http://en.wikipedia.org/w/index.php?title=File:Enoyl-ACP_reductase.png  License: Creative Commons Zero  Contributors: Bochyboch
File:Anaerobic desaturation.png  Source: http://en.wikipedia.org/w/index.php?title=File:Anaerobic_desaturation.png  License: Creative Commons Zero  Contributors: Bochyboch
File:Aerobic desaturation.png  Source: http://en.wikipedia.org/w/index.php?title=File:Aerobic_desaturation.png  License: Creative Commons Zero  Contributors: Bochyboch
Image:Branched fatty acid synthesis-valine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Branched_fatty_acid_synthesis-valine.png  License: Creative Commons Zero
 Contributors: Bochyboch
Image:Branched fatty acid synthesis-leucine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Branched_fatty_acid_synthesis-leucine.png  License: Creative Commons Zero
 Contributors: Bochyboch
Image:Branched fatty acid synthesis-isoleucine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Branched_fatty_acid_synthesis-isoleucine.png  License: Creative Commons Zero
 Contributors: Bochyboch
File:11-cyclohexyludencanioc acid.png  Source: http://en.wikipedia.org/w/index.php?title=File:11-cyclohexyludencanioc_acid.png  License: Creative Commons Zero  Contributors: Bochyboch
File:Tuberculostearic acid synthesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Tuberculostearic_acid_synthesis.png  License: Creative Commons Zero  Contributors:
Bochyboch
Image:Biotin_carboxylase_rainbow.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biotin_carboxylase_rainbow.png  License: Creative Commons Zero  Contributors: Nw.NPC
Image:BCCP.png  Source: http://en.wikipedia.org/w/index.php?title=File:BCCP.png  License: Creative Commons Zero  Contributors: Nw.NPC
Image:Carboxytransferase_2F9Y_E-Coli.png  Source: http://en.wikipedia.org/w/index.php?title=File:Carboxytransferase_2F9Y_E-Coli.png  License: Creative Commons Zero  Contributors:
Nw.NPC
Image:ACAC mechanism.png  Source: http://en.wikipedia.org/w/index.php?title=File:ACAC_mechanism.png  License: Public Domain  Contributors: Original uploader was BorisTM at
en.wikipedia
Image:Control of Acetyl CoA Carboxylase corrected.png  Source: http://en.wikipedia.org/w/index.php?title=File:Control_of_Acetyl_CoA_Carboxylase_corrected.png  License: Public
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File:FattyAcid-Activation.png  Source: http://en.wikipedia.org/w/index.php?title=File:FattyAcid-Activation.png  License: Public Domain  Contributors: Butko
Image:LCHAD deficiency.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:LCHAD_deficiency.jpg  License: GNU Free Documentation License  Contributors:
User:Samir_(The_Scope)
Image:Beta-Oxidation1.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-Oxidation1.svg  License: Public Domain  Contributors: NEUROtiker
Image:Beta-Oxidation2.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-Oxidation2.svg  License: Public Domain  Contributors: NEUROtiker
Image:Beta-Oxidation3.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-Oxidation3.svg  License: Public Domain  Contributors: NEUROtiker
Image:Beta-Oxidation4.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-Oxidation4.svg  License: Public Domain  Contributors: NEUROtiker
File:Nitrogen Cycle.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Nitrogen_Cycle.jpg  License: Public Domain  Contributors: Environmental Protection Agency
Image:A sectioned alder root nodule gall.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:A_sectioned_alder_root_nodule_gall.JPG  License: Public Domain  Contributors:
Rosser1954
Image:An alder root nodule gall.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:An_alder_root_nodule_gall.JPG  License: Public Domain  Contributors: Rosser1954
Image:NitrogenReduction.png  Source: http://en.wikipedia.org/w/index.php?title=File:NitrogenReduction.png  License: GNU Free Documentation License  Contributors: user:Rosarinagazo
Image:Nucleotides 1.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleotides_1.svg  License: Public Domain  Contributors: Boris (PNG), SVG by Sjef
Image:Ribose structure 2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Ribose_structure_2.png  License: GNU Free Documentation License  Contributors: Kauczuk, Stepa
Image:Nucleotides syn2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleotides_syn2.png  License: Public Domain  Contributors: Original uploader was BorisTM at
en.wikipedia
Image:Nucleotides syn1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleotides_syn1.png  License: Public Domain  Contributors: Original uploader was BorisTM at
en.wikipedia
Image:Nucleotides syn3.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nucleotides_syn3.png  License: Public domain  Contributors: User:Ronhjones
Image:Urea cycle.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Urea_cycle.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Yikrazuul
File:Urea-Cycle scheme 2006-01.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Urea-Cycle_scheme_2006-01.svg  License: Public Domain  Contributors: Ayacop, Benjah-bmm27
File:Urea cycle 2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Urea_cycle_2.png  License: Public domain  Contributors: Original uploader was BorisTM at en.wikipedia
Image:Epinephrine structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Epinephrine_structure.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Acdx
Image:Signal transduction v1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Signal_transduction_v1.png  License: GNU Free Documentation License  Contributors: Original
uploader was Roadnottaken at en.wikipedia
Image:Signal transduction publications graph.jpeg  Source: http://en.wikipedia.org/w/index.php?title=File:Signal_transduction_publications_graph.jpeg  License: Public Domain
 Contributors: K.murphy, Tamiasciurus, 1 anonymous edits
Image:Integrin sig trans overview.jpeg  Source: http://en.wikipedia.org/w/index.php?title=File:Integrin_sig_trans_overview.jpeg  License: Public Domain  Contributors: K.murphy, Rjwilmsi, 1
anonymous edits
File:Blue circle for diabetes.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Blue_circle_for_diabetes.svg  License: Public Domain  Contributors: IntDiabetesFed
Image Sources, Licenses and Contributors 426

File:Main symptoms of diabetes.png  Source: http://en.wikipedia.org/w/index.php?title=File:Main_symptoms_of_diabetes.png  License: Public Domain  Contributors: Mikael Häggström
Image:Suckale08 fig3 glucose insulin day.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Suckale08_fig3_glucose_insulin_day.jpg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: Jakob Suckale, Michele Solimena
Image:Glucose-insulin-release.png  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose-insulin-release.png  License: GNU Free Documentation License  Contributors: Original
uploader was Prisonblues at en.wikipedia
File:Diabetes world map - 2000.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Diabetes_world_map_-_2000.svg  License: Creative Commons Attribution-Sharealike 2.5
 Contributors: Lokal_Profil
Image:Diabetes mellitus world map - DALY - WHO2004.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Diabetes_mellitus_world_map_-_DALY_-_WHO2004.svg  License:
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File:Loudspeaker.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Loudspeaker.svg  License: Public Domain  Contributors: Bayo, Gmaxwell, Husky, Iamunknown, Mirithing,
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Image:DNA replication split.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_replication_split.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported
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File:DNA replication.theora.ogv  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_replication.theora.ogv  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
Cookatoo.ergo.ZooM
Image:DNA polymerase.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_polymerase.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors:
Madprime
Image:DNA replication en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_replication_en.svg  License: Public Domain  Contributors: LadyofHats Mariana Ruiz
Image:1axc tricolor.png  Source: http://en.wikipedia.org/w/index.php?title=File:1axc_tricolor.png  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Opabinia
regalis
Image:Cell Cycle 2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cell_Cycle_2.png  License: GNU Free Documentation License  Contributors: Original uploader was Zephyris at
en.wikipedia
Image:brokechromo.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Brokechromo.jpg  License: GNU Free Documentation License  Contributors: Multichill, Square87, Wickey, 2
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Image:Ssvsds.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Ssvsds.jpg  License: GNU Free Documentation License  Contributors: Bestiasonica, Bkell, Square87
Image:Uracil base glycosidase.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Uracil_base_glycosidase.jpg  License: Public Domain  Contributors: Original uploader was
TimVickers at en.wikipedia
Image:DNA Repair.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_Repair.jpg  License: Public Domain  Contributors: Courtesy of Tom Ellenberger, Washington University
School of Medicine in St. Louis.
Image:Dnarepair1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Dnarepair1.png  License: unknown  Contributors: Harold Brenner
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File:simple transcription elongation1.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Simple_transcription_elongation1.svg  License: Public Domain  Contributors: Forluvoft
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File:Transcription label en.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Transcription_label_en.jpg  License: GNU Free Documentation License  Contributors: InfoCan, Jacopo
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File:RetroTranscription.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:RetroTranscription.jpg  License: Public Domain  Contributors: Cyberugo
File:Gene expression control.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gene_expression_control.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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Image:TRNA-Phe yeast 1ehz.png  Source: http://en.wikipedia.org/w/index.php?title=File:TRNA-Phe_yeast_1ehz.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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Image:Insulinpath.png  Source: http://en.wikipedia.org/w/index.php?title=File:Insulinpath.png  License: Creative Commons Attribution 2.5  Contributors: Original uploader was Takometer at
en.wikipedia
Image:GeneticCode22.svg  Source: http://en.wikipedia.org/w/index.php?title=File:GeneticCode22.svg  License: Public Domain  Contributors: İnfoCan
Image:Proteaosome 1fnt side.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteaosome_1fnt_side.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
Thomas Splettstoesser
Image:Proteaosome 1fnt top.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteaosome_1fnt_top.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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Image:1G0U subunits sideview.png  Source: http://en.wikipedia.org/w/index.php?title=File:1G0U_subunits_sideview.png  License: GNU Free Documentation License  Contributors:
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Image:Proteasome cutaway 2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteasome_cutaway_2.png  License: GNU Free Documentation License  Contributors: Opabinia
regalis
Image:Hslvu ecoli.png  Source: http://en.wikipedia.org/w/index.php?title=File:Hslvu_ecoli.png  License: GNU Free Documentation License  Contributors: Opabinia regalis
Image:Bortezomib.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Bortezomib.svg  License: Public Domain  Contributors: Benjah-bmm27, Fvasconcellos
Image:2f16 bortezomib pink.png  Source: http://en.wikipedia.org/w/index.php?title=File:2f16_bortezomib_pink.png  License: GNU Free Documentation License  Contributors: Opabinia
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