2.

1 [BIOCHEMISTRY] Introduction to Metabolism

[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva
July 24, 2013
Dr. Balcueva
Go K, Golingan, Gomez, Gonzales A., Gonzales S, Gorospe, Hamtig, Hechanova

OUTLINE
I. Metabolism Catabolic Processes
A. Categories of Metabolism
Aerobic: Glucose  pyruvate  acetyl CoA
II. Intermediary Metabolism
Glycolysis
A. Energy Metabolism
Anaerobic: Glucose  Lactate
III. Metabolic Pathways
Fatty acids  Acetyl CoA
IV. Metabolic Fuels
+
β – oxidation NADH-H and FADH
2
A. Fates of Glucose
(For chemiosmotic production of ATP)
B. Fates of Lipids
+
C. Fates of Amino Acids Acetyl CoA oxidation  NADH-H and FADH2
Citric Acid Cycle (For chemiosmotic production of ATP)
V. Intracellular Location of Basic Pathways
VI. Metabolic Regulation
All 3 food groups converge here
A. Patterns of Metabolic Regulation
Electron Electrons passed down to O
2
VII. Clinical Correlation
Transport
Chemiosmotic coupling
VIII. Appendix System
IX. Competencies
Nitrogen:
AA Catabolism -Redistributed if reduced
-Eliminated by urea cycle if excess
OBJECTIVES
Table 1. Catabolic Processes and their Products
General Objective:

To explain thoroughly how cells carry out and regulate

2. Anabolism
complex reaction sequences
- Synthesis of complex organic molecules needed for
Specific Objectives:
cell maintenance, growth and reproduction, i.e.:
1. To be able to differentiate between anabolic and
 Glycogenesis
catabolic pathways
 Gluconeogenesis
2. To be able to explain briefly how carbohydrates. Lipids,

and proteins are metabolized

Anabolic Processes
3. To be able to correlate relationships between each
pathway Glycogenesis Glucose  Glycogen
Gluconeogenesis Pyruvate  Glucose

Palmitate Biosynthesis Acetyl CoA  Fatty Acids

Reference: Murray RK, Bender DA. Botham KM, Kennelly PJ,
Non-essential AA α – ketoacids 
Rodwell VW, Weil PA. 2009. Harper’s Illustrated Biochemistry,
th
biosynthesis aminotransferase rxn
28 Edition. McGraw-Hill Companies; UERM Class 2016A
Purine & pyrimidine Nitrogen donors  Ring
Trans; and lecture slides.
nucleotide biosynthesis structures

Protein biosynthesis Translation

Special Notes: Bold – emphasis
Nucleic Acid biosynthesis Replication, Transcription

Table 2. Anabolic Processes and their Products

I. METABOLISM

- Entire network of chemical reactions carried out by living

Review:
cells
Catabolic Anabolic
- Thousands of reactions simultaneously occuring
Complex  Simple Simple  Complex
- Controlled so that unwanted accumulations or deficiencies of
(Break down) (Biosynthesis)
intermediate products do not occur
Exergonic Endergonic
- Causes of accumulation/deficiencies:
Energy releasing Energy requiring
 Nutritional, coenzyme, cofactor deficiency
Table 3. Catabolic vs. Anabolic Processes
 Hormonal imbalance

 Presence of drugs and toxins

3. Amphibolic

- Act as links between anabolism and catabolism

Metabolism includes:
- At the crossroad between the 2 pathways, i.e.:
1. Interconversion of chemical compounds within the body
 Citric Acid Cycle  usually catabolic but
2. Pathways taken by molecules
intermediates can be used as precursors of
3. Interrelationships between the pathways
other rxns
4. Regulating mechanisms

II. INTERMEDIARY METABOLISM

Categories:
- Applied to reactions involving the low molecular weight
1. Catabolism
molecules that are metabolites in the degradation or
- Degradation of complex substances to liberate
biosynthesis of biopolymers
smaller molecules and energy, i.e.:

 Degradation of CHON (protein) to AA (amino

Energy Metabolism:
acids)
- Part of intermediary metabolism consisting of pathways that
 Triglycerides to FA (fatty acids)
store or generate metabolic energy
 Glucose to Pyruvate

- [1 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova
[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva
- Most organisms derive both the raw materials and the - Requirement for metabolic
fuel is relatively constant
energy for biosynthesis from organic fuel molecules such as throughout the day
(physical activity increases metabolic rate
glucose only by 40-50% over metabolic rate)
- Need to form reserves of glycogen and triacylglycerol for use
III. METABOLIC PATHWAYS during intervening time when there is no intake of food
- Obesity: Intake of metabolic fuels is consistently greater
- Sequences of reactions that include the reactants,
intermediates, products and the enzymes involved than energy expenditure; surplus
is stored largely as
triacylglycerol in the adipose tissue
- 3 molecules catabolized to produce energy:
- Emaciation: Intake of metabolic fuels is consistently lower
 Carbohydrates
than energy expenditure, there are negligible reserves of fat
 Protein
and carbohydrate; amino acids from protein turnover are
 Fats
used for energy-yielding metabolism rather than replacement
- Products of digestion:
protein synthesis
 Glucose

 Amino acids
IV. METABOLIC FUELS
 Fatty acids and glycerol
- In different phases/ levels of glucose in the body:
- All the products of digestion are metabolized to a common
 Fed state – metabolic fuel is glucose
product: acetyl-CoA
 Fasting state – glycogen, fatty acids, amino acids,
 Acetyl-CoA is oxidized by the citric acid cycle (CAC)
ketone bodies
 CAC substrate
- Major hormones that control utilization of fuel: Insulin and
- Carbohydrates  simple sugars (glucose)  Acetyl-CoA
Glucagon
- Protein  Amino acids (composed of carbon skeleton and
 Insulin
amino group)  Acetyl-CoA
o In both liver and skeletal muscle, insulin acts to
- Fat  Fatty acids + glycerol  Acetyl-CoA
stimulate glycogen synthetase and inhibit glycogen
phosphorylase
o In adipose tissue, insulin stimulates glucose uptake,
its conversion to fatty acids, and esterification to
TAG. Extracellular lipoprotein lipase is synthesized
and activated in response to insulin.
 Glucagon
o Inhibits glycogen synthetase and activates glycogen
phosphorylase in the liver.
o In adipose tissue, increased glucagon results in
inhibition of lipogenesis.

Fates of Glucose
1. Converted to pyruvate  acetyl CoA + CO + H O
2 2

2. Glycogen – storage for glucose in the liver and skeletal

muscle
3. Pentose phosphate pathway - provides NADPH and
ribose sugar for nucleic acid synthesis
4. Triose phosphates – glycerol moeity provides for synthesis
of triacylglycerides
5. Pyruvate, α-ketoglutarate and oxaloacetate – precursors
of amino acids

Glycolysis
- Can occur anaerobically (oxygen absent) but instead of
pyruvate, the product will be lactate
Figure 1. Overview of the metabolic pathways
- Linked to oxidative phosphorylation and thus, also

producing ATP
- Amino acids are not stored in the body
Pentose Phosphate Pathway
 Excess/not needed amino group is degraded and
- A source of reducing equivalents but instead NADPH is
excreted as urea; carbon skeleton catabolized to acetyl-
used for biosynthesis
CoA and converted to fats or glucose
- Source of ribose for nucleotide and nucleic acid synthesis
- Glucose stored as glycogen in the liver and muscles
- In liver and skeletal muscles: reduction of glutathione
- Triacylglycerol stored in the adipose tissue
Acyl glycerol (fat) Pathway
- Citric Acid Cycle: Acetyl CoA is oxidized so energy is
- Triose phosphate  glycerol moiety of triacylglycerols
released as reducing equivalent (2H) which is captured by
Amino Acid Synthesis
acceptors (ex. NADP, NAD, ADP, FMN, etc.)
- Via pyruvate and/or via intermediates of TCA
 Energy released: not wasted, but stored; can be brought
Steroid Synthesis
to mitochondria to be converted to ATP (in electron
- Acetyl-CoA is a precursor of fatty acids and cholesterol
transport chain)
Glycogenesis
 Releases CO2 as well
- Formation of glycogen when glucose in in excess
Gluconeogenesis
Metabolic process:
- Synthesis of glucose from non-carbohydrate sources such
- Nature of diet sets the basic pattern of metabolism
as lactate, amino acids, glycerol

- [2 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova
[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva

Figure 4. Overview of the major pathways and end products in amino

acid metabolism

- Integration of metabolism at the tissue and organ level:

 Glucose and amino acids are absorbed by the liver via

Figure 2. Interrelationships of Carbohydrate Metabolic Pathways

hepatic portal vein

 Liver maintains blood level by:

Fates of Lipids
o Glycogenolysis
1. Oxidizes to CO and H O with reducing equivalents
2 2
o Gluconeogenesis
2. Precursor for cholesterol and other steroids
3. Forms ketone bodies (acetoacetate and 3-hydroxybutyrate
[fuels in prolonged fasting])

Figure 5. Transport and Fate of carbohydrates and amino acid

substrates and metabolites

Dietary Lipids:
Hydrolyzed to monoacylglycerols and fatty acids

Re-esterified in intestinal mucosa and packaged with protein

Lymphatic system as chylomicrons

Figure 3. Overview of major lipid metabolism pathways 

Metabolized by muscle and adipose tissue via lipoprotein lipase
Fates of Amino Acids
- Very low density lipoproteins (VLDL)
1. Oxidized to CO and H O (only the carbon skeleton of the
2 2
o Triacylglycerol (TAG) from lipogenesis, fatty acids, and
AA side-chains are left alone)
chylomicron remnants and secreted into the circulation
2. Gluconeogenesis – AAs can be deaminated and
- Ketone Bodies
precursors can be formed ie. alanine to pyruvate
o Partial oxidation of fatty acids in the liver
3. Form ketone bodies (again, only carbon skeleton used)
o Used as fuel by extrahepatic tissues including the brain
but not the erythrocytes
 - [3 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova
[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva
- Products of lipid digestion enter the circulation as
chylomicrons

Figure 6. Transport and Fate of major lipid substrates and metabolites.

[FFA, free fatty acids; LPL, lipoprotein lipase; MG, monoacylglycerol;
TG, triacylglycerol; VLDL, very low density lipoprotein]

- Many metabolic fuels are inconvertible

 Fatty acids, and ketone bodies formed from them
cannot be used for the synthesis of glucose
 The reaction of pyruvate dehydrogenase, forming acetyl
CoA, is irreversible

Figure 7. Intracellular location and overview of major metabolic

o For every 2 carbon unit from acetyl CoA that enters
pathways in a liver perenchymal cell
the citric acid cycle, there is a loss of 2 carbon
(AA metabolism ofone or more essntial amino acids;
atoms as CO before oxaloacetate is formed.
2
AAmetabolism of more nonessential amino acids)
 Lysine and leucine yield only acetyl CoA on oxidation.

o Cannot be used for gluconeogenesis

 Phenylalanine, tyrosine, tryptophan, and isoleucine give
rise to both acetyl CoA and intermediates that can be
used for gluconeogenesis
 Ketogenic – used to refer to amino acids that give rise
to acetyl CoA
 Glucose is always required by the CNS and RBCs.

V. INTRACELLULAR LOCATIONS OF BASIC PATHWAYS

- Pathways in the cytoplasm:
 Glycolysis
 Pentose Phosphate Ppathway
 Lipid Synthesis
 Protein Synthesis
 Gluconeogenesis
 Glycogenesis and Glycogenolysis

- Pathways in the mitochondria:

 Citric Acid Cycle

 Electron Transport Chain Figure 8. Relative changes in metabolic parameters

during onset of
starvation
 ATP Synthesis

 Synthesis of Ketone Bodies

- During the onset of starvation, blood glucose levels are
 Beta Oxidation of Fatty Acids
maintained through the production of glucose from glycogen,

proteins, and fats. At first glycogen is broken down into

glucose with the aid of glucagon. However, only enough
glycogen is stored in the liver to last a few hours. Increasing
demands for glucose continuously increases glycogen
breakdown, which eventually depletes its amount in the liver.
Thereafter, blood glucose levels are maintained by the
breakdown of fats that will become the primary energy
source. The liver metabolizes fatty acids into ketone bodies
that can be used as a source of energy. (McGraw-Hill
Education)
-

- [4 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova
[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva
Fed 40 Hours 7 Days
 Skeletal muscles: It utilizes glucose as its energy
Fasting starvation
source, resulting to lactate and CO2 formation. It stores
Glucose 5.5 3.6 3.5
glycogen for muscle contraction and represents a
Free fatty 0.30 1.15 1.19
considerable amount ofprotein, reserved for use during
acids
starvation.
Ketone Negligible 2.9 4.5
 Adipose tissue: It is considered the main fuel reserve
bodies
of the body, used during starvation. Glucagon activates
Table 4. Plasma Concentrations of Metabolic Fuels (mmol/L) in the Fed
a hormone-sensitive lipase, which hydrolyzes
and Fasting States (The amount of Ketone bodies (negligible in Fed
State) and Free fatty acids increase as one approaches the starvation
triacylglycerols yielding glycerol and fatty acids. These
state. The opposite is true for Glucose)
are then released into the bloodstream as lipoproteins.

These are taken up by tissues, except the brain and

Energy O2 CO2 RQ (CO2 Energy
RBC, and oxidized as fuel.
yield consumed produced prod/O2 (kJ/L
 Brain: Usually neurons use only glucose as energy
(kJ/g) (L/g) (L/g) consumed) O2)
source. Since the brain stores only a very small amount
Carbohydrates
16 0.829 0.829 1.00 20
of glycogen, it needs a steady supply of glucose. During
Protein 17 0.966 0.782 0.81 20
long fasts, it oxidizes ketone bodies.
Fat 37 2.016 1.427 0.71 20
Alcohol  Kidney: It can perform gluconeogenesis and release
29 1.429 0.966 0.66 20
glucose into the bloodstream. It is also responsible for
Table 5. Energy Yields, Oxygen Consumption, and Carbon Dioxide
Production in the Oxidation of Metabolic Fuels
the excretion of urea, electrolytes, etc.
 Heart: Myocardium (cardiac muscle cells) is able to
STARVE-FEED CYCLE
produce energy from several substrates: fatty acids,
 Feed: refers to the intake of meals (the variable fuel input)
glucose, lactate, pyruvate, ketone bodies and even
after which the fuel is stored (as glycogen and
aminoacids. Preference of individual substrates
triacylglycerol) to meet metabolic needs of fasting.
representing the particular sources of energy depends
 Fed State: glucose as its major fuel; its respiratory on their current
concentration in both blood and cardiac
quotient is the ratio of CO produced to O consumed
2 2 muscle cells. The selection of substrates is also
o Insulin: controls uptake of glucose in muscle cells determined by natural
capacity of particular enzymatic
and adipose tissues systems of the cardiac muscle cell, which limitates
o GLUT4: glucose transporter in muscles and
predominantly the utilization of atypical sources of
adipose tissues energy also in case of their high concentration in blood.
 Fasting State: the metabolic status of a person who has
 Erythrocytes: The RBC has no nucleus or mitochondria
not eaten overnight; the metabolic state achieved after
to metabolize fatty and amino acids for the provision of
complete digestion and absorption of a meal; stimulates
energy substrates. Energy metabolism in the RBC is
mobilization of the metabolic fuel reserves; raises
almost exclusively through the breakdown of glucose.
circulating glucose

(Source:
VI. METABOLIC REGULATION
http://www.biochem.ucl.ac.uk/~dab/MSc%20clinbioc/MSc%20gluc
- Most pathways are irreversible under physiologic conditions
ose%20homeostasis.pdf)
- When a metabolite enters the pathway, each step occurs in

sequence without backing up or wasting cellular material or

Reasons for multistep pathway:
energy
1. Limited reaction- specificity of enzymes; each active site
- Reactions are regulated so as to proceed in only one
catalyzes only a single step of the pathway
direction
2. To control energy input and output – energy flow is

mediated by energy donors and acceptors

- Patterns of Metabolic Regulation
3. Catabolism of metabolic fuels yield 3 types of compounds
1. Allosteric Modification
that mediate the release of energy:
a. Feedback inhibition – when the end product of a
a) acetyl CoA
pathway controls its own rate of synthesis
b) nucleoside triphosphate (ATP)
b. Feedforward activation – when a metabolite
c) reduced coenzymes (NADH,FADH)
produced early in the pathway activates an enzyme
4. Some compounds can be substrates or products of more
that catalyzes a reaction further down the pathway.
than 1 enzyme so they can have 2 or more metabolic
A  B  C  D  E  P
functions.
|_______________
5. To establish control points:

- Balance of energy supply and demand in living cells

2. Covalent modification – alters catalytic rate by
- Ability to respond to internal signals or change in the
attachment to some group by a covalent bond (usually a
environment
phosphate group)

 Phosphorylation:
Major metabolic features of principal organs
o activates enzymes regulating catabolic
For the summary of the major metabolic features of the principal
pathways
organs, see appendix
o inhibits enzymes regulating anabolic pathways

o catalyzed by protein kinases

 Liver: Digestion of carbohydrates and proteins to
 Dephosphorylation:
glucose and amino acids are directed to the liver
o inhibits enzymes regulating catabolic pathways
through the hepatic portal vein. The liver also
o activates enzymes regulating anabolic
deaminates excess amino acids, forming urea, which is
pathways
delivered to the kidneys for excretion.
o catalyzed by protein phosphatase

- [5 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova
[BIOCHEMISTRY] 2.1 Introduction to Metabolism – Dr. Balcueva
3. Supply of Substrate o ↑ rate of protein synthesis in response to ↑availability
of
amino acids and metabolic acids is a response also to
 ATP or ADP
4. Hormones insulin action

 Insulin and Glucagon

Diabetes Mellitus

- Inability to utilize glucose can either be:

VII. CLINICAL CORRELATION
o Receptor resistance to insulin (Type II)
Cachexia
o ↓ insulin due to destruction of β-cells of pancreas (Type
- Release of cytokines in response to tumors and other
I)
pathologic conditions
- Happens in prolonged starvation (Harper’s)  Hyperglycemic patients
o Depletion of adipose tissue reserves (increased  No insulin = ↑ gluconeogenesis
and ↑lipolysis =
metabolic rate) ketogenesis in liver
o Catabolism of muscle tissue and used as fuel (increased o In uncontrolled
diabetes, ketoacidosis may occur and
protein catabolism) lead to coma
o For the fetus, ↑ demand for glucose by the fetus +
 Death results when essential tissue proteins are
lactose synthesis in lactation = ketosis
catabolized and not replaced.
 Mild ketosis with hypoglycemia (Harper’s)

- Associated with cancer

APPENDIX
Summary of the Major Metabolic Features of Principal Organs

COMPETENCIES
- Given a normal person, identify biochemical pathways or processes of
carbohydrates that are involved to achieve normal growth and
development.
- Apply the biochemical concepts and principles that will help explain the growth
and development of the normal person
- Correlate the biochemical or molecular basis with the growth and development of
the normal person

- [6 of 6] -
[BIOCHEMISTRY] 21- Go K, Golingan, Gomez, Gonzales A, Gonzales S, Gorospe, Hamtig,
Hechanova