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# BIOCHEMISTRY FLASH CARDS

Acidic dissociation
1. General expression: HA is the acid (proton donor) and A- is the conjugate base (proton
acceptor):
2. An acid dissociates in water to yield a hydrogen ion (H+) and its conjugate base
3. A base combines with H+ in water to form its conjugate acid
k1[HA] = forward rate, k-1[H+][A-] = reverse rate
Measures of acidity
1. pKa
When forward & reverse rates are equal, acidic dissociation constant, Ka, is defined by:
o k1/k-1 = [H+][A-] / [HA] = Ka
Expresses the STRENGTH OF AN ACID
pKa = -log[Ka]
Strong acid has pKa of W2 (H+ binds loosely to conjugate base)
Weak acid has a pKa of D10 (H+ binds tightly to conjugate base)
2. pH
Henderson-Hasselbalch equation: pH = pKa + log [A-]/[HA]
A measure of the ACIDITY OF A SOLUTION
pH = -log[H+]
Neutral solution has a [H+] of 10-7 pH = 7
Acidic solution has a [H+] > 10-7 pH < 7
Alkaline solution has a [H+] < 10-7 pH > 7
Buffers and Buffering capacity
1. A solution that contains a mixture of a weak acid and its conjugate base
2. It resists changes in [H+] on addition of acid or alkali
3. The buffering capacity of a solution is determined by the acid-base concentration and the pKa
of the weak acid
Maximum buffering effect occurs when:
o [weak acid] = [conjugate base]
When the buffer effect is at its maximum:

## o pH of the solution = pKa of the acid

4. Buffering effect is seen on a titration curve for a weak acid
The shape of the curve is the same for all weak acids
At the midpoint of the curve, the pH = pKa
The buffering region extends one pH unit above and below the pKa
What acid-base pair is an effective buffer in physiologic fluids?
What acid-base pair is the principal buffer in plasma and extracellular fluid (ECF)?
1. What acid-base pair is effective buffer in physiolog fluids?
H2PO4- and HPO422. What acid-base pair is the principal buffer in plasma and ECF?
CO2-H2CO3-HCO3- system (carbon dioxide-carbonic acid-bicarb)
CO2 + H2O carbonic anhydrase H2CO3 H+ + HCO3 Note: carbonic anhydrase converts CO2 to H2CO3 in RBCs
In this system, CO2 is an acid, so H-H equation is:
o pH = 6.1 + log [HCO3-] / (0.0301)PCO2
This system is effective around physiologic pH of 7.4, even though the pKa is only 6.1, for 4
reasons:
o Supply of CO2 from oxidative metabolism is unlimited, so effective concentration of CO2 is
very high
o Equilibration of CO2 with H2CO3 is very rapid
o CO2 removal by lungs allows for rapid changes in [H2CO3]
o Kidney can retain or excrete HCO3-, thus changing the concentration of the conjugate base
Acid-Base Disorders:
Acidosis and Alkalosis
1. Acidosis
Occurs when pH of blood and ECF falls < 7.35
Results in CNS depression
When severe, can lead to coma and death
Respiratory acidosis: pCO2 as a result of hypoventilation
Metabolic acidosis: [HCO3-] as a result of the addition of an acid stronger than H2CO3 to the
ECF
2. Alkalosis
Occurs when pH of blood and ECF is >7.45
When severe, can result in tetany
Respiratory alkalosis: pCO2 as result of hyperventilation
Metabolic alkalosis: [HCO3-] as a result of excess acid loss (e.g., vomiting) or addition of a
base (e.g., oral antacids)
Diabetic ketoacidosis

## 1. Combination of high blood levels of ketone bodies and a metabolic acidosis

2. Pathogenesis
Uncontrolled insulin-dep DM (type 1) glucose utilization, hyperglycemia fatty acid
oxidation
fatty acid oxidation excessive production of acetoacetic and 3-hydroxybutyric acids and
acetone (ketone bodies)
Acids dissociate at body pH and release H+ metabolic acidosis
3. Clinical picture
Dehydration
Lethargy
Vomiting
Drowsiness
Coma
4. Therapy: correct the hyperglycemia, dehydration, & acidosis
Insulin to correct the hyperglycemia
Fluids (physiologic saline) to treat dehydration
In severe cases: sodium bicarbonate to correct acidosis
Amino acids grouped by the properties of their R-groups
1. Aliphatic, nonpolar (hydrophobic)
Glycine
Alanine
Valine
Leucine
Isoleucine
Proline
2. Aromatic, nonpolar
Phenylalanine
Tyrosine
Tryptophan
3. Sulfer-containing
Cysteine
Methionine
4. Hydroxyl, mildly polar (uncharged, hydrophilic)
Serine
Threonine
5. Basic, polar

Lysine
Arginine
Histidine
6. Acidic, polar
Aspartic acid
Asparagine
Glutamic acid
Glutamine
Secondary structures of proteins and collagen
1. Secondary structure = arrangement of H bonds between peptide nitrogens & carbonyl oxygens
of different amino acids
2. Helical coils
Hydrogen-bonded nitrogens & oxygens are on nearby amino acids
Right-handed alpha helix most common
o Alpha-keratin in hair and nails
o Myoglobin has several alpha-helical regions
Proline, glycine, and asparagine helix breakers
3. Beta sheets (pleated sheets) may run parallel or antiparallel
Hydrogen bonds between residues on neighboring peptide chains
4. Left-handed helical strands
Wound into a supercoiled triple helix in collagen
Collagen major structural protein in the body
o Primary structure: repeating glycine-X-Y sequences
o X and Y are freqeuntly proline or lysine
o Contains hydroxyproline & hydroxylysine
Protein Denaturation Agents
1. Extremes of pH (e.g., strong acid or alkali)
2. Ionic detergents (e.g., sodium dodecylsulfate/SDS)
3. Chaotropic agents (e.g., urea, guanidine)
4. Heavy metal ions (e.g., Hg++)
5. Organic solvents (e.g., alcohol or acetone)
6. High temperature
7. Surface films (e.g., as when egg whites are beaten)
Sickle cell anemia
1. Caused by mutant sickle cell hemoglobin (Hgb S)
Hydrophobic valine replaces hydrophilic glutamate at position 6 of the beta-chain of normal

hemoglobin A (Hgb A)
2. Sickle cell disease
Individuals with homozygous genotype (SS)
Have only Hgb S in their RBCs
Symptoms
o Severe anemia: deoxy Hgb S produces fibrous precipitates formation of sickle cells shorter
life span severe anemia
o Acute episodes of vaso-occlusion sickle cell crisis
Sickle cells cant pass thru capillaries vasocclusion
Disabling pain that requires hospitalization
3. Sickle cell trait
Individuals with heterozygous genotype (AS)
Have both Hgb A and Hgb S in their RBCs
Symptoms
o Usually asymptomatic
o Episodes of hematuria
Scurvy
1. Defective collagen synthesis resulting from a vitamin C (ascorbic acid) deficiency
2. Consequences of abnormal collagen
Defective wound healing
Defective tooth formation
Loosening of teeth
Bleeding gums
Rupture of capillaries
3. Ascorbic acid is required for hydroxylation of proline and lysine during post-translational
modification of collagen
4. Pathogenesis
Hydroxylating rxn requires hydroxylase, O2, & Fe2+
Vit C is required to maintain iron in its oxidation state (Fe2+)
Hydroxyproline forms H-bonds that stabilize collagen helix
Symptoms of scurvy are thus the result of weakend collagen when these hydrogen bonds are
missing
Free energy change
1. The quanitity of energy from chemical reactions that is available to do work (DG)
2. The DG of a rxn A + B C + D is:
DG = DG0 + RTln ([C][D]) / [A][B])
o where DG0 is the standard free-energy change (when concentrations of all reactants and

products are 1M and pH = 7), R is the gas constant (1.987 cal/molK) and T is the absolute
temperature
3. When the rxn has reached equilibrium:
DG0 = RTlnKeq
Thermodynamic spontaneity: Exergonic and Endergonic Rxns
1. Exergonic rxns are spontaneous (rxn goes to the right)
Keq > 1
DG0 is negative
Final concentration of the products, C and D, is greater than that of the reactants, A and B
2. Endergonic rxns are nonspontaneous (rxn goes to the left)
Keq < 1
DG0 is positive
Final concentration of the reactants, A and B, is greater than that of the products, C and D
3. Note: DG0 CANNOT predict spontaneity under intracellular conditions
Intracellular spontaneity is a function of actual concentrations as well as Keq, DG, NOT DG0
Enthalpy, entropy, and free-energy change
1. Enthalpy (DH)
The amount of heat generated or absorbed in a rxn
2. Entropy (DS)
Measure of the change in randomness or disorder of system
when a salt crystal dissolves, when a solute diffuses from a more concentrated to a less
concentrated solution, and when a protein is denatured
when a complex molecule is synthesized from smaller substrates
3. Free-energy change (DG)
Is related to enthalpy and entropy as follows:
o DG = DH - T DS (where T = absolute temp in Kelvins)
Catalysts and the Rate of Reaction
1. Rate of reaction
The DG0 provides no info concerning the rate of conversion from A to B
When A is converted to B, it first goes through an energy barrier called the transition state, AB
The activation energy (DG) = energy required to scale the energy barrier and form the
transition state
The greater the DG, the lower the rate of the rxn converting A to B
2. Catalysts (mostly enzymes) result in a:
Lower DG
Faster reaction rate

Michaelis-Menten equation
1. Describes the kinetics of enzyme rxns
2. In enzyme-catalyzed rxns:
k1 k3
E + S ES E + P
k2
Where E=enzyme, S=substrate, P=product, k1-3 = rate constants
3. Velocity (v) of product formation is related to [ES]:
o v = k3[ES] where k3 is also called kcat
4. Michaelis-Menten eq predicts velocity if [enzyme] is constant:
Where Vm = max velocity & Km is the Michaelis constant
5. Km = [substrate] at which v = Vm ([S] = Km)
6. A plot of velocity versus [S] is a rectangular hyperbola
Lineweaver-Burk Equation
1. Form of the Michaelis-Menten eq, which is sometimes known as the double-reciprocal
equation:
1 = Km + [S] = Km x 1 + 1
v = Vm[S] Vm [S] Vm
2. The slope is Km/Vm
3. The Y-intercept = 1/Vm
4. The X-intercept is 1/Km
Enzyme Regulation:
How doe Inhibitors affect the Lineweaver-Burk plots?
1. Competitive inhibitors
apparent Km
Vm remains the same
slope
X-intercept has smaller absolute value
Y-intercept is unchanged
2. Noncompetitive inhibitors
Vm
Km unchanged
slope
X-intercept is unchanged
Y-intercept is larger
3. Uncompetitive inhibitors (bind only to ES complex)
Both Km & Vm are different lines on the plot are parallel

Allosteric regulation of enyzmes: Definition, How do they affect Km, and Example of
Hexokinase
1. Low-molec wgt effector binds to enzyme at a specific site other than active site (the allosteric
site) & alters its activity
2. Allosteric enzymes usually have >1 subunit and >1 active site
Active sites that interact cooperatively: velocity vs, [S] = sigmoid
Binding of 1 substrate facilitates binding of substrate at other sites
3. Effectors may have a + or effect on activity
Positive effectors the apparent Km
Negative effectors the apparaent Km
4. Example: muscle hexokinase
Hexokinase catalyzes 1st rxn in use of glucose my muscle cells:
o Glucose + ATP glucose-6-P + ADP
Hexokinase has a low Km compared to blood [glucose], so it is saturated and operates at its Vm
When glycolysis slows down, gluc-6-P accumulates gluc-6-P allosterically inhibits
hexokinase (keeps gluc-6-P in balance)
Other mechanisms of enzyme regulation:
1. Induction/repression of enzyme synthesis
2. Covalent modificataion
3. Protein-protein interaction
1. Induction/repression of enzyme synthesis
Cytochrome P450 enzymes in the liver (degrade and detoxify drugs) are induced by the drugs
themselves
2. Covalent modificataion
Phosphorylase (enzyme that breaks down glycogen) is activated by phosphorylation of a
specific hydroxyl group
This phosphorylation is stimulated by hormones that elevate blood glucose, such as glucagon
and Epi
3. Protein-protein interaction between enzyme & regulatory protein
Pancreatic lipase (digests dietary fat) is assisted by colipase
Colipase anchors lipase to the surface of fat droplets
Mechanism and Treatment of Methanol & Ethylene glycol Poisoning
1. Mechanism of poisoning
Toxicity is caused by the action of their metabolites
In both cases, the 1st oxidation is carried out by alcohol dehydrogenase
o Methanol formaldehyde + formic acid
Eyes very sensitive to formaldehyde blindness

## o Ethylene glycol glycoaldehyde, oxalate, and lactate

Deposition of oxalate crystals in kidney kidney failure
2. Treatment
Initial infusion of ethanol competitive substrate displaces methanol or ethylene glycol from
active site of alcohol dehydrogenase
Prevents continued production of toxic metabolites
Citric acid cycle:
Location, Pathway, and Initial Substrate
1. Location
Mitochondria (found in all cells except RBCs)
2. Pathway
It is the final common pathway of oxidiative metabolism
3. Initial Substrate: Acetyl Coenzyme A (ACETYL CoA)
Condenses with oxaloacetate (OAA) to begin the cycle
4. Where does acetyl CoA come from?
The catabolism of carbs, fats, & proteins
o Glucose catabolism eventually produces pyruvate acetyl CoA via pyruvate dehydrogenase
o Fatty acids generate acetyl CoA via b-oxidation
o Some amino acids are degraded to acetyl CoA
What are the products of one revolution of the citric acid cycle?
1. 2 CO2 (most CO2 from metabolism)
2. Regeneration of one mole of OAA
4. 1 GTP 1 ATP
TOTAL OF 12 ATPs/acetyl CoA
Describe the anaplerotic rxns that provide OAA and other citric acid cycle intermediates
1. Pyruvate carboxylase in the liver & kidney:
Pyruvate + ATP + HCO3- OAA + ADP + Pi
2. Phosphoenolpyruvate (PEP) carboxykinase in heart and skeletal muscle:
PEP + CO2 + GDP OAA + GTP
3. Malic enzyme in many tissues:
4. Glutamate dehydrogenase in the liver:

## Regulation of the citric acid cycle

1. Step: Acetyl CoA + OAA citrate
Enzyme: citrate synthase
Inhibitors: ATP ( Km), long-chain acyl-CoA
Enzyme: isocitrate dehydrogenase
3. Step: a-ketoglutarate + NAD+ + CoASH succinyl CoA + NADH + CO2
Enzyme: a-ketoglutarate dehydrogenase (note: requires same cofactors as the pyruvate
dehydrogenase complex)
Electron Transport Chain (ETC) & Oxidative Phosphorylation
(BOTH in MITOCHONDRIA)
1. ETS: electrons pass from NADH or FADH2 to ultimately reduce O2 and produce H2O
2. Oxidative phosphorylation: uses energy derived from flow of electrons thru ETS to drive
synthesis of ATP from ADP and Pi
NADH dehydrog. = Complex I, Succinate dehydrog. = Complex II (where FADH2 enters not
pictured here), Cytochrome bc1 = Complex III, Cytochrome oxidase = Complex IV
Chemiosmotic hypothesis
1. Describes coupling of electron flow thru ETS to ATP
2. Respiratory complexes as proton pumps:
As electrons (e-) pass thru complexes I, III, & IV, hydrogens are pumped across inner
membrane to intermembrane space
The [H+] in the intermembrane space relative to matrix
This generates a proton-motive force as result of 2 factors:
o Difference in pH (DpH)
o Difference in electrical potential (Dy) between the intermembrane space and the mitochondrial
matrix
3. ATP synthase complex (complex V)
Hydrogen ions pass back into the matrix thru complex V, and in doing so, drive the synthesis of
ATP
o Passage of pair of e- from NADH to O2 3ATP
o Passage of e- pair from FADH2 to O2 (bypass I) 2ATP
Uncouplers and Inhibitors of ETS

1. Uncoupling
Carry H+ across inner mit membrane w/o going thru complex V
This short-circuits the proton gradient and uncouples electron flow from ATP synthesis
Energy, instead of used to make ATP, is dissipated as heat
Uncoupling agents:
o Dinitrophenol (2,4-DNP) former diet drug
Caused blindness (retina has rate of oxidativ metblism)
o Thermogenin helps to maintain normal body temp
Found normally in brown fat of newborn mammals
2. Inhibitors (via blocking e- flow thru complexes or direct action)
Complex I Amobarbital (barbiturate), Rotenone (insecticide), Piericidin A (antibiotic), Amytal
Complex II Antimycin A (antibiotic)
Complex IV Cyanide, Hydrogen sulfide, Carbon monoxide
ATP synthase Oligomycin
Carbohydrate digestion and absorption
1. Digestion
Disacharides (sucrose),oligosacharides (dextrins),& polysacharides (starch) are cleaved into
monosaccharides (glucose, fructose)
Starch: storage from of carbs in plants
o Hydrolyzed to maltose, maltotriose, and a-dextrins by a-amylase in saliva and pancreatic juice
Disaccharides & oligosaccharides
o Hydrolyzed to monosaccharides by enzymes on the surface of epithelial cells in the small
intestine
2. Absorption
Monosaccharides absorbed directly by carrier-mediated transport
These sugars (primarily glucose) travel via portal vein to liver for:
o Oxidation to CO2 and H2O for energy
o Storage as glycogen
o Conversion to triglyceride (fat)
o Release into general circulation (as glucose)
Glycogen metabolism
[Glycogen: carb storage, found chiefly in liver & muscle]
1. Glycogenesis (glycogen synthesis)
Activated substrate: Uridine diphosphate-glucose
Branching enzyme amylo (14) to (16) transglycosylase creates branches w/a-1,6 linkages
Stimulator: insulin (via dephosphorylation in muscle, liver, & fat)
Inhibitors: glucagon (liver), Epi (muscle & liver), phosphorylase (liver), cAMP, Ca2+ (muscle)

## 2. Glycogenolysis (glycogen breakdown)

Phosphorylase releases units of glucose 1-P from nonreducing end
Phosphoglucomutase converts glucose 1-P to glucose 6-P
Debranching system releases glucose residues from a-1,6 bonds
Stimulators: sames as inhibitors of glycogenesis
Inhibitor: insulin (via dephosphorylation in muscle, liver, and fat)
Glycolysis:
Location, Anaerobic and Aerobic
1. Location: cytosol in most tissues of the body
2. Anaerobic (without oxygen)
Glucose 2Lactate + 2ATP
Characteristic of skeletal muscle after prolonged exercise
Lactate dehydrogenase converts pyruvate to lactate
3. Aerobic:
Glucose + 6O2 6CO2 + 6H2O + 36-38 ATP
Charactersitic of the brain
NADH produced is oxidized by the mitochondrial ETS
ATP is generated by oxidative phosphorylation
Describe the first step in glycolysis
1. Phosphorylation involves rxn of glucose in presence of hexokinase OR glucokinase to form
glucose 6-phosphate
Hexokinase is found in the cytosol of most tissues:
o Low specificity (catalzyes phosphorylation of a wide variety of hexoses)
o Low Km (its saturated at normal blood [glucose])
o Inhibited by glucose 6-P (prevents cells from accumulating too much glucose since
phosphorylation traps glucose inside cells)
Glucokinase is present in the liver & pancreas (b-cells):
o High specificity for glucose
o High Km (above the normal blood [glucose])
o Inhibited by fructose 6-P (ensures glucose will be phosphorylated only as fast as it is
metabolized)
What happens in the 2 phases of glycolysis?
1. In the first phase (5 reactions):
1 mole of glucose is converted to 2 moles of glyceraldehyde 3-P
2 moles of ATP are consumed for each mole of glucose
2. In the second phase (5 reactions):

## Two moles of glyceraldehyde 3-P are oxidized to 2 moles of pyruvate

4 moles of ATP and 2 moles of NADH are generated for each mole of glucose
What do the following do:
1. Glycerol phosphate shuttle
2. Malate-aspartate shuttle
NADH produced in the cytosol DOES NOT pass through the mitochondrial inner membrane, but
1. Glycerol phosphate shuttle (most tissues)
It generates 2 ATP/cytosolic NADH = 36 moles of ATP/glucose
2. Malate-aspartate shuttle (heart, muscle, & liver)
It generates 3 ATP/cytosolic NADH = 38 ATP/glucose
Gluconeogenesis
1. Occurs primarily in the liver & kidney
2. Synthesis of glucose from small noncarb precursors (such as lactate and alanine)
3. Involves the reversible rxns of glycolysis
4. To bypass nonreversible steps of glycolysis, separate rxns occur:
Conversion of pyruvate to PEP bypasses pyruvate kinase
Conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by fructose 1,6-bisphosphatase
bypasses phosphofructokinase
Conversion of glucose 6-P to glucose by glucose 6-phosphatase bypasses hexokinase
5. Glucose from gluconeogenesis is released into the bloodstream for transport to tissues such as
the brain and exercising muscle
6. Gluconeogenic substrates:
Lactate
Pyruvate
Glycerol
Substances that can be converted to oxalacetate via the citric acid cycle (such as amino acid
carbon skeletons)
Cori cycle
1. Shuttling of gluconeogenic substrates between RBCs and muscle to liver, allowing muscle to
function anaerobically (net 2 ATP)
2. Lactate from exercising or ischemic muscle is carried by the circulation to the liver and serves
as a substrate for gluconeogenesis

3. The liver releases the resynthesized glucose into the circulation for transport back to the
muscle
Regulation of glycolysis
1. All are the irreversible steps:
Fructose 6-P fructose-1,6-BP via phosphofructokinase
o Stimulators: AMP, fructose 2,6-BP (in liver)
o Inhibitors: ATP, citrate
o Rate-limiting step
D-glucose glucose-6-P via hexokinase/glucokinase*
o Inhibitors: glucose-6-P
PEP pyruvate via pyruvate kinase
o Inhibitors: ATP, alanine
o Stimulators: fructose-1,6-BP (in muscle)
Pyruvate acetyl CoA via pyruvate dehydrogenase
o Inhibitors: ATP, NADH, acetyl CoA
2. Induced by insulin
Gluconeogenesis regulation
1. All are the irreversible steps:
Pyruvate OAA via Pyruvate carboxylase (mitochond)
o Requires biotin, ATP
o Activated by acetyl CoA
OAA PEP via PEP carboxykinase
o Requires GTP
Fructose-1,6-BP fructose-6-P via Fructose-1,6-BPase
Glucose-6-P glucose via Glucose-6-phosphatase
2. These enzymes are only found in liver, kidney, intestinal epithel
3. Muscle cannot participate in gluconeogenesis
4. Hypoglycemia is caused by a deficiency of these key enzymes
5. Induced by glucocorticoids, glucagon, cAMP
6. Suppressed by insulin
Pnemonic: Pathway Produces Fresh Glucose
Pyruvate dehydrogenase complex
1. Contains 3 enzymes that require 5 cofactors:
Pyrophosphate (from thiamine)
Lipoic acid
CoA (from pantothenate)

2. Reaction:
3. The complex is similar to the a-ketoglutarate dehydrogenase complex (same cofactors, similar
substrate and action)
4. Cofactors are the first 4 B vitamins plus lipoic acid:
B1 (thiamine; TPP)
B5 (pantothenate CoA)
Lipoic acid
Pentose phosphate pathway
1. Sites: lactating mammary glands, liver, adrenal cortex all sites of fatty acid or steroid
synthesis
2. Begins with glucose 6-P
3. The irreversible oxidative portion generates NADPH
NADPH needed for: fatty acid and cholesterol (steroid) synthesis, maintaining reduced
glutathione inside RBCs
4. The reversible nonxidative portion rearranges the sugars so they can reenter the glycolytic
pathway
5. Ribose 5-P, which is needed for nucleotide synthesis, can be formed from glucose 6-P by
either arm
6. Major regulatory enzyme: glucose 6-P dehydrogenase
Glucose 6-P 6-phosphogluconolactone
Sucrose and Lactose Metabolism
1. Sucrase converts sucrose to glucose and fructose
Hexokinase can convert fructose fructose 6-P (muscle, kidney)
Fructose enters glycolysis by a different route in the liver
Dihydroxyacetone phophate (DHAP) enters glycolysis directly
After glyceraldehyde is reduced to glycerol, it is phosphorylated and then reoxidized to DHAP
2. Lactase converts lactose to glucose + galactose
Galactokinase converts galactose galactose 1-P
Galactose 1-P glucose 1-P glycolysis

## Glycogen Storage Diseases

Result in abnl glycogen metabolism & glycogen in cells
DEFFECT TISSUE SIGNS, ETC.
Von Gierkes(type I) Glucose 6-P Liver & kidney Hepatomegaly, Failure to thrive,
Hypoglycemia, Ketosis, Hyperuricemia, Hyperlipidemia
Pompes (type II) a-1,4-glucosidase Lysosomes, All organs Failure of heart & lungs Death <2 yo
Coris(type III) Debranch enzyme Muscle & liver Similar to I, but milder
Anderson(type IV) Branching enzyme Liver & spleen Liver cirrhosis, death <2 y
McArdle (type V) Phosphorylase Muscle Painful muscle cramps w/exercise
Hers (type VI) Phosphorylase Liver Similar to type 1, but milder
Type VII Phosphofructokinase Muscle Similar to type V
Type VIII Phosphorylas kinase Liver Mild hepatomegaly, mild hypoglycemia
Hereditary enzyme deficiencies in lactose and sucrose metabolism
1. Hereditary enzyme deficiences in sucrose metablism:
Fructokinase deficiency essential fructosuria
o Benign disorder
Fructose 1-P aldolase deficiency hereditary fructose intolerance
o Characterized by severe hypoglycemia after ingesting fructose (or sucrose), jaundice, cirrhosis
2. Inherited enzyme deficiencies in lactose metabolism:
Lactase deficiency milk intolerance
o Develops in adult life (age-dep) or hereditary (blacks, Asians)
Galactokinase deficiency mild galactosemia
o Early cataract formation
Galactose 1-P uridyltransferase deficiency severe galactosemia (AUTOSOMAL
RECESSIVE)
o Cataract, hepatosplenomeg, growth failure, retardation, death
o Treatment: exclude galactose & lactose from diet
Pyruvate dehydrogenase deficiency
1. Pyruvate dehydrogenase deficiency neurologic defects
2. Causes backup of substrate (pyruvate & alanine), resulting in lactic acidosis
3. Treatment: intake of ketogenic nutrients (Lysine & Leucine are the only purely ketogenic
amino acids)
Glucose-6-phosphate dehydrogenase deficiency
2. Background:
G6PD is the rate limiting enzyme in HMP (hexose monophosphate) shunt, which includes the

## pentose phosphate pathwy (which yields NADPH)

NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and
peroxides
3. Manifestations of disease:
4. Pathogenesis:
Poor RBC defense against oxidizing agents (fava beans, sulfonamides, primaquine) and
antituberculosis drugs
5. More prevalent among blacks
6. Heinz bodies: altered Hemoglobin precipitates w/in RBCs
Lipid digestion
1. In mouth:
Medium-chain triacylglycerol (TGs) are hydrolyzed by lipase
Continues in stomach, producing a mix of diacylglycerols & FFAs
2. In the duodenum:
Lipids are emulsified by bile salts (made from cholesterol in liver)
3. In small intestine:
Emulsified fats are hydrolyzed by pancreatic lipase
Phospholipids are hydrolyzed by phospholipase A
Cholesterol esters are hydrolyzed by cholesterol esterase
4. Mixed micelles form, which contain:
Fatty acids
Diacylglyc
Monoacyl
Phospholipi
Cholesterol
VitA,D,E, K
Bile acids
5. Micelles absorbed in small intestine further metabolized
Medium-chain TGs are hydrolyzed
Medium-chain fatty acids (8-10 carbons) pass into portal vein
Long-chain fatty acids (>12 carbons) are reincorporated into TGs
TGs go into chylomicrons lymphatics circulation via thoracic duct
How are lipids transported to tissues?
1. Lipids are transported to tissues in the blood plasma primarily as lipoproteins:
Spherical particles w/a core that contain varying proportions of hydrophobic triacylglycerols &
cholesterol esters
Outer layer of cholesterol, phospholipids, and specific apoproteins

Lipoprotein absorption
1. Exogenous lipid (from intestine), except for medium-chain fatty acids, is released into the
plasma as chylomicrons
Chylomicrons contain a high proportion of TGs
TG is hydrolyzed to FFAs and glycerol by lipoprotein lipase on the surface of capillary
endothelium in muscle and adipose tissue
The cholesterol rich chylomicron remnants travel to the liver, where they are taken up by
receptor-mediated endocytosis (RME)
2. Endogenous lipid (from liver) is released into blood as VLDLs
VLDL TG is hydrolyzed by lipoprotein lipase to FFAs and glycerol, yielding low-density
lipoproteins (LDLs)
LDLs are removed from circulation by RME in tissues that contain LDL receptors (tissues that
need cholesterol, but mostly in liver)
LDL cholesterol:
o Inhibits HMG CoA reductase (RLS in cholesterol synthesis)
o Down-regulates LDL receptor synthesis LDL uptake
High density lipoproteins (HDLs) are made in the liver
Lipoprotein functions and associated apolipoproteins:
Chylomicrons
1. Delivers dietary triglycerides to peripheral tissues and dietary cholesterol to liver
2. Secreted by intestinal epithelial cells
3. Excess causes pancreatitis, lipemia retinalis, eruptive xanthomas
4. Associated apolipoproteins:
B-48 mediates secretion
As are used for formation of new HDL
C-II activates lipoprotein lipase
E mediates remnant uptake by liver
Lipoprotein functions and associated apolipoproteins:
VLDL
1. Delivers hepatic triglycerides to peripheral tissues
2. Secreted by liver
3. Excess causes pancreatitis
4. Associated apolipoproteins:
B-100 mediates secretion
C-II activates lipoprotein lipase
E mediates remnant uptake by liver

## Lipoprotein functions and associated apolipoproteins:

LDL
1. Transports hepatic cholesterol to peripheral tissues
2. Formed by lipoprotein lipase modification of VLDL in peripheral tissue
3. Taken up by target cells via RME
4. Excess causes atherosclerosis, xanthomas, and arcus corneaa (senilis?)
5. Associated apolipoproteins:
B-100 mediates binding to cell surface receptor for endocytosis
Lipoprotein functions and associated apolipoproteins:
HDL
1. Mediates centripetal transport of cholesterol (i.e. reverse cholesterol transport, from periphery
to liver, i.e. transports cholesterol from periphery to liver)
2. Acts as a repository for apoC & apoE (which are needed for chylomicron and VLDL
metabolism)
3. Secreted from both liver and intestine
4. Associated apolipoproteins:
As help form HDL structure
A-I in particular activates LCAT (which catalyzes esterification of cholesterol)
CETP mediates transfer of cholesteryl esters to other lipoprotein particles
Pneumonic: HDL is Healthy, LDL is Lousy
Oxidation of fatty acids
1. Occurs in mitochondrial matrix. The overall process is:
RCH2CH2COOH b-oxidation CH3COSCoA Citric acid cycle CO2+ H2O
2. Fatty acids must first be activated to their acyl CoA thioesters
Long-chain (LC) fatty acids (>12) activated in cytosol LC acyl CoAs are shuttled into mitoch
matrix by carnitine transport syst
MCFAs pass directly into the mitoch & are activated in the matrix
3. Fatty acyl CoA is then oxidized to CO2 and H2O by b-oxidation:
Continues in cycle until its completely converted to acetyl CoA
Each cycle generates 5 ATPs via ETS and 12 ATPs via combined action of citric acid cycle and
ETS
Terminal 3 carbons of odd-numbered fatty acids yield propionyl CoA as the final product,
which can:
o Enter the citric acid cycle (after carboxylation to succinyl CoA in a 3-rxn sequence requiring
biotin and Vit B12)
o Be used for gluconeogenesis

Ketogenesis
1. The formation of acetoacetate and b-hydroxybutyrate from metabolism of acetyl CoA in the
liver
2. Reaction:
Acetyl CoA + acetoacetyl CoA hydroxymethylglutaryl CoA (HMG CoA)
HMG CoA acetoacetate and acetyl CoA
3. How is acetoacetate used in the body?
Extrahepatic tissues (especially heart) can activate acetoacetate at the expense of succinyl CoA
and burn acetoacetyl CoA for energy
Glucose-starved brain can use acetoacetate for fuel (b/c its freely soluble in blood and easily
crosses the BBB)
Fatty acid synthesis
1. Carried out by fatty acid synthase, a cytosolic complex
2. Primary substrates:
Acetyl CoA: formed in mitoch, mainly by pyruvate dehydrogenase
o Its transported to cytosol by citrate-malate-pyruvate shuttle
Malonyl CoA: formed by biotin-linked carboxylation of actyl CoA
3. The acetyl and malonyl moieties are transferred from the sulfur of CoA to activate sulfhydryl
groups in the fatty acid synthase
4. 7 cycles lead to production of palmityl:enzyme, which is hydrolyzed to yield products
palmitate & fatty acid synthase
5. Palmitate is the precursor for longer & unsaturated fatty acids
Chain-lengthening occurs in the mitoch and ER (C16C18etc)
Desaturating system is also present in the ER
o Inserts double bonds no further than 9 carbons from the carboxylic acid group
What do the limitations of the desaturating system result in?
1. The limitations of the desaturating system impose a dietary requirement for essential fatty
acids (those w/double bonds >10 carbons from the carboxyl end)
Lineoleic acid
o Precursor for arachidonic acid (which is beginning of cascade that synthesizes prostaglandins,
thromboxanes, and eicosanoids)
Linolenic acids
Glycerolipid synthesis

1. This process is carried out by the liver, adipose tissue, and the intestine
2. Pathways begin w/glycerol 3-P, which is mainly produced by reducing dihydroxyacetone
3. Succesive transfers of acyl groups from acyl CoA to carbons 1 and 2 of glycerol 3-phosphate
produce phosphatidate, which can then be converted to a variety of lipids:
Triacylglycerol (from transfer of acyl group from acyl CoA)
Phosphatidyl choline & phosphatidyl ethanolamine (from transfer of base from its cytidine
diP/CDP derivative)
Phosphatidylserine (from exchange of serine for choline)
Phosphatidylinositol (from reaction of CDP-diacylglycerol with inositol)
Sphingolipid synthesis
1. Begins with palmityl CoA and serine
Produces dihydrosphingosine and sphingosine
2. Sphingosine can then by acylated to produce ceramide
Cholesterol synthesis
1. Cholesterol is made by the liver and intestinal mucosa from acetyl CoA in a multistep process
2. Key intermediate = HMG CoA
HMG CoA reductase: regulatory enzyme that catalyzes HMG CoA + NADPH mevalonic acid
Increasing amounts of intracellular cholesterol lead to inhibition of HMG CoA reducate and
3. Overall reaction:
Acetoacetyl CoA + acetyl CoA HMG CoA synthase HMG CoA HMG CoA reductase
mevalonic acid cholesterol
What are the fates of the products of cholesterol synthesis?
1. Mevalonic acid
Precursor of a number of natural products called terpenes, which include vit A, vit K, coenzyme
Q, and natural rubber
2. Cholesterol
Converted to steroid hormones in the adrenal cortex, ovary, placenta, and testes
Majority is oxidized to bile acids in the liver
7-dehydrocholesterol is the starting point for synthesis of vit D
Lipid malabsorption

## 1. Leads to excessive fat in the feces (steatorrhea)

2. Occurs for a variety of reasons:
Bile duct obstruction
o ~50% of dietary fat appears in the stools as soaps (metal salts of LCFAs)
o Absence of bile pigments leads to clay-colored stools
o Deficiency of the ADEK vitamins may result
Pancreatic duct obstruction
o Stool contains undigested fat
o Absorption of ADEK vitamins is not sufficiently impaired to lead to deficiency symptoms
Diseases of the small intestine (e.g., celiac disease, abetalipoproteinemia, nontropical sprue,
IBD)
Hyperlipidemias
1. Familial hypercholesterolemia
Results from defective LDL receptors
Findings: severe atherosclerosis, early death from CAD
Tx: HMG CoA reductase inhibitors (statins)
2. Hypertriglyceridemia
Can result from either overproduction of VLDL or defective lipolysis of VLDL triglycerides
Findings: cholesterol levels may be mildly
3. Mixed hyperlipidemias
BOTH serum cholesterol & serum triglycerides are
There is both overproduction of VLDL and defective lipolysis of triglyceride-rich lipoproteins
(VLDL and chylmicrons)
There is a danger of acute pancreatitis
Inheritied defects and deficiencies that disrupt fatty acid oxidation
1. Inherited defects in the carnitine transport system, which have widely varying symptoms:
Hypoglycemia
Muscle wasting w/accumulation of fat in muscle
Feeding fat w/medium-chain triacylglycerols (e.g., butterfat) is helpful in some cases, b/c
MCFAs can bypass carnitine transport system
2. Inherited deficiencies in the acyl CoA dehydrogenase, the most common being medium-chain
(C6-C12) acyl CoA dehydrogenase deficiency
Hypoketotic hypoglycemia and dicarboxylic aciduria occur, with vomiting, lethargy, and coma
This is believed to account for the condition called Reye-like syndrome
Sphingolipid Storage Diseases

## Disease Accumulated Substance Clinical Manifestations

Tay-Sachs Ganglioside GM2 Mental retardation (MR), blindness, red spot on macula, death by
3rd yr
Gauchers Glucocerebroside Hepatosplenomeg, bone erosion, MR
Fabrys Ceramide trihexoside Rash, kidney failure, lower extremity pain
Niemann-Pick Sphingomyelin Hepatosplenomegaly, MR
Globoid cell leukodystrophy Galactocerebroside MR, myelin absent(also called Krabbes
disease)
Metachromatic leukodystrophy Sulfatide MR, metachromasia, nerves stain yellowish brown
w/crystal violet
Gen gangliosidosis Ganglioside GM1 MR, hepatomegaly, skeletal abnormalities
Sandhoffs Ganglioside GM2, globoside Same as Tay-Sachs, but more rapid course
Fucosidosis Pentahexosylfuco-glycolipd Cerebral degeneration, spasticity, thick skin
Urea Cycle
1. Converts NH4+ (which is toxic, esp to CNS) to urea
2. Occurs in the liver
3. Urea is excreted in the urine
4. NH4+ + CO2 carbamoyl phosphate synthetase I
carbamoyl P + ornithine ornithine transcarbamoylase
citrulline + aspartate + ATP argininosuccinate synthetase
argininosuccinate argininosuccinate lyase fumarate +
arginine + H20 arginase UREA + ornithine
Urine byproduct
How does detoxification of NH4+ occur in peripheral tissues?
1. In most tissues:
Glutamine synthetase incorporates NH4+ into glutamate to form glutamine, which is carried by
circulation to the liver
In the liver, glutaminase hydrolyzes glutamine back to NH4+ and glutamate
2. In skeletal muscle:
Glutamate dehydrogenase and glutamate-pyruvate aminotransferase incorporate NH4+ into
alanine
Alanine is carried to the liver, where transdeamination results in converstion of alanine back to
pyruvate and NH4+
Hyperammonemia

1. May be caused by insufficent removal of NH4+, resulting from disorders that involve one of
the enzymes in the urea cycle
2. Signs and Symptoms
Blood NH4+ concentrations above the normal range (30-60 mM)
Mental retardation, seizure, coma, and death
3. Enzyme defects
Low activity of carbamoyl P synthetase or ornithine-carbamoyl transferase [NH4+] in blood
& urine NH4+ intoxication
Defective argininosuccinate synthetase, argininosuccinase, OR arginase blood levels of
metabolite preceding defect
o NH4+ levels may also rise
4. Treatment
Restriction of dietary protein
Intake of mixes of keto acids that correspond to essential amin acid
Eating benzoate & phenylacetate: alternate path for NH4+ excretion
Carbon skeletons of amino acids
1. Amino acids can be grouped into families based on the point where their carbon skeletons
enter the TCA cycle
2. AcetylCoA/Ketogenic fam(blue:keto-& glucogenic; red:ketogen only)
Isoleucine, leucine, lysine, phenylalanine, tryptophan, and tyrosine
Phenylalanine tyrosine via phenylalanine hydroxylase
Tyrosine is starting compound for:
o Epi and NE, T3 and T4, Dopamine, Melanin
3. a-Ketoglutarat fam (arginine,histidine,glutamate,gluatmine,proline)
Histidine precursor of histamine
Glutamate excitatory neurotransm, can be converted to GABA
4. Succinyl CoA family (isoleucine, methionine, valine)
Methyl of methionine participates in methylation rxns as S-adenosylmethionine (SAM)
5. Fumarate family (phenylalanine and tyrosine)
6. Oxaloacetate family (asparagine and aspartate)
7. Pyruvate fam (alanine,cysteine,glycine,serine,threonine, tryptophan)
Essential amino acids
1. Isoleucine
2. Leucine
3. Lysine
4. Phenylalanine
5. Tryptophan
6. Histidine
7. Methionine

8. Valine
9. Threonine
Phenylketonuria (PKU)
1. Results from a deficiency of:
Phenylalanine (Phe) hydroxylase OR
Dihydropteridine reductase
2. Findings
Phe in the blood (hyperphenylalaninemia)
Phe builds up to toxic concentrations in body fluids, resulting in CNS damage with mental
retardation
Phe inhibits melanin synthesis hypopigmentation
3. An alternative pathway for Phe breakdown produces phenylketones, which spill into th eurine
4. In those affected, tyrosine is an essential amino acid
5. Treatment: restricting dietary protein (phenylalanine)
Albinism
1. No tyrosinase (1st enzyme on pathway to melanin)
2. Have little or no melanin and are:
Easily sunburned
Very susceptible to skin carcinoma
Photophobic b/c of lack of pigment in iris of eye
Homocystinuria
1. May result from several defects:
Cystathionine synthase (CS) deficiency
affinity of CS for its coenzyme, pyridoxal phosphate (PLP) (may respond to megadoses of
pyridoxine/vit B6)
Methyl tetrahydrofolate homocyst methyltransferase deficiency
Vit B12 coenzyme deficiency (may respond to vit B12)
2. Finding: homocysteine accumulation in blood, appears in urine
3. Pathologic changes
Dislocation of optic lens
Mental retardation
Osteoporosis and other skeletal abnormalities
Atherosclerosis and thromboembolism
4. Pts unresponsive to vitamin therapy may be treated with:

## Synthetic diets low in methionine

Betaine (trimethylglycine) alternative methyl group donor
Maple-syrup urine disease
1. Results from a deficiency in the branched-chain 2-keto acid decarboxylase
2. Findings: branched chain keto acids derived from isoleucine, leucine, and valine appear in the
urine, giving it a maple syrup-like odor
3. Elevated keto acids cause severe brain damage, with death in the first year of life
4. Treatment
A few respond to megadoses of thiamine (vitamin B1)
Those that dont: synthetic diets low in branched-chain amino acids
Histidinemia
1. Deficiency in histidine-a-deaminase (the 1st enzyme in histidine catabolism)
2. Characterized by elevated histidine in blood plasma and excessive histidine metabolites in
urine
3. Symptoms:
Mental retardation and speech defects (both are rare)
4. Treatment: not usually indicated
Origin of the atoms in the purine ring
PURINE nucoleotide synthesis
De novo synthesis:
1. Inosine monophosphate (IMP), AMP, & GMP inhibit PRPP synthetase
2. Committed step: conversion of PRPP to 5-phosphoribosyl-1-amine
PRPP activates glutamine PRPP amidotransferase
Inhibited by end products (IMP, GMP, AMP) of the pathway
Purines made by salvage of preformed purine bases:
1. Involves 2 enzymes:
Hypoxanthine-guanine phophoribosyltransferase (HGPRT)
o Comp inhibited by IMP and GMP
o Inhibited by AMP
Regulation of purine synthesis
1. Regulation provides a steady supply of purine nucleotides
2. GMP and AMP inhibit 1st step in their own synthesis from IMP
3. Reciprocal substrate effect: GTP is a substrate in AMP synthesis, and ATP is a substrate in

GMP synthesis
Balances supply of adenine and guanine ribonucleotides
4. Interconversion among purines ensures control of their levels
AMP deaminase converts AMP back to IMP
GMP reductase converts GMP back to IMP
IMP is the starting point for synthesis of AMP and GMP
Origin of the atoms in the pyrimidine ring
De novo pyrimidine synthesis
1. In mammals, 1st 3 steps occur on one multifunctional enzyme called CAD, which stands for
the names of the enzymes
CO2 + glutamine CAP synthetase II carbamoyl-P (CAP)
Synthesis of dihydroorotic acid is a 2-step process:
o Committed step: aspartate + CAP aspartate transcarbamoylase carbamoyl aspartate
o Carbam aspartate dihydrorotase dihydroorotic acid + H2O
2. Dihydroorate forms UMP
Dihydroorate orotic acid
Orotic acid + PRPP orotidylate (OMP)
Decarboxylation of OMP uridylate (UMP)
These 2 steps occur on 1 protein (if defected: orotic aciduria)
3. Synthesis of remaining pyrimidines involves UMP
Phosphorylation of UMP UDP + UTP
Addition of amino group from glutamine to UTP CTP
Regulation of pyrimidine synthesis
1. CAP synthetase II regulation
Inhibited by UTP
Activated by ATP and PRPP
2. CTP itself inhibits CTP synthetase
Salvage of pyrimidines
Accomplished by the enzyme pyrimidine phosphoribosyl transferase, which can use orotic acid,
uracil or thymine, but NOT CYTOSINE
Deoxyribonucleotide synthesis
Formation of deoxyribonucleotides (for DNA synthesis) involves reduction of sugar of
ribonucleoside diphosphates:
1. Ribonucleotide reductase

## Leads to reduction of ADP, GDP, CDP, or UDP to deoxyribonucs

Its reducing power is from 2 sulfhydryl groups on thioredoxin
Using NADPH + H+, thioredoxin reductase converts oxidized thioredoxin back to the reduced
form
Regulation controls the overall supply of deoxyribonucleotides
o Rxn proceeds only in presence of nucleotide triphosphate
o dATP: allosteric inhibitor
o Other deoxynucleosides interact w/enzyme to alter specificity
2. Thymidylate synthase
Catalyzes formation of dTMP (deoxythymidylate) from dUMP
Coenzyme: N5, N10-methylene tetrahydrafolate (regenerated after each rxn by dihydrofolate
reductase)
1. Purine degradation (product: Uric acid is exreted in urine)
Sequential actions of 2 groups of enzymes (nucleases and nucleotidases) lead to hydrolysis of
nucleic acids to nucleosides
Purine nucleoside phosphorylase splits inosine and guanosine to ribose 1-P and free bases
hypoxanthine and guanine
Guanine is deaminated to xanthine
Hypoxanthine & xanthine xanthine oxidase uric acid
2. Pyrimidine degradation (products = b-amino acids, CO2, NH4+)
Degraded to free bases uracil or thymine
A 3-enzyme rxn (reduction, ring opening, deamination-decarboxylation) converts uracil to CO2,
NH4+, and b-alanine and thymine to CO2, NH4+, & b-aminoisobutyrate
THUS: urinary b-aminoisobutyrate is an indicator of DNA turnover (may be during chemo or
Disorders caused by deficiencies in enzymes involved in nucleotide metabolism
Hereditary orotic aciduria Orotate phosphoribosyl transferase and/or OMP decarboxylase
Retarded growth,Anemia Synthetic cytdine or uridine (UTP formed acts as inhib of carbamoy-P
synthetase II)
Purine phosphorylas deficiency purine uric acid formation Impaired T-cell function
SCID Adenosine deaminase T- & B-cell dysfunction w/early death from infection Gene therapy
Lesch-Nyhan HGPRT (deficient or absent) purine synthesis, hyperuricemia, severe neuro
problem (spastic, MR, self-mutilation) Allopurinol - deposition of sodium urate crystals, but
doesnt ameliorate neuro symptoms
Anticancer drugs that interfere w/nucleotide metabolism
1. Hydroxyurea
Inhibits nucleoside diphosphate reductase (enzyme that converts ribonucleotides to

deoxyribonucleotides)
2. Aminopterin and methotrexate
Inhibit dihydrofolate reductase (enzyme that converts dihydrofolate to tetrahydrofolate)
3. Fluoredeoxyuridylate
Inhibits thymidylate synthetase (enzyme that converts dUMP to dTMP)
Gout
1. May result from a disorder in purine metabolism
2. Is associated w/hyperuricemia
3. Primary gout: overproduction of purine nucleotides
Mutations in PRPP synthetase loss of feedback inhibition by purine nucleotides
A partial HGPRT deficiency less PRPP is consumed by salvage enzyes PRPP activates
PRPP amidotransferase
4. Secondary gout
Due to radation therapy, CA chemo (b/c they cell death)
5. Treatment: allopurinol
Xanthine oxidase catalyzes oxidation of allopurinol to alloxanthine, which is a potent inhibitor
of the enzyme
Result: uric acid levels fall, hypoxanthine & xanthine levels rise (is OK, b/c they dont form
crystals)
Energy expenditure (3 components)
1. Basal energy expenditure (BEE)
resting energy expenditure
Energy used for metabolic processes at rest
Represents >60% of total energy expenditure
Related to the lean body mass
2. Thermic effect of food
Energy required for digesting and absorbing food
Amounts to ~10% of energy expenditure
3. Activity-related expenditure
20-30% of daily energy expenditure
Caloric yield from foods and what % they should be in diet
1. Carbs: 4 kcal/g
50-60% of caloric intake
2. Proteins: 4 kcal/g
10-20% of caloric intake (0.8 g/kg body weight/day)

3. Fats: 9 kcal/g
No more than 30% of caloric intake
4. Alcohol: 7 kcal/g
Fats:
Essential fatty acids, Deficiency, and Excess storage
1. Essential fatty acids (EFAs):
Linoleic acid
Linolenic acid
2. Deficiency
Mainly seen in low-birth-weight infants maintained on artificial formulas and adults on TPN
Characteristic system: scaly dermatitis
3. Excess fat
Stored as triacylglycerol
Marasmus vs. Kwashiorker
Marasmus Kwashiorker
Insufficient food, including both calories and protein Starvation with edema often due to protein
deficient diet
Depleted subQ fat Pitting edemaFlaky paint dermatosis: dark patches on skin that peel
Liver ketogenesisbrain&heart fuel Large liver due to fatty infilatration
Muscle wasting (break protein for gluconeogenesis & protein synthes) Muscle wasting less
severe
Frequent infections Frequent infections
Low body temp
Micronutrient deficiencies Other nutrient deficiencies
Slowed growth(<60% expected wgt) Growth failure(>60% expected wgt)
Death when energy & protein reserves exhausted Poor appetitie (anorexia)Watery stools
w/undigested foodMental changes (apathetic)
Vitamin A
1. Functions:
11-cis-retinal prosthetic group of rhodopsin
Beta-carotene antioxidant NOT TOXIC at high doses
Retinyl phosphate mannose acceptor/donor in glycoprotein synth
Retinol & retinoic acid regulate tissue growth & differentiation
2. Deficiency signs and symptoms:
Night blindness, Xerophthalmia (cornea keratinizes: Bitot spots)

## o Leading cause of child blindness in 3rd world nations

Follicular hyperkeratosis (rough, tough skin)
Anemia
resistance to infection
susceptibility to cancer
3. Toxicity (prolonged ingestion of 15,000-50,000 equivalents/day)
Bone pain, scaly dermatitis, hepatosplenomegaly, nausea, diarrhea
4. Clinical usage: For acne and psoriasis
Vitamin D
1. Functions: regulation of Ca+ metabolism
Stimulates synth of Ca+-binding protein aids absorption
In combo w/PTH, blood Ca+ by:
o bone demineralization by stimulating osteoblastic activity
o Simulates Ca+ reabsorption by distal renal tubules
2. Sources:
Major: skin (UV: 7-dehydrocholesterol Vit D3/cholecalciferol)
Diet (vit D3) and foods fortified w/vit D2
3. Activation
Liver: Vit D3 25(OH)D3
Kidney: 25(OH)D3 active 1,25(OH)2D3 (stimulated by PTH)
4. Deficiency
Rickets (kids): soft bones, stunted growth
Bone demineraliz may also result from vit D inactive forms by steroids
5. Toxicity: (hyperCa+, metast calcification, bone demineraliz, kidney stones)
Seen in sarcoidosis (epithelioid macroph convert vit.D to its active form)
Vitamin E
1. Function
Protection of membranes & proteins from free-radical damage
Includes isomers of tocopherol:
tocopherol is regenerated
2. Deficiency
Secondary to impaired lipid absorption (cystic fibrosis, celiac disease, chronic cholestasis,
pancreatic insufficiency, abetalipoproteinemia)
Signs & Symptoms:
o Ataxia
o Impaired reflexes
o Myopathy

o Muscle weakness
o Hemolytic anemia (b/c of fragility of RBCs)
o Retinal degeneration
Vitamin K
1. Function
Post-translational carboxylation of glutamyl residues in Ca+-binding proteins: factors VII, IX,
&X
2. Deficiency ( PT, aPTT, but nl bleeding time)
Impaired blood clotting bruising, bleeding
Causes:
o Fat malabsorption
o Drugs that interfere w/vit K metabolism (warfarin)
o Antibiotics that suppress bowel flora
3. Vitamin K in infants
Neonates are born w/low stores of vit K
Vit K crosses placental barrier poorly
Newborns given single injection of vit K
High doses: anemia, hyperbilirubinemia, kernicterus
The B vitamins
1. B1 = Thiamine
2. B2 = Riboflavin
3. B3 = Niacin
4. B5 = Pantothenate (pantothenic acid)
5. B6 = Pyridoxine (pyridoxamine, pyridoxal)
6. B12 = cobalamin
Thiamine (vitamin B1)
1. Thiamine pyrophosphate (TPP): required for nerve transmission & is coenzyme for several
key enzymes:
Pyruvate & a-ketoglutarate dehydrogenase(glycolysis, TCA)
Transketolase (pentose phosphate pathway)
Branched-chain keto-acid dehydrogenase (valine, leucine, isoleucine metabolism)
2. Deficiency leads to beriberi, which occurs in 3 stages:
Early: loss of appetite, constipation, nausea, periph neuropathy, irritability, fatigue
Moderately severe: Wernicke-Korsakoff syndrome (mental confusion, ataxia, ophthalmoplegia)

## o Dry: atrophy & weakness of muscles

o Wet:edema,high-output cardiac failure,pulm congestion
Riboflavin (vitamin B2)
1. Function:
Converted to re-dox coenzymes FAD & FMN
2. Deficiency signs & symptoms:
Angular cheilitis
Glossitis (red and swollen tongue)
Scaly dermatitis (esp at nasolabial folds & around scrotum)
Corneal vascularization
Niacin (vitamin B3)
2. Deficiency
Causes:
o Hartnup disease
o Malignant carcinoid syndrome
o INH
Mild deficiency: glossitis
Severe deficiency: pellagra the 3 Ds
o Dermatitis
o Diarrhea
o Dementia
3. High doses
Vasodilation (very rapid flushing)
Metobolic changes: blood cholesterol & LDLs
Vitamin B6 (pyridoxine, pyridoxamine, & pyridoxal)
1. Function
Coenzyme involved in transamination (e.g., ALT & AST), decarboxylation, and transsulfuration (rxns of amino acid metabolism)
2. Deficiency (inducible by INH)
Mild: irritability, nervousness, depression
Severe: periph neuropathy, convulsions, occasional sideroblastic anemia
Other symptoms: eczema, seborrheic dermatitis around ears, nose, and mouth; chapped lips;
glossitis; angular stomatitis

3. Clinical usefulness:
High doses: tx homocystinuria (defective cystathione b-synthase)
Vitamin B6: Pantothenic acid
1. Function
Essential component of coenzyme A (CoA) and of fatty acid synthase
Cofactor for acyl transfers
2. Deficiency (very rare)
Vague presentation, little concern to humans
Biotin
1. Function
Covalently linked biotin = prosthetic group for carboxylation enzymes (e.g. pyruvate
carboxylase, acetyl CoA carboxylase) (NOT decarboxylations)
2. Deficiency (rare)
Signs and symptoms:
o Dermatitis
o Hair loss
o Atrophy tongue papilla
o Gray mucous memb
o Paresthesa,muscle pain
o Hypercholesterlemia
o ECG abnormalities
Causes
o Antibiotic use (since intestinal bacteria make biotin)
o Eating Avidin (raw egg whites)
Binds biotin in a nondigestible form
If you eat >20 eggs/day
Folic acid
1. Function
Polyglutamate derivatives of tetrahydrofolate serve as coenzymes in 1-carbon transfer rxns:
o Purine & pyrimidine synthesis
o Thymidylate synthesis
o Conversion of homocysteine to methionine
o Serine-glycine interconversion

2. Deficiency
Signs & symptoms:
o Megaloblastic anemia
o Neural tube defects
o blood homocysteine associated w/atherosclerotic disease
Can be caused by several drugs:
o Methotrexate (chemo)
o Trimethoprim (antibact)
o Pyrimethamin(antimalari)
o Diphenylhydantoin (anticonvulsant)
o Primidone (anticonvuls)
Vitamin B12 (cobalamin)
1. Functions
Coenzyme for methylmalonyl CoA succinyl CoA (methylmalonyl CoA mutase) in propionyl
CoA metabolism
Coenzyme for methyl transfer between tetrahydrofolate & methionine (homocysteine methyl
transferase)
2. Deficiency:
Signs & Symptoms:
o Megloblastic anemia
o Paresthesia, optic neuropathy, subacute combined degenerat
o Prolonged deficiency irreversible nervous system damage
Causes:
o Intake of no animal products (vegans)
o Achlorhydria, intrinsic factor (impaired absorption)
o Malabsorption (impaired pancreatic function, sprue, enteritis, D. latum, absence of terminal
ileum/Crohns)
3. Use Schilling test to detect deficiency
Vitamin C (ascorbic acid)
1. Functions
Coenzyme for re-dox rxns, including:
o Post-translational hydroxylation of proline & lysine in maturation of collagen
o Carnitine synthesis
o Tyrosine metabolism
o Catecholamine neurotransmitter synthesis
Antioxidant
Facilitator of iron absorption
2. Deficiency
Signs & symptoms:

o Mild: capillary fragility w/easy bruising & petechiae (pinpoint hemorrhages in skin), immune
function
o Severe: scurvy ( wound healing, osteoporosis, hemorrhage, anemia, swollen gums, teeth may
fall out)
y
Symptoms of Mineral Deficiencies
Mineral Deficiency-Associated Conditions
Calcium ParesthesiaTetanyBone fractures, bone painOsteomalacia (as in vit D deficiency)
Iodine GoiterCretinism
Iron AnemiaFatigue, tachycardia, dyspnea
Magnesium Neuromusc excitability, paresthesiaDepressed PTH release
Phosphorus (as phosphate) Deficiency rarely occurs
Zinc Growth retardation & hypogonadismDry, scaly skinMental lethargyImparied taste & smell,
poor appetite