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Biochem
Acidic dissociation
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Biochem
1. General expression: HA is the acid (proton donor) andA- is the conjugate base (proton acceptor):
2. An acid dissociates in water to yield a hydrogen ion (H+) andits 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
2
Acid (acetic acid) Conjugate base (acetate)
CH3COOH --> H+ + CH3COO-
Ammonia (base) Ammonium ion (conjugate acid)
NH3 + H+ --> NH4
+
k1
HA --> H+
+ A-
k-1
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Biochem
Measures of acidity
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Biochem
1. pKa
When forward & reverse rates are equal, acidic dissociationconstant, 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 of2 (H+ binds loosely to conjugate base)
Weak acid has a pKa of10 (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
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Biochem
Acidic solution has a [H+] > 10-7 pH < 7 Alkaline solution has a [H+] < 10-7 pH > 7
Buffers and Buffering capacity
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Biochem
1. A solution that contains a mixture of a weak acid and its
conjugate base2. It resists changes in [H+] on addition of acid or alkali
3. The buffering capacity of a solution is determined by th
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 ac
The shape of the curve is the same for all weak acids
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Biochem
At the midpoint of the curve, the pH = pKa The buffering region extends one pH unit above and belo
the pKa
What acid-base pair is an effective buffer in physiologic fluid
What acid-base pair is the principal buffer in plasma and
extracellular fluid (ECF)?
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Biochem
1. What acid-base pair is effective buffer in physiolog fluids?
H2PO4- and HPO42-2. What acid-base pair is the principal buffer in plasma and ECF?
CO2-H2CO3-HCO3- system (carbon dioxide-carbonic acid-bicar
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 thouthe pKa is only 6.1, for 4 reasons:
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Biochem
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 concentrat
of the conjugate base
Acid-Base Disorders:Acidosis and Alkalosis
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Biochem
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 hypoventilati Metabolic acidosis: [HCO3-] as a result of the addition o
an acid stronger than H2CO3 to the ECF
2. Alkalosis
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Biochem
Occurs when pH of blood and ECF is >7.45 Leads to neuromuscular hyperexcitability When severe, can result in tetany
Respiratory alkalosis: pCO2as result of hyperventilatio Metabolic alkalosis: [HCO3-] as a result of excess acid
loss (e.g., vomiting) or addition of a base (e.g., oral antacid
Diabetic ketoacidosis
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Biochem
1. Combination of high blood levels of ketone bodies and ametabolic acidosis
2. Pathogenesis
Uncontrolled insulin-dep DM (type 1)glucose utilization,hyperglycemia fatty acid oxidation
fatty acid oxidation excessive production of acetoacetic an3-hydroxybutyric acids and acetone (ketone bodies)
Acids dissociate at body pH and release H+metabolic acido
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Biochem
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
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Biochem
1. Aliphatic, nonpolar (hydrophobic)
Glycine Alanine
Valine Leucine
Isoleucine Proline
2. Aromatic, nonpolar
Phenylalanine Tyrosine Tryptophan
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Biochem
3. Sulfer-containing
Cysteine Methionine4. Hydroxyl, mildly polar (uncharged, hydrophilic)
Serine Threonine5. Basic, polar
Lysine Arginine Histidine6. Acidic, polar
Aspartic acid Asparagine
Glutamic acid Glutamine
Secondary structures of proteins and collagen
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Pg. 7 for
structures
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Biochem
1. Secondary structure = arrangement of H bonds between peptid
nitrogens & carbonyl oxygens of different amino acids
2. Helical coils
Hydrogen-bonded nitrogens & oxygens are on nearby amino aci
Right-handed alpha helix most common
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Biochem
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 chain4. 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
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Biochem
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)
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i h
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Biochem
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)
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Biochem
Sickle cell anemia
1. Caused by mutant sickle cell hemoglobin (Hgb S)
Hydrophobic valine replaces hydrophilic glutamate at position 6 of thbeta-chain of normal hemoglobin A (Hgb A)
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Biochem
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 asymptomatico Episodes ofhematuria
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Biochem
Scurvy
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Biochem
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 (Fe Hydroxyproline forms H-bonds that stabilize collagen heli
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Biochem
Symptoms of scurvy are thus the result of weakendcollagen when these hydrogen bonds are missing
Free energy change
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Biochem
1. The quanitity of energy from chemical reactions that is
available to do work ( G)2. The G of a rxn A + B C + D is:
G = G0 + RTln ([C][D]) / [A][B])o where G0 is the standard free-energy change
(when concentrations of all reactants and productare 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:
G0 = RTlnKeq
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Biochem
Thermodynamic spontaneity: Exergonic and Endergonic Rxn
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Biochem
1. Exergonic rxns are spontaneous (rxn goes to the right)
Keq > 1 G0 is negative Final concentration of the products, C and D, is greater tha
that of the reactants, A and B
2. Endergonic rxns are nonspontaneous (rxn goes to the left)
Keq < 1 G0 is positive Final concentration of the reactants, A and B, is greater tha
that of the products, C and D
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Biochem
3. Note: G0 CANNOT predict spontaneity underintracellular conditions
Intracellular spontaneity is a function of actual
concentrations as well as Keq, G, NOT G0
Enthalpy, entropy, and free-energy change
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oc e
1. Enthalpy ( H) The amount of heat generated or absorbed in a rxn
2. Entropy ( S) Measure of the change in randomness or disorder of system when a salt crystal dissolves, when a solute diffuses fro
a more concentrated to a less concentrated solution, and
when a protein is denatured
when a complex molecule is synthesized from smaller
substrates
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3. Free-energy change ( G) Is related to enthalpy and entropy as follows:
o G = H - T S (where T = absolute temp in
Kelvins)
Catalysts and the Rate of Reaction
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1. Rate of reaction
The G0 provides no info concerning the rate ofconversion from A to B
When A is converted to B, it first goes through anenergy barrier called the transition state, A-B
The activation energy ( G) = energy required to
scale the energy barrier and form the transition state
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The greater the G, the lower the rate of therxn converting A to B
2. Catalysts (mostly enzymes) result in a:
Lower G Faster reaction rate
Michaelis-Menten equation
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1. Describes the kinetics of enzyme rxns2. In enzyme-catalyzed rxns:
k1 k3E + S ES E + P
k2
Where E=enzyme, S=substrate, P=product, k1-3 = rate constant3. Velocity (v) of product formation is related to [ES]:
o v = k3[ES] where k3 is also called kcat
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4. Michaelis-Menten eq predicts velocity if [enzyme] is
constant:
Where Vm = max velocity & Km is the Michaelis constant5. Km = [substrate] at which v = Vm ([S] = Km)
6. A plot of velocity versus [S] is a rectangular hyperbola
Lineweaver-Burk Equation
Vm[S]
v = Km+[S]
Biochem
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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
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3. The Y-intercept = 1/Vm4. The X-intercept is 1/Km
Enzyme Regulation:
How doe Inhibitors affect the Lineweaver-Burk plots?
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1. Competitive inhibitors
apparent Km Vm remains the same slope X-intercept has smaller absolute value
Y-intercept is unchanged
Biochem
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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 paral
Allosteric regulation of enyzmes: Definition, How do they
affect Km, and Example of Hexokinase
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1. Low-molec wgt effector binds to enzyme at a specific site oththan 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] = sigmoi Binding of 1 substrate facilitates binding of substrate at other sit
3. Effectors may have a + or effect on activity
Biochem
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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 issaturatedand operates at its Vm
When glycolysis slows down, gluc-6-P accumulates gluc-6-Pallosterically inhibits hexokinase (keeps gluc-6-P in balance)
Other mechanisms of enzyme regulation:
1. Induction/repression of enzyme synthesis
Biochem
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2. Covalent modificataion
3. Protein-protein interaction
1. Induction/repression of enzyme synthesis
Cytochrome P450 enzymes in the liver (degrade anddetoxify drugs) are induced by the drugs themselves
2. Covalent modificataion
Biochem
Ph h l ( th t b k d l )
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Phosphorylase (enzyme that breaks down glycogen)is activated by phosphorylation of a specific hydroxyl grou
This phosphorylation is stimulated by hormones that elevablood glucose, such as glucagon and Epi
3. Protein-protein interactionbetween enzyme & regulatoryprotein
Pancreatic lipase (digests dietary fat) is assisted by colipas Colipase anchors lipase to the surface of fat droplets
Mechanism and Treatment of Methanol & Ethylene glycol
Poisoning
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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
Biochem
o M th l f ld h d + f i id
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o Methanol formaldehyde + formic acid
Eyes very sensitive to formaldehydeblindneso Ethylene glycol glycoaldehyde, oxalate, and lacta
Deposition of oxalate crystals in kidneykidnefailure
2. Treatment
Initial infusion of ethanol competitive substratedisplaces methanol or ethylene glycol from active site of
alcohol dehydrogenase Prevents continued production of toxic metabolites
Citric acid cycle:
Biochem
Location Pathway and Initial Substrate45
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Location, Pathway, and Initial Substrate
1. Location
Mitochondria (found in all cells except RBCs)
2. Pathway
Biochem
It is the final common pathway of oxidiative46
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It is thefinal common pathway of oxidiativemetabolism
3. Initial Substrate: Acetyl Coenzyme A (ACETYL CoA)
Condenses with oxaloacetate (OAA) to begin the cyc4. 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 -oxidationo Some amino acids are degraded to acetyl CoA
Biochem
What are the products of one revolution of the citric47
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What are the products of one revolution of the citric
acid cycle?
1. 2 CO2 (most CO2 from metabolism)
Biochem
2 Regeneration of one mole of OAA48
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2. Regeneration of one mole of OAA
3. 3 NADH & 1 FADH2 11 ATPs (via oxidative
phosphorylation)
4. 1 GTP 1 ATP
TOTAL OF 12 ATPs/acetyl CoA
Oxidative Phosph:
1 NADH = 3 ATP
1 FADH2 = 2 ATP
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Describe the anaplerotic rxns that provide OAA and other
citric acid cycle intermediates
1. Pyruvate carboxylase in the liver & kidney:
Biochem
Pyruvate + ATP + HCO3- OAA + ADP + Pi50
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Pyruvate + ATP + HCO3 OAA + ADP + Pi2. Phosphoenolpyruvate (PEP) carboxykinase in heart an
skeletal muscle:
PEP + CO2 + GDP OAA + GTP3. Malic enzyme in many tissues: Pyruvate + HCO3- + NAD(P)Malate + NAD(P)+
4. Glutamate dehydrogenase in the liver:
Glutamate + NAD(P)+ + H2O -ketoglutarate +NAD(P)H + NH4+
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Regulation of the citric acid cycle
Biochem
1. Step: Acetyl CoA + OAA citrate52
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1. Step: Acetyl CoA OAA citrate
Enzyme: citrate synthase Inhibitors: ATP ( Km), long-chain acyl-CoA
2. Step: Isocitrate + NAD+
-ketoglutarate + NADH + CO2 Enzyme: isocitrate dehydrogenase Allosteric activator: ADP Inhibitors: ATP, NADH
3. Step: -ketoglutarate + NAD+ + CoASH succinyl CoA +NADH + CO2
Enzyme: -ketoglutarate dehydrogenase (note: requiressame cofactors as the pyruvate dehydrogenase complex)
Inhibitors: succinyl CoA, NADH
Regulated mainly by need for ATP, & therefore by supply of NAD+
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Electron Transport Chain (ETC) & Oxidative Phosphorylatio(BOTH in MITOCHONDRIA)
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NADH Q cytochrom
ATP ATP synthase-- Proton gradientO2
H2O
NADH
dehydrogenase
Ubiquinone-c
oxidoreductase
(Cytochrome bc1)
Cytochrome
oxidase
1. ETS: electrons pass from NADH or FADH2 to ultimately reduO2 and produce H2O
2. Oxidative phosphorylation: uses energy derived from flow oelectrons thru ETS to drive synthesis of ATP from ADP and P
Biochem
NADH dehydrog. = Complex I, Succinate dehydrog. = Complex55
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II (where FADH2 enters not pictured here), Cytochrome bc1 = Comple
III, Cytochrome oxidase = Complex IV
Chemiosmotic hypothesis
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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, hydrogeare pumped across inner membrane to intermembrane spac
The [H+] in the intermembrane space relative to matrix This generates a proton-motive force as result of 2 factor
o Difference in pH ( pH)o Difference in electrical potential ( ) between the
intermembrane space and the mitochondrial matrix
3. ATP synthase complex (complex V)
Biochem
Hydrogen ions pass back into the matrix thru57
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y g pcomplex 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)
2A
Uncouplers and Inhibitors of ETS
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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 oxidativmetblism)
Biochem
o Thermogeninhelps to maintain normal body
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temp
Found normally in brown fat of newborn mammals2. Inhibitors (via blocking e- flow thru complexes ordirect actio
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
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1. Digestion
Disacharides (sucrose),oligosacharides (dextrins),& polysachari(starch) are cleaved into monosaccharides (glucose, fructose)
Starch : storage from of carbs in plants
Biochem
o Hydrolyzed to maltose, maltotriose, and -dextrins61
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by -amylase in saliva and pancreatic juice Disaccharides & oligosaccharides
o Hydrolyzed to monosaccharides by enzymes on the surfac
of epithelial cells in the small intestine
2. Absorption
Monosaccharides absorbed directly by carrier-mediated transpor These sugars (primarily glucose) travel via portal vein to liver fo
o
Oxidation to CO2 and H2O for energyo Storage as glycogen
o Conversion to triglyceride (fat)
o Release into general circulation (as glucose)
Biochem
Glycogen metabolism62
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[Glycogen: carb storage, found chiefly in liver & muscle]
1. Glycogenesis (glycogen synthesis)
Biochem
Activated substrate: Uridine diphosphate-glucose63
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Glycogen synthaseadds to nonreduc end of chains in -1,4 lin Branching enzyme amylo (14) to (16) transglycosylase
creates branches w/ -1,6 linkages Stimulator: insulin (via dephosphorylation in muscle, liver, & f Inhibitors: glucagon (liver), Epi (muscle & liver), phosphorylas
(liver), cAMP, Ca2+ (muscle)
2. Glycogenolysis (glycogen breakdown)
Phosphorylasereleases units of glucose 1-P from nonreducingend
Phosphoglucomutase converts glucose 1-P to glucose 6-P Debranching system releases glucose residues from -1,6 bond Stimulators: sames as inhibitors of glycogenesis
Biochem
Inhibitor: insulin (via dephosphorylation in muscle, liver,d f )
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and fat)
Glycolysis:
Location, Anaerobic and Aerobic
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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 ET
ATP is generated by oxidative phosphorylation
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Describe the first step in glycolysis
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1. Phosphorylation involves rxn of glucose in presence ofhexokinase 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 fromaccumulating too much glucose since phosphorylatio
traps glucose inside cells)
Glucokinase is present in the liver & pancreas ( -cells):o High specificity for glucose
Biochem
o High Km (above the normal blood [glucose])
i i f 6 ( l ill b
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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?
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1. In the first phase (5 reactions):
1 mole of glucose is converted to 2 moles ofglyceraldehyde 3-P
2 moles of ATP are consumed for each mole of gluco2. In the second phase (5 reactions):
Two moles of glyceraldehyde 3-P are oxidized to 2moles of pyruvate
4 moles of ATP and 2 moles of NADH are generatedfor each mole of glucose
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What do the following do:
1. Glycerol phosphate shuttle
2. Malate-aspartate shuttle
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NADH produced in the cytosol DOES NOT pass through the
mitochondrial inner membrane, but is instead shuttled in by:1. Glycerol phosphate shuttle (most tissues)
Transfers electrons from cytosolic NADH to mitoch FADH It generates 2 ATP/cytosolic NADH = 36 moles of
ATP/glucose2. Malate-aspartate shuttle (heart, muscle, & liver)
Transfers electrons to mitochondrial NADH It generates 3 ATP/cytosolic NADH = 38 ATP/glucose
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Gluconeogenesis
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1. Occurs primarily in the liver & kidney2. Synthesis of glucose from small noncarb precursors (such as lactate a
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-phosphateby fructose 1,6-bisphosphatase bypasses phosphofructokinase
Conversion of glucose 6-P to glucose by glucose 6-phosphatasebypasses hexokinase
Biochem5. Glucose from gluconeogenesis is released into the
bloodstream for transport to tissues such as the brain and exercising
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p g
muscle
6. Gluconeogenic substrates:
Lactate Pyruvate Glycerol Substances that can be converted to oxalacetate via the citric acicycle (such as amino acid carbon skeletons)
Cori cycle
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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
Biochem
3. The liver releases the resynthesized glucose into the
circulation for transport back to the muscle
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circulation for transport back to the muscle
Regulation of glycolysis
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1. All are the irreversible steps:
Fructose 6-P fructose-1,6-BP via phosphofructokinao Stimulators : AMP, fructose 2,6-BP (in liver)
o Inhibitors : ATP, citrate
o Rate-limiting step
D-glucose glucose-6-P via hexokinase/glucokinase*
Biochem
o Inhibitors : glucose-6-P
PEP pyruvate via pyruvate kinase
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PEP pyruvate via pyruvate kinaseo Inhibitors : ATP, alanine
o Stimulators : fructose-1,6-BP (in muscle)
Pyruvate acetyl CoA via pyruvate dehydrogenaseo Stimulators : CoA, NAD, ADP, pyruvate
o Inhibitors : ATP, NADH, acetyl CoA
2. Induced by insulin
Gluconeogenesis regulation
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1. All are the irreversible steps: Pyruvate OAA via Pyruvate carboxylase (mitochondo Requires biotin, ATP
o Activated by acetyl CoA
OAA PEP via PEP carboxykinase
Biochem
o Requires GTP
Fructose-1,6-BP fructose-6-P via Fructose-1,6-BPas80
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, ,
Glucose-6-P glucose via Glucose-6-phosphatase2. These enzymes are only found in liver, kidney, intestinal epith
3. Muscle cannot participate in gluconeogenesis4. Hypoglycemia is caused by a deficiency of these key enzymes
5. Induced by glucocorticoids, glucagon, cAMP6. Suppressed by insulin
Pnemonic: Pathway Produces Fresh Glucose
Pyruvate dehydrogenase complex
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1. Contains 3 enzymes that require 5 cofactors: Pyrophosphate (from thiamine) Lipoic acid CoA (from pantothenate) FAD (riboflavin)
Biochem
NAD (niacin)2. Reaction:
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Pyruvate + NAD+ + CoA acetyl-CoA + CO2 + NADH3. 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) B2 (FAD)
B3 (NAD)
B5 (pantothenate CoA Lipoic acid
Pentose phosphate pathway
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1. Sites: lactating mammary glands, liver, adrenal cortex all site
of fatty acid or steroid synthesis
2. Begins with glucose 6-P
3. The irreversible oxidative portion generates NADPH
Biochem NADPH needed for: fatty acid and cholesterol
(steroid) synthesis, maintaining reduced glutathione inside
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RBCs
4. The reversible nonxidative portion rearranges the sugars s
they can reenter the glycolytic pathway5. 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-phosphogluconolactone7. Stimulators : NADP+, insulin8. Inhibitors : NADPH
Sucrose and Lactose Metabolism
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1. Sucrase converts sucrose to glucose and fructose
Hexokinase can convert fructose fructose 6-P (muscle,kidney)
Biochem Fructose enters glycolysis by a different route in the
liver
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Dihydroxyacetone phophate (DHAP) enters glycolysisdirectly
After glyceraldehyde is reduced to glycerol, it isphosphorylated 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
BiochemGlycogen Storage Diseases
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Result in abnl glycogen metabolism & glycogen in cells
DEFFECT TISSUE SIGNS, ETC.
BiochemVon Gierkes
(type I)
Glucose 6-P Liver &
kidney
Hepatomegaly,
Failure to thrive, Hypoglyc
Ketosis, Hyperuricemia,
H li id i
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Hyperlipidemia
Pompes
(type II)
-1,4-glucosidase Lysosomes,All organs
Failure of heart & lungs
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1. Hereditary enzyme deficiences in sucrose metablism:
Biochem
Fructokinase deficiency essential fructosuriao Benign disorder
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Fructose 1-P aldolase deficiency hereditary fructose intolerano Characterized by severe hypoglycemia after ingesting
fructose (or sucrose), jaundice, cirrhosis2. Inherited enzyme deficiencies in lactose metabolism:
Lactase deficiency milk intoleranceo Develops in adult life (age-dep) or hereditary (blacks, Asia
Galactokinase deficiency mild galactosemiao Early cataract formation
Galactose 1-P uridyltransferase deficiency severe galactosem(AUTOSOMAL RECESSIVE)
o Cataract, hepatosplenomeg, growth failure, retardation, dea
o Treatment: exclude galactose & lactose from diet
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Pyruvate dehydrogenase deficiency
Biochem
1. Pyruvate dehydrogenase deficiency neurologic defects
2 C b k f b ( & l i ) l i
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2. Causes backup of substrate (pyruvate & alanine), resultin
in lactic acidosis
3. Treatment: intake of ketogenic nutrients (Lysine &Leucine are the only purely ketogenic amino acids)
Biochem
Gl cose 6 phosphate deh drogenase deficienc
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Glucose-6-phosphate dehydrogenase deficiency
Biochem1. X-linked recessive
2. Background:
G6PD i th t li iti i HMP (h
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G6PD is the rate limiting enzyme in HMP (hexosemonophosphate) shunt, which includes the pentose
phosphate pathwy (which yields NADPH) NADPH is necessary to keep glutathione reduced, which i
turn detoxifies free radicals and peroxides
3. Manifestations of disease:
NADPH in RBCshemolytic anemia4. 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 RBC
Biochem
Lipid digestion
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Lipid digestion
Biochem1. In mouth:
Medium-chain triacylglycerol (TGs) are hydrolyzed by lipase Continues in stomach, producing a mix of diacylglycerols & FFAs
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, p g y g y
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 acid
5. Micelles absorbed in small intestine further metabolized Medium-chain TGs are hydrolyzed Medium-chain fatty acids (8-10 carbons) pass into portal vein
Biochem Long-chain fatty acids (>12 carbons) are reincorporated intoTGs
TGs go into chylomicrons lymphatics circulation via thoracic duc
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g y y p
How are lipids transported to tissues?
Biochem 98
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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 specificapoproteins
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Lipoprotein absorption
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1. Exogenous lipid (from intestine), except for medium-chain fatty aci
is released into the plasma as chylomicrons Chylomicrons contain a high proportion of TGs
TG is hydrolyzed to FFAs and glycerol by lipoprotein lipase onthe surface of capillary endothelium in muscle and adipose tissu
The cholesterol rich chylomicron remnants travel to the liver,
where they are taken up by receptor-mediated endocytosis (RME2. Endogenous lipid (from liver) is released into blood as VLDLs
VLDL TG is hydrolyzed by lipoprotein lipase to FFAs andglycerol, yielding low-density lipoproteins (LDLs)
Biochem LDLs are removed from circulation by RME in tissues
that contain LDL receptors (tissues that need cholesterol, but
mostly in liver)
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y )
LDL cholesterol:
o Inhibits HMG CoA reductase (RLS in cholesterol synthesio Down-regulates LDL receptor synthesisLDL uptake
High density lipoproteins (HDLs) are made in the liver
Lipoprotein functions and associated apolipoproteins:Chylomicrons
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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:
Biochem B-48 mediates secretion As are used for formation of new HDL C II activates lipoprotein lipase
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C-II activates lipoprotein lipase E mediates remnant uptake by liver
Lipoprotein functions and associated apolipoproteins:
VLDL
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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
Biochem
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Lipoprotein functions and associated apolipoproteins:
LDL
Biochem106
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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?)
Biochem
5. Associated apolipoproteins:
B-100 mediates binding to cell surface receptor forendocytosis
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y
Lipoprotein functions and associated apolipoproteins:
HDL
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1. Mediates centripetal transport of cholesterol (i.e. reverse
cholesterol transport, from periphery to liver, i.e. transpor
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
Biochem
4. Associated apolipoproteins:
As help form HDL structure A-I in particular activates LCAT (which catalyzes
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p ( y
esterification of cholesterol)
CETP mediates transfer of cholesteryl esters to otherlipoprotein particles
Pneumonic: HDL is Healthy, LDL is Lousy
Oxidation of fatty acids
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1. Occurs in mitochondrial matrix. The overall process is:RCH2CH2COOH -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 acCoAs are shuttled into mitoch matrix by carnitine transport sy
Biochem
MCFAs pass directly into the mitoch & are activated inthe matrix
3. Fatty acyl CoA is then oxidized to CO2 and H2O by -id i
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oxidation:
Continues in cycle until its completely converted to acetyl CoA Each cycle generates 5 ATPs via ETS and 12 ATPs via combinaction of citric acid cycle and ETS
Terminal 3 carbons of odd-numbered fatty acids yield propionyCoA as the final product, which can:
o Enter the citric acid cycle (after carboxylation to succinylCoA in a 3-rxn sequence requiring biotin and Vit B12)
o Be used for gluconeogenesis
Biochem
Ketogenesis112
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1. The formation ofacetoacetate and -hydroxybutyratefrommetabolism of acetyl CoA in the liver
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Biochem
Fatty acid synthesis114
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1. Carried out by fatty acid synthase, a cytosolic complex
Biochem
2. Primary substrates :
Acetyl CoA: formed in mitoch, mainly by pyruvate dehydrogeno Its transported to cytosol by citrate-malate-pyruvate shuttl
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Malonyl CoA: formed by biotin-linked carboxylation of actyl C
3. The acetyl and malonyl moieties are transferred from the sulfuof CoA to activate sulfhydryl groups in the fatty acid synthase
4. 7 cycles lead to production of palmityl:enzyme, which ishydrolyzed to yield products palmitate & fatty acid syntha
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 Requires NADPH and O2
o Inserts double bonds no further than 9 carbons from the
carboxylic acid group
Biochem
What do the limitations of the desaturating system result in?
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Biochem
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)
Li l i id
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Lineoleic acid
o Precursor for arachidonic acid (which is beginninof cascade that synthesizes prostaglandins,
thromboxanes, and eicosanoids)
Linolenic acids
Biochem
Glycerolipid synthesis
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Biochem
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 byreducing dihydroxyacetone phosphate w/NADPH
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reducing dihydroxyacetone phosphate w/NADPH
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-diacylglycero
with inositol)
Biochem
Sphingolipid synthesis
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Biochem
1. Begins with palmityl CoA and serine
Produces dihydrosphingosine and sphingosine2. Sphingosine can then by acylated to produce ceramide
Additi l b dd d t th C OH f
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Additional groups may be added to the C1-OH of
ceramides
Biochem
Cholesterol synthesis
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Biochem
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
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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 accelerated
degradation of the enzyme
3. Overall reaction:
Acetoacetyl CoA + acetyl CoA HMG CoA synthase HMG CoA
HMG CoA reductase mevalonic acidcholesterol
Biochem
What are the fates of the products of cholesterol synthesis?
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Biochem
1. Mevalonic acid
Precursor of a number of natural products calledterpenes, which include vit A, vit K, coenzyme Q, an
natural rubber
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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 synthesi
ofvit D
Biochem
Lipid malabsorption
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Biochem
1. Leads to excessive fat in the feces (steatorrhea)2. Occurs for a variety of reasons:
Bile duct obstructiono ~50% of dietary fat appears in the stools as soaps
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o ~50% of dietary fat appears in the stools as soaps
(metal salts of LCFAs)o Absence of bile pigments leads to clay-colored stool
o Deficiency of the ADEK vitamins may result
Pancreatic duct obstructiono 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)
Biochem
Hyperlipidemias
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Biochem
1. Familial hypercholesterolemia
Results from defective LDL receptors Findings: severe atherosclerosis, early death from CAD
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g , y
Tx: HMG CoA reductase inhibitors (statins)2. Hypertriglyceridemia Can result from either overproduction of VLDL or defectiv
lipolysis of VLDL triglycerides
Findings: cholesterol levels may be mildly
3. Mixed hyperlipidemias BOTH serum cholesterol & serum triglycerides are
Biochem
There is both overproduction of VLDL and defectivelipolysis of triglyceride-rich lipoproteins (VLDL and
chylmicrons)
There is a danger of acute pancreatitis
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g p
Inheritied defects and deficiencies that disrupt fatty acid
oxidation
Biochem
1. Inherited defects in the carnitine transport system, which hav
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p y ,
widely varying symptoms: Hypoglycemia Muscle wasting w/accumulation of fat in muscle Feeding fat w/medium-chain triacylglycerols (e.g., butterfa
is helpful in some cases, b/c MCFAs can bypass carnitine
transport system2. Inherited deficiencies in the acyl CoA dehydrogenase, the mo
common being medium-chain (C6-C12) acyl CoA
dehydrogenase deficiency
Biochem
Hypoketotic hypoglycemia and dicarboxylic aciduriaoccur, with vomiting, lethargy, and coma
This is believed to account for the condition called Reye-like syndrome
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Sphingolipid Storage Diseases
Biochem 133
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Disease
Accumulated
Substance Clinical Manifestations
Tay-SachsGanglioside GM2 Mental retardation (MR), blindness, r
spot on macula, death by 3rd yr
Gauchers Glucocerebroside Hepatosplenomeg, bone erosion, MR
FabrysCeramide
trihexoside
Rash, kidney failure, lower extremity
painNiemann-Pick Sphingomyelin Hepatosplenomegaly, MR
Globoid cell
leukodystrophy
Galactocerebroside MR, myelin absent
(also called Krabbes disease)
Metachromatic Sulfatide MR, metachromasia, nerves stainyellowish brown w/crystal violet
Biochem
leukodystrophy
Gen gangliosidosisGanglioside GM1 MR, hepatomegaly, skeletal
abnormalities
SandhoffsGanglioside GM2,
globoside
Same as Tay-Sachs, but more rapid
course
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Fucosidosis
Pentahexosylfuco-
glycolipd
Cerebral degeneration, spasticity, thic
skin
Urea Cycle
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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 transcarbamoylasecitrulline + aspartate + ATP argininosuccinate synthetase
argininosuccinate argininosuccinate lyase fumarate +
arginine + H20 arginaseUREA + ornithine
Biochem
Urine byprodu
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How does detoxification of NH4+ occur in peripheral tissues?
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1. In most tissues:
Glutamine synthetase incorporates NH4+ into glutamate toform glutamine, which is carried by circulation to the liver
In the liver, glutaminase hydrolyzes glutamine back to NH
and glutamate2. In skeletal muscle:
Glutamate dehydrogenase and glutamate-pyruvateaminotransferase incorporate NH4
+ into alanine
Biochem
Alanine is carried to the liver, wheretransdeamination results in converstion of alanine back to
pyruvate and NH4+
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Hyperammonemia
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1. May be caused by insufficent removal of NH4+, resulting fromdisorders that involve one of the enzymes in the urea cycle
2. Signs and Symptoms Blood NH4+ concentrations above the normal range (30-60 M Mental retardation, seizure, coma, and death
3. Enzyme defects
Biochem
Low activity of carbamoyl P synthetase or ornithine-carbamoyl transferase [NH4
+] in blood & urine NH4+
intoxication
Defective argininosuccinate synthetase, argininosuccinase, ORi bl d l l f t b lit di d f t
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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 a
Eating benzoate & phenylacetate: alternate path for NH4+
excret
Carbon skeletons of amino acids
Biochem 141
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1. Amino acids can be grouped into families based on the point wheretheir carbon skeletons enter the TCA cycle
2. AcetylCoA/Ketogenic fam(blue:keto-& glucogenic; red:ketogen on
Isoleucine, leucine, lysine,phenylalanine, tryptophan, and tyros Phenylalanine tyrosine via phenylalanine hydroxylase
Biochem
Tyrosine is starting compound for:o Epi and NE, T3 and T4, Dopamine, Melanin
3. -Ketoglutarat fam (arginine,histidine,glutamate,gluatmine,prolin Histidine precursor of histamine Glutamate excitatory neurotransm can be converted to GABA
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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
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1. Isoleucine
2. Leucine
Biochem
3. Lysine4. Phenylalanine
5. Tryptophan
6. Histidine
7 Methionine
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7. Methionine
8. Valine
9. Threonine
Biochem
Phenylketonuria (PKU)
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1. Results from a deficiency of:
Phenylalanine (Phe) hydroxylase OR
Biochem
Dihydropteridine reductase2. Findings
Phe in the blood (hyperphenylalaninemia) Phe builds up to toxic concentrations in body fluids,
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resulting in CNS damage with mental retardation Phe inhibits melanin synthesis hypopigmentation3. 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)
Biochem
Albinism
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1. No tyrosinase (1st enzyme on pathway to melanin)
2. Have little or no melanin and are:
Biochem
Easily sunburned Very susceptible to skin carcinoma Photophobic b/c of lack of pigment in iris of eye
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Biochem
Homocystinuria
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1. May result from several defects:
Cystathionine synthase (CS) deficiency
Biochem
affinity of CS for its coenzyme, pyridoxal phosphate(PLP) (may respond to megadoses of pyridoxine/vit B6)
Methyl tetrahydrofolate homocyst methyltransferase deficie Vit B12 coenzyme deficiency (may respond to vit B12)
2 Finding: homocysteine accumulation in blood appears in urin
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2. Finding: homocysteine accumulation in blood, appears in urin3. 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
Biochem
Maple-syrup urine disease
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Biochem
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
a maple syrup-like odor
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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-chaiamino acids
Biochem
Histidinemia
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Biochem
1. Deficiency in histidine- -deaminase (the 1stenzyme in histidine catabolism)
2. Characterized by elevated histidine in blood plasma and
excessive histidine metabolites in urine
3. Symptoms:
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3. Symptoms:
Mental retardation and speech defects (both are rare)4. Treatment: not usually indicated
Biochem
Origin of the atoms in the purine ring
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N
te
C
C
NH
C
N3, N9: glutamine
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Biochem
PURINE nucoleotide synthesis
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Biochem
De novo synthesis:
158
PATHWAY: (remember: purines = adenine and guanine)
Ribose 5-P PRPP synthetase PRPPglutamine PRPP amidotransferase 5
phosphoribosyl-1-amine 9 rxns IMP + Asp + GTP AMP
IMP + Gln + ATP + NAD GMP
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1. Inosine monophosphate (IMP), AMP, & GMP inhibit PRPP syntheta2. 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
Adenine phosphoribosyl transferaseo Inhibited by AMP
Biochem
Regulation of purine synthesis
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Biochem
1. Regulation provides a steady supply of purinenucleotides
2. GMP and AMP inhibit 1st step in their own synthesis from IMP
3. Reciprocal substrate effect: GTP is a substrate in AMPsynthesis, and ATP is a substrate in GMP synthesis
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Balances supply of adenine and guanine ribonucleotides4. 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
Biochem
Origin of the atoms in the pyrimidine ring
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N
N
C
C
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Biochem
De novo pyrimidine synthesis
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Biochem
1. In mammals, 1st
3 steps occur on one multifunctionalenzyme called CAD, which stands for the names of the enzym
CO2 + glutamine CAP synthetase II carbamoyl-P (CAP) Synthesis of dihydroorotic acid is a 2-step process:
o Committed step: aspartate + CAP aspartate
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transcarbamoylase carbamoyl aspartate
o Carbam aspartate dihydrorotase dihydroorotic acid + H
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 acidur
3. Synthesis of remaining pyrimidines involves UMP
Biochem
Phosphorylation of UMP UDP + UTP Addition of amino group from glutamine to UTP CTP
Regulation of pyrimidine synthesis
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Biochem
1. CAP synthetase II regulation
Inhibited by UTP Activated by ATP and PRPP
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2. CTP itself inhibits CTP synthetase
Biochem
Salvage of pyrimidines
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Biochem
Accomplished by the enzyme pyrimidine phosphoribosyl
transferase, which can use orotic acid, uracil or thymine, bu
NOT CYTOSINE
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Biochem
Deoxyribonucleotide synthesis
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Biochem
Formation of deoxyribonucleotides (for DNA synthesis) involvesreduction of sugar of ribonucleoside diphosphates:
1. Ribonucleotide reductase
L d t d ti f ADP GDP CDP UDP t d ib
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Leads to reduction of ADP, GDP, CDP, or UDP to deoxyribonu 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 deoxyribonucleotideo Rxn proceeds only in presence of nucleotide triphosphate
o dATP: allosteric inhibitor
o Other deoxynucleosides interact w/enzyme to alter specific
2. Thymidylate synthase
Biochem
Catalyzes formation of dTMP (deoxythymidylate) fromdUMP
Coenzyme : N5, N10-methylene tetrahydrafolate (regenerated afteeach rxn by dihydrofolate reductase)
N l tid d d ti
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Nucleotide degradation
Biochem
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
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nucleotidases) lead to hydrolysis of nucleic acids to nucleosides Deaminase converts adenosine/deoxyadenosine to deoxy-/inosin 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 oxidaseuric acid2. Pyrimidine degradation (products = -amino acids, CO2,
NH4+)
Degraded to free bases uracil or thymine
Biochem
A 3-enzyme rxn (reduction, ring opening, deamination-decarboxylation) converts uracil to CO2, NH4+, and -alanine anthymine to CO2, NH4
+, & -aminoisobutyrate
THUS: urinary -aminoisobutyrate is an indicator of DNAturnover (may be during chemo or radiation therapy)
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Disorders caused by deficiencies in enzymes involved in
nucleotide metabolism
Biochem
Hereditary
orotic
Orotate
phosphoribosyl
Retarded growth,
Anemia
Synthetic cytdi
or uridine (UT
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oroticaciduria
phosphoribosyltransferase
and/or OMP
decarboxylase
Anemia or uridine (UTformed acts as
inhib of carbam
P synthetase II
Purine
phosphorylas
deficiency
purine
uric acid
formation
Impaired T-cell
function
SCID Adenosinedeaminase
T- & B-cell dysfunction
w/early death from
infection
Gene therapy
Lesch-Nyhan HGPRT purine synthesis, Allopurinol -
Biochem
(deficient or
absent)
hyperuricemia, severe
neuro problem (spastic,
MR, self-mutilation)
deposition ofsodium urate
crystals, but
doesnt amelio
neuro symptom
Anticancer drugs that interfere w/nucleotide metabolism
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Anticancer drugs that interfere w/nucleotide metabolism
Biochem
1. Hydroxyurea
Inhibits nucleoside diphosphate reductase (enzyme th
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Inhibits nucleoside diphosphate reductase (enzyme thconverts ribonucleotides to deoxyribonucleotides)
2. Aminopterin and methotrexate
Inhibit dihydrofolate reductase (enzyme that converts
dihydrofolate to tetrahydrofolate)3. Fluoredeoxyuridylate
Inhibits thymidylate synthetase (enzyme that convertsdUMP to dTMP)
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Gout
Biochem
1. May result from a disorder in purine metabolism
2 Is associated w/hyperuricemia
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2. Is associated w/hyperuricemia3. Primary gout: overproduction of purine nucleotides
Mutations in PRPP synthetase loss of feedback inhibitiby purine nucleotides
A partial HGPRT deficiency less PRPP is consumed bysalvage enzyes PRPP activates PRPP amidotransfera
4. Secondary gout
Due to radation therapy, CA chemo (b/c they cell death
Biochem
5. Treatment: allopurinol Xanthine oxidase catalyzes oxidation of allopurinol toalloxanthine, which is a potent inhibitor of the enzyme
Result: uric acid levels fall, hypoxanthine & xanthine leverise (is OK, b/c they dont form crystals)
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Energy expenditure (3 components)
Biochem
1. Basal energy expenditure (BEE)
resting energy expenditure
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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
Biochem
20-30% of daily energy expenditure
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Caloric yield from foods and what % they should be in diet
Biochem
1. Carbs: 4 kcal/g
50-60% of caloric intake
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50 60% of caloric intake2. 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 intake4. Alcohol: 7 kcal/g
Biochem 183
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Fats:
Essential fatty acids, Deficiency, and Excess storage
Biochem
1. Essential fatty acids (EFAs):
Linoleic acid
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Linoleic acid Linolenic acid
2. Deficiency
Mainly seen in low-birth-weight infants maintained o
artificial formulas and adults on TPN Characteristic system: scaly dermatitis3. Excess fat
Stored as triacylglycerol
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Marasmus vs. Kwashiorker
Biochem
Marasmus Kwashiorker
Insufficient food, including bothcalories and protein
Starvation with edema often due protein deficient diet
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, gcalories and protein protein deficient diet
Depleted subQ fat Pitting edema
Flaky paint dermatosis: dark patch
on skin that peel
Liver ketogenesisbrain&heart fuel Large liver due to fatty infilatratio
Muscle wasting (breakprotein forgluconeogenesis & protein synthes)
Muscle wasting less severe
Frequent infections Frequent infections
Low body temp
Biochem
Micronutrient deficiencies Other nutrient deficiencies
Slowed growth(60% expected w
Death when energy & protein
reserves exhausted
Poor appetitie (anorexia)
Watery stools w/undigested food
Mental changes (apathetic)
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Vitamin A
Biochem
1. Functions:
11-cis-retinal prosthetic group of rhodopsinB i id NOT TOXIC hi h d
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p g p p Beta-carotene antioxidant NOT TOXIC at high doses Retinyl phosphate mannose acceptor/donor in glycoprotein syn Retinol & retinoic acid regulate tissue growth & differentiation
2. Deficiency signs and symptoms:
Night blindness, Xerophthalmia (cornea keratinizes: Bitot spotso Leading cause of child blindness in 3rd world nations
Follicular hyperkeratosis (rough, tough skin) Anemia
Biochem
resistance to infection susceptibility to cancer3. Toxicity (prolonged ingestion of 15,000-50,000 equivalents/da
Bone pain, scaly dermatitis, hepatosplenomegaly, nausea, diarrh4. Clinical usage: For acne and psoriasis
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Vitamin D
Biochem
1 Functions: regulation of Ca+ metabolism
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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 tubules2. Sources:
Major: skin (UV: 7-dehydrocholesterol Vit D3/cholecalciferol) Diet (vit D3) and foods fortified w/vit D2
Biochem
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
Osteomalacia (adults): pathologic fractures B d i li l lt f it D i ti f b t
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Bone demineraliz may also result from vit D inactive forms by stero5. Toxicity: (hyperCa+, metast calcification, bone demineraliz, kidney stones)
Seen in sarcoidosis (epithelioid macroph convert vit.D to its active form
Vitamin E
Biochem 192
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1. Function
Protection of membranes & proteins from free-radical damage
Includes isomers of tocopherol:o Tocopherol + free radicals tocopheroxyl radical vit C
reduces tocopheroxyl radical tocopherol is regenerated
2. Deficiency
Biochem
Secondary to impaired lipid absorption (cystic fibrosis,celiac disease, chronic cholestasis, pancreatic insufficiency,
abetalipoproteinemia)
Signs & Symptoms :o Ataxia
o Impaired reflexes
o Myopathy
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o Muscle weakness
o Hemolytic anemia (b/c of fragility of RBCs)
o Retinal degeneration
Vitamin K
Biochem 194
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1. Function
Post-translational carboxylation of glutamyl residues in Cabinding proteins: factors VII, IX, & X
2. Deficiency ( PT, aPTT, but nl bleeding time)
Biochem
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
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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
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1. B1 = Thiamine2. B2 = Riboflavin
3. B3 = Niacin
Biochem
4. B5 = Pantothenate (pantothenic acid)
5. B6 = Pyridoxine (pyridoxamine, pyridoxal)
6. B12 = cobalamin
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Thiamine (vitamin B1)
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1. Thiamine pyrophosphate (TPP): required for nervetransmission & is coenzyme for several key enzymes:
Biochem
Pyruvate & -ketoglutaratedehydrogenase(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
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Early : loss of appetite, constipation, nausea, periphneuropathy, irritability, fatigue
Moderately severe : Wernicke-Korsakoff syndrome (mentaconfusion, ataxia, ophthalmoplegia)
Severe (in addtion to polyneuritis):o Dry: atrophy & weakness of muscles
o Wet:edema,high-output cardiac failure,pulm congesti
Biochem
Riboflavin (vitamin B2)
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Biochem
1. Function:
Converted to re-dox coenzymes FAD & FMN2. Deficiency signs & symptoms:
Angular cheilitis Glossitis (red and swollen tongue)
Scaly dermatitis (esp at nasolabial folds & aroundt )
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scrotum)
Corneal vascularization
Biochem
Niacin (vitamin B3)
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Biochem
1. Function:converted to redox coenzymes NAD & NADP2. Deficiency
Causes :o Hartnup disease
o Malignant carcinoid syndrome
o INH Mild deficiency: glossitis
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Mild deficiency : glossitis
Severe deficiency : pellagra the 3 Dso Dermatitis
o Diarrhea
o Dementia
3. High doses
Vasodilation (very rapid flushing)
Biochem
Metobolic changes: blood cholesterol & LDLs
Vitamin B6 (pyridoxine, pyridoxamine, & pyridoxal)
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Biochem
1. Function
Coenzyme involved in transamination (e.g., ALT & AST)decarboxylation, and trans-sulfuration (rxns of amino acid
metabolism)
2. Deficiency (inducible by INH)
Mild: irritability, nervousness, depression
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Severe: periph neuropathy, convulsions, occasionalsideroblastic anemia
Other symptoms: eczema, seborrheic dermatitis around ear
nose, and mouth; chapped lips; glossitis; angular stomatiti3. Clinical usefulness:
High doses: tx homocystinuria (defective cystathione -synthase)
Biochem
Vitamin B6: Pantothenic acid
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Biochem
1. Function
Essential component of coenzyme A (CoA) and of fatacid synthase
Cofactor for acyl transfers
2. Deficiency (very rare) Vague presentation little concern to humans
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Vague presentation, little concern to humans
Dermatitis, enteritis, alopecia, adrenal insufficiency
Biochem
Biotin
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Biochem
1. Function
Covalently linked biotin = prosthetic group for carboxylatenzymes (e.g. pyruvate carboxylase, acetyl CoA
carboxylase) (NOT decarboxylations)
2. Deficiency (rare)
Signs and symptoms:D titi P th l
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o Dermatitis
o Hair loss
o Atrophy tongue papilla
o Gray mucous memb
o Paresthesa,muscle pa
o Hypercholesterlemia
o ECG abnormalities
Causeso Antibiotic use (since intestinal bacteria make biotin)
o Eating Avidin (raw egg whites)
Biochem
Binds biotin in a nondigestible form If you eat >20 eggs/day
Folic acid
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Biochem
1. Function
Polyglutamate derivatives of tetrahydrofolate serve as coenzymein 1-carbon transfer rxns:
o Purine & pyrimidine synthesis
o Thymidylate synthesis
o Conversion of homocysteine to methionine
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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 disea
Biochem
Can be caused by several drugs :o Methotrexate (chemo)
o Trimethoprim (antibact)
o Pyrimethamin(antimalari)
o Diphenylhydantoin
(anticonvulsant)
o Primidone (anticonvul
Vitamin B12 (cobalamin)
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Biochem
1. Functions
Coenzyme for methylmalonyl CoA
succinyl CoA(methylmalonyl CoA mutase) in propionyl CoA metabolism
C f th l t f b t t t h d f l t &
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Coenzyme for methyl transfer between tetrahydrofolate &methionine (homocysteine methyl transferase)
2. Deficiency:
Signs & Symptoms :o Megloblastic anemia
o Paresthesia, optic neuropathy, subacute combined degener
o Prolonged deficiency irreversible nervous system dama
Biochem
Causes :o Intake of no animal products (vegans)
o Achlorhydria, intrinsic factor (impaired absorption)
o Malabsorption (impaired pancreatic function, sprue, enterit
D. latum, absence of terminal ileum/Crohns)
3. Use Schilling test to detect deficiency
Vitamin C (ascorbic acid)
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Vitamin C (ascorbic acid)
Biochem
1. Functions
C f d i l di
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Coenzyme for re-dox rxns, including:o Post-translational hydroxylation of proline & lysine in
maturation of collagen
o
Carnitine synthesiso Tyrosine metabolism
o Catecholamine neurotransmitter synthesis
Antioxidant
Biochem
Facilitator of iron absorption2. 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 ou
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y
Symptoms of Mineral Deficiencies
Biochem
Mi l D fi i A i t d C diti
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Mineral Deficiency-Associated ConditionsCalcium Paresthesia
Tetany
Bone fractures, bone painOsteomalacia (as in vit D deficiency)
Iodine Goiter
Cretinism
Biochem
Iron Anemia
Fatigue, tachycardia, dyspneaMagnesium Neuromusc excitability, paresthesia
Depressed PTH release
Phosphorus (as phosphate) Deficiency rarely occurs
Zinc Growth retardation & hypogonadism
Dry, scaly skinMental lethargy
Imparied taste & smell poor appetite
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Imparied taste & smell, poor appetite
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