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Acidic dissociation
Biochem
Biochem
Measures of acidity
Biochem
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 (H+ binds loosely to conjugate base) 2 Weak acid has a pKa of 10 (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
Biochem
Acidic solution has a [H+] > 10 pH < 7 Alkaline solution has a [H+] < 10-7 pH > 7
-7
Biochem
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
Biochem
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)?
Biochem
1. 2.
What acid-base pair is effective buffer in physiolog fluids? H2PO4- and HPO42What 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:
Biochem
o o o o
Supply of CO2 from oxidative metabolism is unlimited, so effective concentration of CO2 is very high Equilibration of CO2 with H2CO3 is very rapid CO2 removal by lungs allows for rapid changes in [H2CO3] Kidney can retain or excrete HCO3-, thus changing the concentration of the conjugate base
Biochem
10
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
Biochem
11
Occurs when pH of blood and ECF is >7.45 Leads to neuromuscular hyperexcitability 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
Biochem
12
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
Biochem
13
3. Clinical picture 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
Dehydration Lethargy Vomiting Drowsiness Coma
Biochem
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Biochem
15
3. Sulfer-containing 4. Hydroxyl, mildly polar (uncharged, hydrophilic) 5. Basic, polar 6. Acidic, polar
Aspartic acid Asparagine Lysine Serine Threonine Arginine Glutamic acid Glutamine Histidine
Pg. 7 for structures
Cysteine
Methionine
Biochem
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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
Biochem
17
o Alpha-keratin in hair and nails o Myoglobin has several alpha-helical regions Proline, glycine, and asparagine helix breakers
o o
o
Primary structure: repeating glycine-X-Y sequences X and Y are freqeuntly proline or lysine Contains hydroxyproline & hydroxylysine
Biochem
18
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)
Biochem
19
4. 5. 6. 7.
Heavy metal ions (e.g., Hg++) Organic solvents (e.g., alcohol or acetone) High temperature Surface films (e.g., as when egg whites are beaten)
Biochem
20
1.
Hydrophobic valine replaces hydrophilic glutamate at position 6 of the beta-chain of normal hemoglobin A (Hgb A)
Biochem
21
o o
Severe anemia: deoxy Hgb S produces fibrous precipitates formation of sickle cells shorter life span severe anemia Acute episodes of vaso-occlusion sickle cell crisis
Sickle cells cant pass thru capillaries vasocclusion Disabling pain that requires hospitalization
Episodes of hematuria
Biochem
22
Scurvy
Biochem
23
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
Biochem
24
Symptoms of scurvy are thus the result of weakend collagen when these hydrogen bonds are missing
Biochem
25
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 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: G0 = RTlnKeq
Biochem
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Biochem
27
Biochem
28
intracellular conditions Intracellular spontaneity is a function of actual concentrations as well as Keq, G, NOT G0
Biochem
29
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 from
a more concentrated to a less concentrated solution, and when a protein is denatured when a complex molecule is synthesized from smaller substrates
Biochem
30
3. Free-energy change ( G)
Is related to enthalpy and entropy as follows: o G = H - T S (where T = absolute temp in Kelvins)
Biochem
31
1. Rate of reaction The G0 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, A-B The activation energy ( G) = energy required to scale the energy barrier and form the transition state
Biochem
32
The greater the G , the lower the rate of the rxn converting A to B 2. Catalysts (mostly enzymes) result in a: Lower G Faster reaction rate
Michaelis-Menten equation
Biochem
33
3. Velocity (v) of product formation is related to [ES]: o v = k3[ES] where k3 is also called kcat
Biochem
34
Vm[S] v = Km+[S]
5. Km = [substrate] at which v = Vm ([S] = Km) 6. A plot of velocity versus [S] is a rectangular hyperbola
Where Vm = max velocity & Km is the Michaelis constant
Lineweaver-Burk Equation
Biochem
35
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
Biochem
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Biochem
37
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 parallel
Allosteric regulation of enyzmes: Definition, How do they affect Km, and Example of Hexokinase
Biochem
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Biochem
40
Positive effectors the apparent Km Negative effectors the apparaent Km 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)
Biochem
41
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
Biochem
42
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
Biochem
43
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
44
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
Biochem
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Biochem
46
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 o
o acetyl CoA via pyruvate dehydrogenase Fatty acids generate acetyl CoA via -oxidation Some amino acids are degraded to acetyl CoA
Biochem
47
What are the products of one revolution of the citric acid cycle?
Biochem
48
2. Regeneration of one mole of OAA 3. 3 NADH & 1 FADH2 11 ATPs (via oxidative phosphorylation) 4. 1 GTP 1 ATP Oxidative Phosph: 1 NADH = 3 ATP 1 FADH2 = 2 ATP TOTAL OF 12 ATPs/acetyl CoA
Biochem
49
Describe the anaplerotic rxns that provide OAA and other citric acid cycle intermediates
Biochem
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50
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: Pyruvate + HCO3- + NAD(P) Malate + NAD(P)+ 4. Glutamate dehydrogenase in the liver: Glutamate + NAD(P)+ + H2O -ketoglutarate +
NAD(P)H + NH4+
Biochem
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Biochem
52
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: requires same cofactors as the pyruvate dehydrogenase complex) Inhibitors: succinyl CoA, NADH
Biochem
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Biochem
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cytochrome c
Biochem
55
NADH dehydrog. = Complex I, Succinate dehydrog. = Complex II (where FADH2 enters not pictured here), Cytochrome bc1 = Complex III, Cytochrome oxidase = Complex IV
Chemiosmotic hypothesis
Biochem
56
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 ( pH) o Difference in electrical potential ( ) between the intermembrane space and the mitochondrial matrix 3. ATP synthase complex (complex V)
Biochem
57
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
Biochem
58
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)
Biochem
59
Thermogenin helps to maintain normal body temp Found normally in brown fat of newborn mammals
Biochem
60
1. Digestion
Disacharides (sucrose),oligosacharides (dextrins),& polysacharides (starch) are cleaved into monosaccharides (glucose, fructose) Starch: storage from of carbs in plants
Biochem
61
Hydrolyzed to maltose, maltotriose, and -dextrins by -amylase in saliva and pancreatic juice Disaccharides & oligosaccharides o Hydrolyzed to monosaccharides by enzymes on the surface of epithelial cells in the small intestine 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)
2. Absorption
Biochem
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Glycogen metabolism
[Glycogen: carb storage, found chiefly in liver & muscle] 1. Glycogenesis (glycogen synthesis)
Biochem
63
Activated substrate: Uridine diphosphate-glucose Glycogen synthase adds to nonreduc end of chains in -1,4 links Branching enzyme amylo (14) to (16) transglycosylase creates branches w/ -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 -1,6 bonds Stimulators: sames as inhibitors of glycogenesis
Biochem
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Biochem
65
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
Biochem
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Biochem
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Biochem
68
o o
High Km (above the normal blood [glucose]) Inhibited by fructose 6-P (ensures glucose will be phosphorylated only as fast as it is metabolized)
Biochem
69
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
Biochem
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Biochem
71
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 FADH2
It generates 2 ATP/cytosolic NADH = 36 moles of ATP/glucose Transfers electrons to mitochondrial NADH It generates 3 ATP/cytosolic NADH = 38 ATP/glucose
Biochem
72
Gluconeogenesis
Biochem
73
1. 2. 3. 4.
Occurs primarily in the liver & kidney Synthesis of glucose from small noncarb precursors (such as lactate and alanine) Involves the reversible rxns of glycolysis 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
Biochem
74
5.
6.
Glucose from gluconeogenesis is released into the bloodstream for transport to tissues such as the brain and exercising muscle 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
Biochem
75
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
76
3. The liver releases the resynthesized glucose into the circulation for transport back to the muscle
Regulation of glycolysis
Biochem
77
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*
Biochem
78
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 Stimulators: CoA, NAD, ADP, pyruvate o Inhibitors: ATP, NADH, acetyl CoA 2. Induced by insulin
Gluconeogenesis regulation
Biochem
79
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
Biochem
80
2. 3. 4. 5. 6.
o Requires GTP Fructose-1,6-BP fructose-6-P via Fructose-1,6-BPase Glucose-6-P glucose via Glucose-6-phosphatase These enzymes are only found in liver, kidney, intestinal epithel Muscle cannot participate in gluconeogenesis Hypoglycemia is caused by a deficiency of these key enzymes Induced by glucocorticoids, glucagon, cAMP Suppressed by insulin Pnemonic: Pathway Produces Fresh Glucose
Biochem
81
Biochem
82
NAD (niacin)
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 B2 (FAD) B3 (NAD)
Biochem
83
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
Biochem
84
4.
5. 6. 7. 8.
NADPH needed for: fatty acid and cholesterol (steroid) synthesis, maintaining reduced glutathione inside RBCs The reversible nonxidative portion rearranges the sugars so they can reenter the glycolytic pathway Ribose 5-P, which is needed for nucleotide synthesis, can be formed from glucose 6-P by either arm Major regulatory enzyme: glucose 6-P dehydrogenase Glucose 6-P 6-phosphogluconolactone Stimulators: NADP+, insulin Inhibitors: NADPH
Biochem
85
1. Sucrase converts sucrose to glucose and fructose Hexokinase can convert fructose fructose 6-P (muscle,
kidney)
Biochem
86
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
Biochem
87
Biochem
Von Gierkes (type I) Pompes (type II) Coris (type III) Anderson (type IV) McArdle (type V) Hers (type VI) Type VII Type VIII
Glucose 6-P
Liver & kidney Lysosomes, All organs Muscle & liver Liver & spleen Muscle Liver Muscle Liver
-1,4-glucosidase Debranch enzyme Branching enzyme Phosphorylase Phosphorylase Phosphofructokinase Phosphorylas kinase
88 Hepatomegaly, Failure to thrive, Hypoglycemia, Ketosis, Hyperuricemia, Hyperlipidemia Failure of heart & lungs Death <2 yo Similar to I, but milder Liver cirrhosis, death <2 y Painful muscle cramps w/exercise Similar to type 1, but milder Similar to type V Mild hepatomegaly, mild hypoglycemia
Biochem
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Biochem
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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
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
Biochem
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Biochem
92
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)
Biochem
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Biochem
94
1. X-linked recessive 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
5. More prevalent among blacks 6. Heinz bodies: altered Hemoglobin precipitates w/in RBCs
Biochem
95
Lipid digestion
Biochem
96
Medium-chain triacylglycerol (TGs) are hydrolyzed by lipase Continues in stomach, producing a mix of diacylglycerols & FFAs Lipids are emulsified by bile salts (made from cholesterol in liver) Emulsified fats are hydrolyzed by pancreatic lipase Phospholipids are hydrolyzed by phospholipase A Cholesterol esters are hydrolyzed by cholesterol esterase
Fatty acids Diacylglyc Monoacyl Phospholipi Cholesterol VitA,D,E, K Bile acids
4. Mixed micelles form, which contain: 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
97
Long-chain fatty acids (>12 carbons) are reincorporated into TGs TGs go into chylomicrons lymphatics circulation via thoracic duct
Biochem
98
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
Biochem
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Lipoprotein absorption
Biochem
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2.
Biochem
101
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
Biochem
102
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
103
B-48 mediates secretion As are used for formation of new HDL C-II activates lipoprotein lipase E mediates remnant uptake by liver
Biochem
104
1. 2. 3. 4.
Delivers hepatic triglycerides to peripheral tissues Secreted by liver Excess causes pancreatitis Associated apolipoproteins: B-100 mediates secretion C-II activates lipoprotein lipase
Biochem
105
Biochem
106
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
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5. Associated apolipoproteins: B-100 mediates binding to cell surface receptor for endocytosis
Biochem
108
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
Biochem
109
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
Biochem
110
Long-chain (LC) fatty acids (>12) activated in cytosol LC acyl CoAs are shuttled into mitoch matrix by carnitine transport syst
Biochem
111
MCFAs pass directly into the mitoch & are activated in the matrix
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
Biochem
112
Ketogenesis
Biochem
113
CoA (HMG CoA) HMG CoA acetoacetate and acetyl CoA Acetoacetate -hydroxybutyrate (requires NADH) 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)
Biochem
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Biochem
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o Its transported to cytosol by citrate-malate-pyruvate shuttle Malonyl CoA: formed by biotin-linked carboxylation of actyl CoA
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
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Biochem
117
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
Biochem
118
Glycerolipid synthesis
Biochem
119
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 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-diacylglycerol with inositol)
Biochem
120
Sphingolipid synthesis
Biochem
121
1. Begins with palmityl CoA and serine Produces dihydrosphingosine and sphingosine 2. Sphingosine can then by acylated to produce ceramide Additional groups may be added to the C1-OH of ceramides
Biochem
122
Cholesterol synthesis
Biochem
123
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 accelerated degradation of the enzyme 3. Overall reaction:
Acetoacetyl CoA + acetyl CoA HMG CoA synthase HMG CoA HMG CoA reductase mevalonic acid cholesterol
Biochem
124
Biochem
125
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
Biochem
126
Lipid malabsorption
Biochem
127
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)
Biochem
128
Hyperlipidemias
Biochem
129
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 3. Mixed hyperlipidemias
BOTH serum cholesterol & serum triglycerides are lipolysis of VLDL triglycerides Findings: cholesterol levels may be mildly
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There is both overproduction of VLDL and defective lipolysis of triglyceride-rich lipoproteins (VLDL and chylmicrons) There is a danger of acute pancreatitis
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Hypoketotic hypoglycemia and dicarboxylic aciduria occur, with vomiting, lethargy, and coma This is believed to account for the condition called Reyelike syndrome
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Accumulated Substance
Ganglioside GM2 Glucocerebroside Ceramide trihexoside Sphingomyelin Galactocerebroside Sulfatide
Clinical Manifestations
Mental retardation (MR), blindness, red spot on macula, death by 3rd yr Hepatosplenomeg, bone erosion, MR Rash, kidney failure, lower extremity pain Hepatosplenomegaly, MR MR, myelin absent (also called Krabbes disease) MR, metachromasia, nerves stain yellowish brown w/crystal violet
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Urea Cycle
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1. 2. 3. 4.
Converts NH4+ (which is toxic, esp to CNS) to urea Occurs in the liver Urea is excreted in the urine 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
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Urine
byproduct
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form glutamine, which is carried by circulation to the liver In the liver, glutaminase hydrolyzes glutamine back to NH4+ and glutamate
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Alanine is carried to the liver, where transdeamination results in converstion of alanine back to pyruvate and NH4+
Hyperammonemia
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Blood NH4+ concentrations above the normal range (30-60 M) Mental retardation, seizure, coma, and death
3. Enzyme defects
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Low activity of carbamoyl P synthetase or ornithinecarbamoyl 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 Restriction of dietary protein Intake of mixes of keto acids that correspond to essential amin acid Eating benzoate & phenylacetate: alternate path for NH4+ excretion
4. Treatment
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1.
2.
Amino acids can be grouped into families based on the point where their carbon skeletons enter the TCA cycle AcetylCoA/Ketogenic fam(blue:keto-& glucogenic; red:ketogen only) Isoleucine, leucine, lysine, phenylalanine, tryptophan, and tyrosine Phenylalanine tyrosine via phenylalanine hydroxylase
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3. 4. 5. 6. 7.
Tyrosine is starting compound for: o Epi and NE, T3 and T4, Dopamine, Melanin -Ketoglutarat fam (arginine,histidine,glutamate,gluatmine,proline) Histidine precursor of histamine Glutamate excitatory neurotransm, can be converted to GABA Succinyl CoA family (isoleucine, methionine, valine) Methyl of methionine participates in methylation rxns as Sadenosylmethionine (SAM) Fumarate family (phenylalanine and tyrosine) Oxaloacetate family (asparagine and aspartate) Pyruvate fam (alanine,cysteine,glycine,serine,threonine, tryptophan)
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1. Isoleucine 2. Leucine
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3. 4. 5. 6. 7. 8. 9.
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Phenylketonuria (PKU)
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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)
Phe builds up to toxic concentrations in body fluids, resulting in CNS damage with mental retardation Phe inhibits melanin synthesis hypopigmentation
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Albinism
1. No tyrosinase (1st enzyme on pathway to melanin) 2. Have little or no melanin and are:
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Easily sunburned Very susceptible to skin carcinoma Photophobic b/c of lack of pigment in iris of eye
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Homocystinuria
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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)
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1. Results from a deficiency in the branched-chain 2keto 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
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Histidinemia
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1. Deficiency in histidine- -deaminase (the 1 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
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De novo synthesis:
PATHWAY: (remember: purines = adenine and guanine)
Ribose 5-P PRPP synthetase PRPPglutamine PRPP amidotransferase 5phosphoribosyl-1-amine 9 rxns IMP + Asp + GTP AMP IMP + Gln + ATP + NAD GMP
1.
Inosine monophosphate (IMP), AMP, & GMP inhibit PRPP synthetase PRPP activates glutamine PRPP amidotransferase Inhibited by end products (IMP, GMP, AMP) of the pathway
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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
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C N
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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
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Phosphorylation of UMP UDP + UTP Addition of amino group from glutamine to UTP CTP
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1. CAP synthetase II regulation Inhibited by UTP Activated by ATP and PRPP 2. CTP itself inhibits CTP synthetase
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Salvage of pyrimidines
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Accomplished by the enzyme pyrimidine phosphoribosyl transferase, which can use orotic acid, uracil or thymine, but NOT CYTOSINE
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Deoxyribonucleotide synthesis
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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
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Catalyzes formation of dTMP (deoxythymidylate) from dUMP Coenzyme: N5, N10-methylene tetrahydrafolate (regenerated after each rxn by dihydrofolate reductase)
Nucleotide degradation
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A 3-enzyme rxn (reduction, ring opening, deaminationdecarboxylation) converts uracil to CO2, NH4+, and -alanine and thymine to CO2, NH4+, & -aminoisobutyrate THUS: urinary -aminoisobutyrate is an indicator of DNA turnover (may be during chemo or radiation therapy)
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Orotate phosphoribosyl transferase and/or OMP decarboxylase purine uric acid formation Adenosine deaminase HGPRT
Synthetic cytdine or uridine (UTP formed acts as inhib of carbamoyP synthetase II)
Impaired T-cell function T- & B-cell dysfunction w/early death from infection purine synthesis, Gene therapy Allopurinol -
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(deficient or absent)
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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)
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Gout
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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)
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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)
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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
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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
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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
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Marasmus Insufficient food, including both calories and protein Depleted subQ fat
Liver ketogenesisbrain&heart fuel Muscle wasting (break protein for gluconeogenesis & protein synthes) Frequent infections Low body temp
Kwashiorker Starvation with edema often due to protein deficient diet Pitting edema Flaky paint dermatosis: dark patches on skin that peel Large liver due to fatty infilatration Muscle wasting less severe Frequent infections
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Micronutrient deficiencies Slowed growth(<60% expected wgt) Death when energy & protein reserves exhausted
Other nutrient deficiencies Growth failure(>60% expected wgt) Poor appetitie (anorexia) Watery stools w/undigested food Mental changes (apathetic)
Vitamin A
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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
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3. Toxicity (prolonged ingestion of 15,000-50,000 equivalents/day) 4. Clinical usage: For acne and psoriasis Vitamin D
Bone pain, scaly dermatitis, hepatosplenomegaly, nausea, diarrhea
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1.
2.
Stimulates synth of Ca+-binding protein aids absorption In combo w/PTH, blood Ca+ by:
bone demineralization by stimulating osteoblastic activity o Simulates Ca+ reabsorption by distal renal tubules Sources:
Major: skin (UV: 7-dehydrocholesterol Vit D3/cholecalciferol) Diet (vit D3) and foods fortified w/vit D2
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3.
Activation
4.
Kidney: 25(OH)D3 active 1,25(OH)2D3 (stimulated by PTH) Deficiency Rickets (kids): soft bones, stunted growth Osteomalacia (adults): pathologic fractures 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
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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
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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
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1. Function Post-translational carboxylation of glutamyl residues in Ca+binding proteins: factors VII, IX, & X 2. Deficiency ( PT, aPTT, but nl bleeding time)
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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
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Pyruvate & -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) Severe (in addtion to polyneuritis): o Dry: atrophy & weakness of muscles o Wet:edema,high-output cardiac failure,pulm congestion
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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
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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 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 synthase)
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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 Dermatitis, enteritis, alopecia, adrenal insufficiency
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Biotin
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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 o o o Dermatitis Hair loss Atrophy tongue papilla Gray mucous memb o o o Paresthesa,muscle pain Hypercholesterlemia ECG abnormalities
Causes o Antibiotic use (since intestinal bacteria make biotin) o Eating Avidin (raw egg whites)
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Folic acid
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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 Signs & symptoms: o Megaloblastic anemia o Neural tube defects o blood homocysteine associated w/atherosclerotic disease
2. Deficiency
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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)
Megloblastic anemia Paresthesia, optic neuropathy, subacute combined degenerat Prolonged deficiency irreversible nervous system damage
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3.
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) Use Schilling test to detect deficiency
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Antioxidant
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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)
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Mineral
Calcium
Deficiency-Associated Conditions
Paresthesia Tetany Bone fractures, bone pain Osteomalacia (as in vit D deficiency) Goiter Cretinism
Iodine
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Anemia Fatigue, tachycardia, dyspnea Neuromusc excitability, paresthesia Depressed PTH release Deficiency rarely occurs Growth retardation & hypogonadism Dry, scaly skin Mental lethargy Imparied taste & smell, poor appetite
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