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220 Cards in this Set
- Front
- Back
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The most common hereditary bleeding disorder in humans is due to a deficiency in which of the following proteins?
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von Willebrand Factor
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Aspirin is a commonly prescribed anticoagulant, but some patients are reportedly aspirin resistant (although this is controversial). A researcher has proposed that a genetic polymorphism in the molecular target for aspirin could be a cause of aspirin resistance. What is the molecular target in question?
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Cyclooxegenase
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An infant was born at home and has not received professional medical care, either prenatally or postnatally. He is brought to the clinic at seven days of age with multiple bruises and evidence of GI bleeding. A heel stick bleeds excessively. His mother indicates she is feeding him exclusively breast milk. His INR is elevated and individual clotting factor tests indicate abnormally low levels of several clotting proteins simultaneously. What is an appropriate diagnosis?
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Vitamin K deficiency - Vitamin K is a cofactor for the enzyme that carboxylates certain glutamate residues in proteins as they are synthesized in liver. A deficiency in this depresses plasma levels of several blood clotting protein including prothrombin, protein C, protein S, and Factors VII, IX, X
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What happens when thrombin removes the fibrinopeptides from fibrinogen?
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A Fibrin clot forms spontaneously from the plasma
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What is likely to be associated with von Willebrand Disease?
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Easy bruising; menorrhagia; recurrent epistaxis; gingival & gastrointestinal bleeding because patients have defective platelet aggregation
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What is the incorrect pairing?
A) Tissue Factor - initiates blood clotting cascade B) Factor VIII - the protein missing in Hemophilia A C) Plasmin - causes fibrinogen to clot D)vWF - adhesive protein for platelets E) Factor VIIIa - chemically crosslinks fibrin |
C - Plasmin converts fibrinogen to clots...Thrombin removes two peptides from polypeptide chains of fibrinogen coverting it into fibrin which clots spontaneously
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What are the basic roles of platelets in blood clotting?
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- platelets change their shape when activated to alter their surface properties and secrete granules
- activated platelets expose negatively charged phospholipids, phosphatidylserine on outer leaflet = surface for assembling blood clotting cascade - platelet aggregation |
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How does aspirin act as an anticoagulant?
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Aspirin targets cyclooxengenase, the first enzyme in the thromboxane A2 pathway. Thromboxane is a protein that promotes adherence and aggregation of ciculating platelets
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What is VWF and in very general terms, what is it's function in platelet biology
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vWF is a protein that forms multimers, binding collagen adhesive receptors on platelets that bind to vWF bound to collage enables platelet aggregation
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What does a deficiency in vWF lead to?
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vWF deficiency leads to von Willebrand disease which is the most common congenital bleeding disorder which results in defective platelet adhesion. Patients may have bleeding diathesis or mucosal bleeding
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What is tissue factor? What is its role in clotting
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Tissue factor is an integral membrane protein on cell surgace. When it is exposed to plasma, TF bind factor VIIa, the first enzyme in the clotting cascade. This triggers the clotting cascade to form a hemostatic plug
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What type of enzyme are most blood clotting factors
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seriene proteases
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what is the last protease in the clotting cascade
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Thrombin (poten platelet activator), this converts fibrinogen to fibrin which spontaneously affregates to form a gel
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How do coumarin (warfarin) drugs function as anticoagulants?
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They are vitamin K analogs that depress vitamin dependent carboxylation of several clotting factors
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What happens to fibrinogen when the fibrinopeptides are removed
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fibrin clot forms
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In general how does heparin act as an anticoagulant
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Heparin accelerates the INACTIVATION of facotr Xa or thrombin
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Why is tPA given to patients who present with a mycardial infarction? Can it be given the day after an MI? What is its side effects
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tPA converts plasminogen to plasmin which degrade fibrin clots. It needs to be given soon after an MI, within a few hours not the day after. Side effects include dissolving clots in the brain which will lead to bleeding in brain
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Which of the following is incorrect concerning blood clotting?
A Tissue factor is the protein that triggers blood clotting. B Activation of prothrombin requires vitamin K-dependent proteins. C Antithrombin helps keep clotting in check. D Fibrinogen spontaneously polymerizes to form a clot. E Plasmin dissolves clots. |
D. Fibrinogen spontaneously polymerizes to form a clot.
FIBRIN polymerizes to form a clot, not fibrinogen. Thrombin converts fibrinogen to fibrin via limited proteolysis. |
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Calcium ions play an important role in the activity in the body of which of the following enzymes?
A UDP-glucuronosyl transferase B Pyruvate carboxylase C Activated factor X D Phenylalanine hydroxylase E Hexokinase |
Activated factor X
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Which of the following is not true of aspirin?
A It inhibits (or more accurately, inactivates) cyclooxygenase. B It inhibits (inactivates) an enzyme whose substrate is arachidonic acid. C It can inhibit platelet thromboxane formation. D It can cause decreased platelet aggregation. E All of the above are true. |
All of the above
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Which of the following is incorrect concerning conversion of fibrinogen to fibrin?
A A vitamin K deficiency in a person will lead to less conversion of fibrinogen to fibrin. B Fibrin polymerization is facilitated by removal of fibrinopeptides from fibrinogen. C Operation of either the intrinsic or extrinsic pathways will lead to more conversion of fibrinogen to fibrin. D The conversion is inhibited in the body where heparin is present. E All of the above are correct. |
All the above
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Which of these proteins should be administered to a patient who has just had a myocardial infarction (MI)?
A Tissue factor B Tissue plasminogen activator (tPA) C Tissue thromboplastin D Fibrinogen E Factor VIII |
tPA activates plasminogen to plasmin, which lyses blood clots. This can restore blood flow to the infarcted heart muscle.
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What would you give a patient who has overdosed on warfarin?
A Vitamin C B Vitamin K C Factor VIII D Tissue plasminogen activator (tPA) E Heparin |
Vitamin K
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What are the two steps for the removal of amino group from an amino acid?
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Transamination - the transfer of alpha amino group of an amino acid to alpha ketoglutarate
Oxidative deamination - liberation of amino group as ammonia |
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What are the enzymes mediating transamination and oxidative deamination
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- Aminotransferases such as Alanine aminotransferase (most common) and Aspartate aminotransferase mediate transamination to produce alpha-keto acid and glutamate.
Glutamate undergoes rapid oxidative deamination by the enzyme Glutamate dehydrogenase |
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What is the diagnostic value of plasma aminotrasgerases (AST and ALT)?
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Aminotransferases are normally intracellular enzymes with low levels in plasma. Elevated plasma levels indicate damage to cells rich in these enzymes (liver, kidney, intestine, muscle). Elevated plasma occurs often in liver disease
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Which of the following is incorrect concerning synthesis of carbamoyl phosphate?
A It is mediated by different enzymes in the cytosol and mitochondria of the liver. B The nitrogen source can be either ammonia or glutamine. C It plays a role in the urea cycle. D It plays a role in pyrimidine synthesis. E All of the above are correct. |
All the above are correct
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Which compound is involved in reducing levels of homocysteine in the blood?
A Serine B N5, N10-methylene tetrahydrofolate C Cysteine D Methionine E Adenosine |
Serine
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What are the two sources of nitrogens in urea?
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NH3 and Aspartate
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Where does the urea cycle occur?
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Urea is synthesized in the liver and excreted in the kidney.
More specifically, the first two steps of the urea cycle occur in the mitochondria and the ramining steps occur in the cytosol |
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What is the regulatory step in the urea cycle? How is the urea cycle regulated
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The first reaction is the most important rate limiting step: formation of carbamoyl phosphate by carbamoyl phosphate synthesase I which needs a positive allosteric activator N-acetylglutamate (synthesized from acteyl CoA and glutamate).
After ingestion of a protein rich meal, N-acetyglutamate increases which provides substrate and regulator of N-acetylglutamate synthesis which leads to increase rate of urea synthesis |
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What are the sources of ammonia in the body
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-from amino acids via oxiative deamination by glutamate dehydrogenase
-from hydrolysis of glutamine by intestinal glutaminase - from bacterial action in intestine via urease -from amines obtained from diet -from purine and pyrimidine catabolism |
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How is ammonia transported in the circulation?
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Urea is transported from liver to kidney through the blood which goes through the glomerular filtrate
Glutamine is a non toxic storage and transportation of NH3 in muscle, liver and CNS. Glutamine is removed by the kidney and deaminated by glutaminase Alanin aminotransferase can also assist with the transport of ammonia |
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How do you treat hyperammonia?
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- limiting protein in diet
-administer phenylbutyrate which is converted to phenylacetate together with glutamine to form phenylacetylglutamine which is excreted in urine - administration of arginine - arginine is an allosteric activator of a synthethase to produce N-acteyleglutamate which activates carbomoyl phosphate synthetase I to promote release of extra ammonia. |
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Why can aspariginase be used to treat leukemic patients?
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Asparaginase hydrolyzes asparagine to aspartate anc can be administered systemically to treat leukemic patients because asparaginase lowers the level of asparagine in the plasma and deprives cancer cells of a required nutrient
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Why can the FIGlu excretion test be used to diagnose folic acid deficiency?
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FIGlu excretion test is a urine test which is an indicator of vitamin B12 or folic acid deficiency or liver disease by measuring the increased amounts of FIGlu in the urine after ingestion of a large dose of histidine.
Histadine is oxidatively deaminated by histidase to urocanic acid which forms N-formiminoglutamate (FIGlu). FIGlu donates its formiminogroup to tetrahydrofolate leaving glutamate. |
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what are the two reactions using B12 derivatives as coenzymes?
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- Resynthesis of methionine from homocysteine via Methylcobalamin (Methyl B12) and Homocysteine methyltransferase
- synthesis of succinyl CoA from propionyl coA |
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Catabolism of methionine: degradation and resynthesis of methionine.
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Degradation: L-methionine -> S-adenosylmethionine (SAM) -> L-homocysteine -> Cystathionine ->L-cysteine -> propionyl coA -> succinyl coA
Resynthesis: L-methionine -> S-adenosylmethionine (SAM) -> L-homocysteine ->L-Methionine using Methylcobalamin (Methyl B12) forming tetrahydrofolate |
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What are the 2 fates of homocysteine?
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- It can be resynthesized to L-Methionine which requires Methylcobalamin
- It can form cysteine which requires vitamin B6 (pyridoxine) - a transsulfuration process |
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Homocystinuria is due to deficiency of which enzyme?
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Cystathionine Beta-synthase. These individuals experience premature vascular disease.
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What is the cause for Maple syrup disease?
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The cause for maple syrup urin disease is a partial or complete deficiency in branched chain alpha-keto acid dehydrogenase, an enzyme complex that decarboxylates leucine, isoleucine and valine.
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In addition to the deficiency of phenylalanine hydroxylase, what else can cause PKU? Why?
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A deficiency in BH2 synthetase or in BH2 reductase, which regenerates BH4 from BH2, because it indirectly raises phenylalanine concentration because phenylalanine hydroxylase requires BH4 as a coenzyme
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Which reactions require BH4 as a coenzyme?
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tyrosine hydroxylase and tryptophan hydroxylase which catalyze reactions leading to synthesis of neurotansmitters
phenylalanine hydroxylase also uses BH4 as a coenzyme in converting L-phenylalanine to L-tyrosine |
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How do you treat hyperammonia?
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- limiting protein in diet
-administer phenylbutyrate which is converted to phenylacetate together with glutamine to form phenylacetylglutamine which is excreted in urine - administration of arginine - arginine is an allosteric activator of a synthethase to produce N-acteyleglutamate which activates carbomoyl phosphate synthetase I to promote release of extra ammonia. |
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Why can aspariginase be used to treat leukemic patients?
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Asparaginase hydrolyzes asparagine to aspartate anc can be administered systemically to treat leukemic patients because asparaginase lowers the level of asparagine in the plasma and deprives cancer cells of a required nutrient
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Why can the FIGlu excretion test be used to diagnose folic acid deficiency?
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FIGlu excretion test is a urine test which is an indicator of vitamin B12 or folic acid deficiency or liver disease by measuring the increased amounts of FIGlu in the urine after ingestion of a large dose of histidine.
Histadine is oxidatively deaminated by histidase to urocanic acid which forms N-formiminoglutamate (FIGlu). FIGlu donates its formiminogroup to tetrahydrofolate leaving glutamate. |
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what are the two reactions using B12 derivatives as coenzymes?
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- Resynthesis of methionine from homocysteine via Methylcobalamin (Methyl B12) and Homocysteine methyltransferase
- synthesis of succinyl CoA from propionyl coA |
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Catabolism of methionine: degradation and resynthesis of methionine.
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Degradation: L-methionine -> S-adenosylmethionine (SAM) -> L-homocysteine -> Cystathionine ->L-cysteine -> propionyl coA -> succinyl coA
Resynthesis: L-methionine -> S-adenosylmethionine (SAM) -> L-homocysteine ->L-Methionine using Methylcobalamin (Methyl B12) forming tetrahydrofolate |
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What are the 2 fates of homocysteine?
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- It can be resynthesized to L-Methionine which requires Methylcobalamin
- It can form cysteine which requires vitamin B6 (pyridoxine) - a transsulfuration process |
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Homocystinuria is due to deficiency of which enzyme?
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Cystathionine Beta-synthase. These individuals experience premature vascular disease.
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What is the cause for Maple syrup disease?
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The cause for maple syrup urin disease is a partial or complete deficiency in branched chain alpha-keto acid dehydrogenase, an enzyme complex that decarboxylates leucine, isoleucine and valine.
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In addition to the deficiency of phenylalanine hydroxylase, what else can cause PKU? Why?
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A deficiency in BH2 synthetase or in BH2 reductase, which regenerates BH4 from BH2, because it indirectly raises phenylalanine concentration because phenylalanine hydroxylase requires BH4 as a coenzyme
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Which reactions require BH4 as a coenzyme?
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tyrosine hydroxylase and tryptophan hydroxylase which catalyze reactions leading to synthesis of neurotansmitters (catecholamines and serotonin, respectively)
phenylalanine hydroxylase also uses BH4 as a coenzyme in converting L-phenylalanine to L-tyrosine |
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What is the source BH2?
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BH2 comes from BH4 after it is used as a coenzyme in phenylalanine, tyrosine, or tryptophan hydroxylase. BH4 is a naturally occuring compound formed from GTP
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How do you treat PKU?
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If it's due to a deficiency in phenylalanin hydroxylase, a special diet low in phenylalanine plus injectable PAH
If the deficit is in BH4, then you would administer BH4 But you cannot restrict phenylalanine because it's an essential amino acid |
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Tetrahydrobiopterin is not involved in the synthesis of which of the following:
A epinephrine B tyrosine C phenylalanine D 5-hydroxytryptophan |
Phenylalanine
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What is the rate-controlling step in heme synthesis?
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The rate controlling step is the first step of the heme biosynthesis which condenses glycine and succinyl coA to form ALA in a reaction catalyzed by ALA synthase. This reaction requires pyridoxal phosphate as a coenzyme
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How is the activity of ALA synthase regulated?
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When prophyrin production exceeds the availability of globin, heme accumulates and is converted to hemin. Hemin decreases the activity of hepatic ALA synthase causing decreaed synthesis of the enzyme through inhibition of mRNA synthesis
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What are the targets of lead
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Heavy metals such as lead inhibits ALA dehydrogenase in the conversion of ALA to porphobilinogen which causes and elevation in ALA and anemia seen in lead poisoning
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What are phorphyrias
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Porphyrias are rare defects in heme synthesis resulting in accumulation and increased excretion of porphyrins or porphyrin precursors. Each porphyria results in the accumulation of a unique pattern of intermediates caused by deficiency of an enzyme in the heme synthetic pathway
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What is prophyrin cutanea tarda
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It is a chronic disease of the liver and erythroid tissues. deficiency in uroporphyrinogen decarboxylase causes virus infections, hepatic iron overload and uroporphyrin accumulates in urine and photosensitivity
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How do you treat phorphyrias?
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Intravenous injection of heme, avoid sunlight and take beta carotene
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What is the major source of heme proteins?
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senescent red blood cells
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What is the end product of heme degradation? How is it excreted from the body?
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Most uribilinogen is oxidized by intestinal bacteria to stercobilin which is excreted in feces
The remaining urobilinogen is transported by the blood to kiney and converted to urobilin which is excreted in urine |
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What is jaundice? what might cause jaundice?
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Jaundice is yellow color skin, nail beds and white of the eyes. This is caused by the increased levels of bilirubin in the body due to mass lysis of RBCs, sickle cell anemia, pyruvate kinase or glucose 6 - phosphate dehydrogenase deficiency. Urobilinogen in the enterhepatic circulation and urine is increased. Unconjugated bilirubin levels become elevated
This could be due to obstruction of bile duct, can be caused by hepatic tumor, bile stones causing bilirunin to be passed into blood instead of small intestine causing GI pain and nausea and stools that are pale in color Also, Jaundice can be caused by deficiency of conjugation of bilirubin because of liver damage and conjugated bilirubin goes into blood |
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What are the precursors of catecholamines?
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Catecholamines are synthesized from tyrosine. Tyrosine is bydroxylated by tyrosine hydroxylase to form DOPA requiring BH4. DOPA is decarboxylated in a reaction requiring pyridoxal phosphate to form dopamine which is hydroxylated to yield norepinephrine
Synthesis occurs in CNS, sympathetic ganglia and adrenal medulla |
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How are catecholamines degraded?
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catecholamines are inactivated by oxidative deamination catalyzed by monoamine oxiase and by O methylation carried out by catechol-o-methyltransferase
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What are the sources for creatine, histamine and serotonin?
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Histamine - formed by decarboxylation of histidine
Serotonin - synthesized from tryptophan Creatine - Synthesized from glycine and guanidino group of arginine + a methyl group from SAM |
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Which of the following statements is incorrect concerning bilirubin or its metabolism?
A It originates from heme. B Its synthesis involves two NADPH-requiring reactions. C It is carried by albumin in the blood. D It is made more soluble in the liver by derivatization. E All of it is excreted in the urine. |
All of it is excreted in the urine
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Congenital erythropoietic prophyria is due to a defect in which enzyme?
A Uroporphyrinogen III cosynthetase B Coproporphyrinogen oxidase C Uroporphyrinogen I synthetase D Uroporphyrinogen decarboxylase |
Uroporphyrinogen III cosynthetase
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What are the different sources for the carbons and nitrogens in the purine ring?
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The atoms of the purine ring are contributed by amino acids (aspartic acid, glycine, and glutamine), CO2 and N10 formyltetrahydrofolate
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What is the rate-limiting step in the purine synthesis? How is it regulated?
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Synthesis of 5'-phosphoribosylamine from PRPP and glutamine mediated by glutamine:phosphoribosyl pyrophosphate amidotransferase is the rate limiting step in purine synthesis. The end products of th epathway (AMP, GMP, and inosine monophosphate) inhibit the enzyme
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How do PABA analogs (sulfonamides) and folic acid analogs (methotrexate) inhibit purine synthesis?
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PABA analogs such as sulfonamides competitively inhit bacterial synthesis of folic acid. Because purine synthesis requires tetrahydrofolate as a coenzymes the drugs slow down this pathway in bacteria
Methotrexate and folic acid derivatices inhit the reduction of dihydrofolate to tetrahydrofolate catalyzed by dihydrofolate reductase. These drugs limit the amount of tetrahydrofolate available for purine synthesis |
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How does Mycophenolic acid inhibit the proliferation of T and B cells
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Mycophenolic acid is a reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase. This drug derives rapidly proliferating T and B cells of key components of nucleic acids
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What is the cause of Lesch-nyhan syndrome?
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This is an X linked recessive disorder associated with a virtually complete deficiency of HGPRT. The inability to salvage hypoxanthine or guanine produces excessive amounts of uric acid. The enzyme deficiency redults in increased levels of PRPP and decreased levels of IMP and GMP causing increased de novo synthesis of purines
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How is the activity of ribonucleotide reductase regulated?
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Ribonucleotide reductase is responsible for maintian a balanced supply of deoxyribonucleotides required for DNA synthesis
There's a single catalytic site and other sites on the enzyme involved in regulating its activity. dATP binding to allosteric site inhibits the overall catalytic activity of the enzyme preventing the reduction of any of the four nucleoside diphosphates preventing DNA synthesis binding of nucleoside triphosphates (ATP) to additional allosteric sites causes an increase in the conversion of different ribonucleotides to deoxyribonucleotides as they are needed for DNA synthesis |
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What is the end product of purine degradation
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Uric Acid
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What causes gout?
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High levels of uric acid in the blood due to underexcretion or overproduction of uric acid
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Which of the following statements is incorrect concerning bilirubin or its metabolism?
A It originates from heme. B Its synthesis involves two NADPH-requiring reactions. C It is carried by albumin in the blood. D It is made more soluble in the liver by derivatization. E All of it is excreted in the urine. |
All of it is excreted in the urine
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Congenital erythropoietic prophyria is due to a defect in which enzyme?
A Uroporphyrinogen III cosynthetase B Coproporphyrinogen oxidase C Uroporphyrinogen I synthetase D Uroporphyrinogen decarboxylase |
Uroporphyrinogen III cosynthetase
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What are the different sources for the carbons and nitrogens in the purine ring?
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The atoms of the purine ring are contributed by amino acids (aspartic acid, glycine, and glutamine), CO2 and N10 formyltetrahydrofolate
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What is the rate-limiting step in the purine synthesis? How is it regulated?
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Synthesis of 5'-phosphoribosylamine from PRPP and glutamine mediated by glutamine:phosphoribosyl pyrophosphate amidotransferase is the rate limiting step in purine synthesis. The end products of th epathway (AMP, GMP, and inosine monophosphate) inhibit the enzyme
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How do PABA analogs (sulfonamides) and folic acid analogs (methotrexate) inhibit purine synthesis?
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PABA analogs such as sulfonamides competitively inhit bacterial synthesis of folic acid. Because purine synthesis requires tetrahydrofolate as a coenzymes the drugs slow down this pathway in bacteria
Methotrexate and folic acid derivatices inhit the reduction of dihydrofolate to tetrahydrofolate catalyzed by dihydrofolate reductase. These drugs limit the amount of tetrahydrofolate available for purine synthesis |
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How does Mycophenolic acid inhibit the proliferation of T and B cells
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Mycophenolic acid is a reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase. This drug derives rapidly proliferating T and B cells of key components of nucleic acids
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What is the cause of Lesch-nyhan syndrome?
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This is an X linked recessive disorder associated with a virtually complete deficiency of HGPRT. The inability to salvage hypoxanthine or guanine produces excessive amounts of uric acid. The enzyme deficiency redults in increased levels of PRPP and decreased levels of IMP and GMP causing increased de novo synthesis of purines
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How is the activity of ribonucleotide reductase regulated?
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Ribonucleotide reductase is responsible for maintian a balanced supply of deoxyribonucleotides required for DNA synthesis
There's a single catalytic site and other sites on the enzyme involved in regulating its activity. dATP binding to allosteric site inhibits the overall catalytic activity of the enzyme preventing the reduction of any of the four nucleoside diphosphates preventing DNA synthesis binding of nucleoside triphosphates (ATP) to additional allosteric sites causes an increase in the conversion of different ribonucleotides to deoxyribonucleotides as they are needed for DNA synthesis |
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What is the end product of purine degradation
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Uric Acid
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What causes gout?
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High levels of uric acid in the blood due to underexcretion or overproduction of uric acid
1) Abnormal PRPP synthetase activity - resistant to feedback 2) Defect in purin salvage pathway - increased PRPP and enhanced purine synthesis (Lesch - Nyhan) 3) Alcohol |
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What is the treatment for gout?
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Prevent deposition of urate crystals
-Colchicine - decreases the movement of granulocytes into deposition area - Allopurinol - inhibits xanthine oxidase - Probenecid and sulfinpyrazone - increases the excretion of uric acid |
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Why does the deficiency of adenosine deaminase cause severe combined immunodeficiency disease
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Deficiency in ADA cause accumulation of adenosine which is converted to its ribonucleotide or deoxyribonucleotide form. As dATP levels rise, ribonucleotide reductase is inhibited thus preventing prodiction of deoxyribose-containing nucleotides and cells cannot make DNA and divide causing a both T cells and B cells to undergo apoptosis.
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What are the different sources for the carbons and nitrogens in the pyrimidine synthesis?
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The sources of the atoms in the pyrimidine ring are glutamine, aspartic acid and CO2
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What cause orotic aciduria?
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Low activities of orotidine phosphate decarboxylase and orotate phosphoribosyltransferase result in poor growth, megaloblastic anemia and excretion of large amounts of orotate in urine
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How does 5-fluorouracil inhibit DNA replication
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5-Fluorouracil which is converted to 5-FdUMP becomes permanently bound to the inactivated thymidylate synthase preventing methylation of dUMP to dTMP the lower the cellular concentral of this essential component of DNA
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Which of the following statements is incorrect concerning purine synthesis?
A The first purine synthesized is inosine-5'-monophosphate. B Two equivalents of N10-Formyl-tetrahydrofolate is required. C The initial committed step involves metabolism of 5'-phosphoribosyl-1-pyrophosphate. D The initial committed step is stimulated by AMP, GMP, and IMP. E All of the above are correct. |
D. The initial committed step is INHIBITED by AMP, GMP and IMP
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What substances inhibits the release of insulin by pancreatic beta cells?
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Epinephrine (secreted in response to stress, trauma, extreme exercise)
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What substances inhibits the release of glucagon by pancreatic alpha cells?
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decreased by high glucose and high insulin levels
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Which of these conditions is typically not associated with insulin resistance?
Type I diabetes Type II diabetes Gestational diabetes Metabolic syndrome |
Type I diabetes is due to autoimmune destruction of Beta cells of the pancreas
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Which of these conditions is most prevalent in the US
Type I diabetes Type II diabetes Metabolic syndrome Gestational diabetes Diabetes insipidus |
Metabolic Syndrome
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What is the fasting glucose level of someone that experiences hypoglycemia?
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less than or equal to 40 mg/dL
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What are the fasting glucose levels of someone that may have pre-diabetes?
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101 - 125 mg/dL
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What controls the release of insulin?
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Insulin is stimulated by glucose, amino acids and GI hormones (secretin)
Inhibited by epinephrine |
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What controls the release of glucagon?
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Low levels of blood glucose and decreased insulin levels stimulate the release of glucagon
High levels of of blood glucose and insulin inhibit the release of glucago |
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What cells make insulin and glucagon
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insulin - Beta cells of pancreatic islets of langerhans
glucagon - Alpha cells of pancreatic islets of langerhans |
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In general, how do the actions of insulin and glucagon differ from each other?
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insulin's overall effect is to decrease plasma glucose concentration
glucagon - increases blood glucose levels by stimulating gluconeogenesis and glycogen breakdown in liver |
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What are the main targets for insulin and glucagon?
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insulin - liver, muscle, adipose
glucagon - liver |
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What is hypoglycemia and what can cause it?
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Hypoglycemia is blood glucose of approximately 40 mg/dL or less
It can be caused by: insulin induced post prandial (exaggerated insulin release after meal) fasting hypoglycemia alcohol intoxication - cause the intermediates of gluconeogenesis to be diverted |
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What is the approximate level that below which symptoms of hypoglycemia will appear?
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~40 mg/dL
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What causes the symptoms of hypoglycemia?
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Impaired glucose delivery to the brain can cause headache, confusion, slurred speech, seizures, coma and death
Abrupt glucose fall causes adrenergic symptoms: anxiety, palpitation, tremor and sweating |
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How do you treat acute hypoglycemia?
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administer glucose
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What hormonal changes cause or accompany diabetes?
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Autoimmune destruction of Beta cells or insulin resistance of receptors accompany diabetes
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What are the 2 main types of diabetes and what is their treatment?
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Type I = insulin dependent, you treat it by giving injections to normalize blood glucose and to prevent ketoacidosis, monitor the efficacy by monitoring blood gluse and HbA1c
Type II - insulin resistance, treat with diet, weight reduction, exercise, various drugs and insulin in some cases |
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What glucose concentrations will lead to the diagnosis of diabetes?
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Fasting glucose levels of >126 mg/dL and non fasting glucose level of >200 mg/dL
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Which statement is incorrect about insulin?
A Insulin is a polypeptide hormone consisting of two disulfide-linked chains. B Insulin is secreted by beta-cells of pancreatic islets in response to high blood glucose and amino acid levels. C Insulin promotes synthesis of glycogen, triacylglycerols, and proteins. D Insulin receptors in target tissues act through c-AMP to promote protein phosphorylation. E One of the actions of insulin is to increase the number of glucose transporters on the surface of adipose and muscle cells. |
D. Insulin receptors are cell membrane tyrosine kinases. They do not act via cAMP.
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Which is the most abundant fuel source in starvation in most people?
A liver glycogen B muscle glycogen C adipose tissue triacylglycerols D liver triacylglycerols E muscle protein |
C. Adipose tissue triacylglycerols
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Which is the correct pairing of a tissue with its main fuel source in starvation?
A liver--glucose B brain--fatty acids C adipose tissue--glucose D erythrocytes--ketone bodies E muscle--fatty acids |
E. Muscle Fatty Acids
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Which of the following is incorrect regarding the metabolic changes in type 1 diabetes?
A Insulin levels are very low or insulin is absent. B Adipose tissue and muscle cannot utilize glucose. C High relative levels of glucagon promote glycogen breakdown and increased gluconeogenesis in the liver. D Hormone sensitive lipase is inactive. E Liver synthesizes ketone bodies from abundant acetyl CoA produced by the oxidation of fatty acids. |
D.
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Per gram, which compound yields the most energy when completely oxidized in the body?
A Glucose B Glycerol tripalmitate (a triacylglycerol) C Fructose D Gelatin (denatured collagen) E Sucrose |
B. Glycerol tripalmitate
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Which of the following nutrients is likely to have the lowest Recommended Dietary Allowance (RDA)?
A vitamin D B ascorbic acid C linoleic acid D phosphorus E protein |
Vitamin D
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Which of the following is not a metabolic response to low plasma calcium levels?
A Increased parathyroid hormone release B Decreased synthesis of 1,25 dihydroxy vitamin D3 C Increased calcium absorption from the intestine D Decreased renal excretion of calcium E Increased calcium mobilization from bone |
B. decreased synthesis of 1, 25 dihydroxy vitamin D3
This active form increases uptake of Ca by intestines, and increases Ca mobilization from bone |
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Which of the following vitamins could be used to treat pellagra?
A biotin B riboflavin C ascorbic acid D thiamine E niacin |
E. niacin
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Which of the following statements is incorrect about vitamin B-12?
A The structure of the cofactors derived from vitamin B-12 contain a corrin ring and a cobalt ion. B Cofactors derived from vitamin B-12 catalyze the reactions of acetyl CoA carboxylase and propionyl CoA carboxylase. C Vitamin B-12 is required for the regeneration of tetrahydrofolate from N-5-methyl-tetrahydrofolate. D Pernicious anemia often results from a deficiency of intrinsic factor which is required for the absorption of vitamin B-12 in the intestine. E Deficiency of vitamin B-12 is characterized by anemia and subsequent neuropsychiatric symptoms. |
B.
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Which of the following statements is incorrect about vitamin A?
A Vitamin A, in the diet, is absorbed in the intestine together with other lipids. B In intestinal epithelial cells, retinol is esterified and released in chylomicrons. C Retinol delivered to the liver in chylomicron remnants can be stored as retinyl palmitate. D Retinol released by the liver is transported in blood bound to serum albumin. E In target tissues, retinol may be oxidized to retinoic acid which binds to nuclear receptors and regulates gene expression. |
D
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What is the primary molecular basis of renal rickets?
A Defect in the intestinal absorption of cholecalciferol and ergocalciferol. B Overproduction of calcitonin by the thyroid. C Decreased capacity to synthesize 1,25-dihydroxy vitamin D3 in the kidney. D Defective vitamin D receptor in intestinal cells. E Inability to reabsorb calcium from glomerular filtrate. |
C
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What are macronutrients and what are micronutrients?
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Macronutrients: fat, carbohydrate and proteins; things that we need in grams or more
Micronutrients: vitamins and minerals; things we need in mg or micrograms |
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What is the calorie contents of different types of food?
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Carbohydrate: 4 kcal/gram
Protein: 4 kcal/gram Fat: 9 kcal/gram Alcohol: 7 kcal/gram |
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What is fiber and why is it good in our diet?
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Fiber is non-digestible carbohydrate (cellulose, lignin, pectin) that normalizes stools, reduces hemorrhoids, decreases bowel exposure to carcinogens; soluble fibers can lower cholesterol
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Which vitamins are fat soluble?
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A, D, E, K
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Which vitamins can be toxic?
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A, D, K
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What is the purpose of vitamin D?
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The active form is 1, 25 - dihydroxycholecalciferol, binds intracellular receptors which affect gene expression regulating plasma levels of Ca and phosphorus
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What is the major symptom of vitamin D deficiency
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• Inability to control calcium and mobilizing excess calcium from bones and teeth to try to keep blood calcium levels constant
• Therefore, you get rickets (infant form of softening of bones) • Osteomalacia in adults |
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Why can renal failure be accompanied by rickets?
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Renal failure causes the decreased ability to form the active form of vitamin D.
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What are the roles of retinoids?
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1) An ingredient of visual pigment
2) Signaling/hormone-like function involved in MAINTAINING the INTEGRITY of various epithelia 3) Antioxidant properties (along with Vitamin C, E, and B- carotene) involved in vision, reproduction, growth, epitheliat tissue maintenance |
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What is biotin a cofactor for?
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carboxylation reactions
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What is vitamin K a cofactor for?
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It is a cofactor in the formation of gamma-carboxyglutamate residues in several blood clotting proteins
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What is the purpose of vitamin E?
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It is an antioxidant
note: not toxic in large doses |
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What is the role of folic acid?
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The active form tetrahydrofolate has a role in one carbon metabolism and transfers which is essential for biosynthesis of purines, pyrimidines and some amino acids
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Why should women of child bearing years take folic acid supplements?
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A deficiency leads to growth failure and megaloblastic anemia due to inhibited DNA synthesis. Take folic acid supplements to prevent neural tube defects
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What causes pernicious anemia?
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a defect in absorption in colbalamin due to deficiency in intrinsic factor
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How is pernicious anemia treated?
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monthly injection of Vit B12 or high oral doses of B12
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What causes Beri-Beri and Wernicke-Korsakoff syndrome?
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Defiencies of thiamin pyrophosphate which is a cofactor in oxidative decarbosylation of alpha-keto acids and in transketolase reactions
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Which of the following statements is correct?
Micronutrients are nutrients that your body requires in gram quantities per day “Dietary fiber” refers to any polysaccharide in the diet The energy yield of dietary fat is 9 kcal/g Body mass index (BMI) is the most accurate measure of obesity Mashed potatoes have a low glycemic index |
The energy yield of dietary fat is 9 kcal/g
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Which of these nutrients are not required in our diet
Carbohydrate Protein Fat Vitamins Minerals |
Carbohydrates
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Pernicious anemia is caused by loss of which type of cells?
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Parietal cells in the stomach that secrete intrinsic factor
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Taking high doses of which of these vitamins can mask the hematopoietic defects seen in vitamin B12 deficiency ?
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Folic Acid
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Where does the enzymatic conversion of 25-hydroxy vitamin D3 to the biologically active form, 1,25-dihydroxy vitamin D3 (also known as calcitriol), occur?
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Kidney
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Which of Andrew's plasma constituents abnormal? (Boy or Girl Chp 7)
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Adndrew had abnormally low levels of cortisol with above normal levels of 17-hydroxyprogesteron and testosterone. He was hyponatraemic and kyperkalemic
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Why are cortisol measurements done at 9 am? (Boy or Girl Chp 7)
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Cortisol measurements are done at 9 because cortisol levels vary throughout the day. it's maximal after waking up and decreases with time, therefore a standard was required
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Which enzyme is deficient in Andrew? (Boy or Girl Chp 7)
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21 - hydroxylase
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Which steroids will be deficient in Andrew and which steroids will be overproduced? Why? (Boy or Girl Chp 7)
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17 - hydroxyprogesterone will be overproduced leading to the over production of testosterone
Cortisol and corticosterone which lead to glucocorticoids and aldosterone, a mineralocorticoid will be deficient This is because the deficiency in the 21-hydroxylase enzyme prevents production of distal products in the pathway and because it lacks normal negative feedback regulation which is exerted by cortisol via anterior pituitary adn ACTH |
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What hormone is secreted by the hypothalamus to stimulate glucocorticoid production in adrenals? What kind of hormone is it? (Boy or Girl Chp 7)
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The metabolic block in Andrew leads to the loss of the normal negative feedback regulation of steroidogenesis which is exerted by cortisol via the anterior pituitary and adrenocorticotropin (ACTH). Because of this, the hypothalamus releases CRH (corticotrophin-releasing hormone, a peptide hormone) which causes the anterior pituitary to release more ACTH to stimulate the adrenal glands to make more glucocorticoids.
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Why does Andrew have adrenal hyperplasia. Why is it reversed when glucocorticoids are given? (Boy or Girl Chp 7)
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He has hyperplasia because of this lack of feedback. It is reversed when glucocorticoids are given because it re-establishes the feedback mechanism.
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How do you withdraw a patient from high-dose glucocorticoid treatment? (Boy or Girl Chp 7)
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You have to wean over several days or weeks because if you don’t it can lead to adrenal insufficiency (it will take sometime for production to ramp up).
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Understand the role of elevated lipoproteins in risk of atherosclerosis. Which lipoproteins are harmful? Which are protective? (Worried about Heart Attach Chp 20)
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LDL is taken up by endothelial cells. Monocytes adhere to endothelial cells and enter in between cells to become macrophages. This produces a foam cell which could rupture and release growth factors to eventually close off the blood vessel.
LDL is main carrier of cholesterol and is harmful. HDL is protective. |
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How is LDL taken up by cells? What regulates this process? (Worried about Heart Attach Chp 20)
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Use endocytosis via clathrin coated pits to apolipoportein in LDL. The endogenously-acquired cholesterol then suppresses de novo cholesterol synthesis.
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What is the rate-limiting enzyme in cholesterol biosynthesis? What drugs target this enzyme? How do these drugs cause a decrease in LDL levels? (Worried about Heart Attack Chp 20)
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The rate-limiting step is HMG-CoA reductase and this is the target of statins They work to decrease LDL levels by limiting the activity of HMG-CoA reductase and forcing the body to take up more cholesterol from blood LDL.
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How do bile acid sequestrants work? Can you name one? (Worried about Heart Attack Chp 20)
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Cholestyramine prevents re-absorption of bile salts from the gut for use as a source of exogenous cholesterol.
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How do you treat a patient heterozygous for mutations in the LDL receptor? What about a homozygous patient? (Worried about Heart Attack Chp 20)
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Heterozygous patients are treated with statins, bile sequestrants. Statins won’t help those homozygous mutations. Instead, they would need to undergo LDL apheresis (dialysis for LDL).
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Why is aspirin an anticoagulant
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It makes platelets unable to synthesize thromboxans A2
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Which of these steroids is not a precursor in the biosynthesis of cortisol?
cholesterol testosterone progesterone pregnenalone |
testosterone
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Elevated levels of which lipoproteins is protective against heart disease?
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HDL
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In one cause of secondary adrenal insufficiency, the hypothalamus fails to respond to low cortisol levels. What would be the direct consequence of this failure on the part of the hypothalamus?
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The hypothalamus doesn't produce enough CRH
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Brian C (Worried about heart attack chp 20) Blood analysis gave an immediate indication of a problem. What component was markedly elevated?
A LDL receptors B Cholesterol C HDL D Chylomicrons E Lipoprotein lipase |
Cholesterol
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VLDL (the precursor to LDL) is synthesized where?
A Small intestine B Kidney C Adrenal medulla D Liver E Adipose tissue |
Liver
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Southern blotting of Brian’s LDL receptor gene required
A blotting a sample of his RNA onto a membrane. B radiolabeling his LDL receptor. C digesting a sample of his DNA with a restriction endonuclease. D subjecting a DNA sample to high-performance liquid chromatography (HPLC). E radiolabeling his DNA in cell culture. |
Digesting a sample of his DNA with a restriction endonuclease
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3-hydroxy-3-methylglutaryl-CoA (or β-hydroxy-β-methylglutaryl-CoA)
A can be converted to cholesterol B is the product of the HMG-CoA reductase C is an immediate precursor of a ketone body D can be converted to glutaric acid E activates squalene isomerase |
Can be converted to cholesterol
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Before food supplementation, what striking change in the concentration of a component of their blood was primarily responsible for their appearance (distended abdomens, and puffy arms and legs)? (Famine in Africa Chp 2)
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A depressed level of serum albumin
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What function, normally provided by this blood component, was deficient in these [Sudanese] children? (Famine in Africa, Chp 2)
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The plasma osmotic (oncotic) pressure that prevents fluid from the blood from infiltrating the extracellular space was impaired because of the missing serum albumin.
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Understand the basic biochemistry behind marasmus versus kwashiorkor (Famine in Africa, Chp 2)
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Marasmus - sever deficiency of all nutrients, especially protein and calories; appears emaciated
Kwashiorker - insufficient protein intake but sufficient caloric intake presents with edema; can be caused by aflatoxin |
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Why do children with kwashiorkor have edema?(Famine in Africa, Chp 2)
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- insufficient dietary protein (main cause) results in low blood plasma protein -> low oncotic pressure in blood which results in decreased reabsorption of fluids from interstitium -> EDEMA
- Aflatoxin poisoning - aflatoxin B1 is metabolized in liver, it's highly reactive, have toxic derivatives which damages of hepatocyte DNA; damaged liver leads to decreased production of serum proteins like albumin; low albumin ->low oncotic pressure -> edema |
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Why do children with kwashiorkor have fatty livers?(Famine in Africa, Chp 2)
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fatty liver is the sign of compromised liver function
causes of liver damage: - protein deficiency: lever removes chylomicrons from blood and makes VLDLs and LDL to export cholesterol; liver requires protein to make apolipoproteins; protein deficiency - decreased ability for liver to export cholesterol, thus fatty liver -Aflatoxin damages hepatocyte DNA ->lipoprotein synthesis is compromised -> lipids accumulate in liver -> fatty liver |
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How is aflatoxin converted into a DNA damaging metabolyte?(Famine in Africa, Chp 2)
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1) Aflatoxin B1 hydroxylated by chtochrome P450 monoxygenase in hepatocyte microsomes results in a highly reactive, toxic derivative that undergoes many reactions -> aflatoxin metabolites bind and damage liver cell DNA
Cytochrome p450 is a family of heme containing enzymes that hydroxylate substrates associated with mitochondria and microsomes Microsomal cytochrome p450 monoxygenase in smooth ER detoxifies foreign compounds; in liver, it metabolizes drugs, toxic compounds and bilirubin |
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What is the treatment for kwashiorkor patients?
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increase dietary calories especially protein BUT you must slowly give amounts of protein so you don't overload the damaged liver with proteins which can cause hyperammonemia if they cannot clear nitrogen from blood and could be potentially fatal
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Understands what happens in fasting and starvation, especially retgarding chages in levels of hormones; utilization of glycogen, fat stores, muscle proteins and production of ketone bodies
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Insulin - decreases
Glucagon - increases epinephrine - increases to inhibit insulin glycogen utilization - increases fat store utilization - increases muscle protein utilization - increases ketone body production - increases |
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(Failure to Thrive, Chp 5) Which of the following correctly predicts if the substrates listed below will be higher or lower in this patient, compared to a normal patient.
A urea - higher B NH3 - lower C citrulline - higher D glutamine - lower |
Citrulline
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Briefly explain how glutamine levels are affected in this patient, John S. (Failure to Thrive, Chp 5)
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With excess NH4+, the reactions described below favor the production of glutamine as the reactions are shifted to the right. In addition, ATP levels will be depleted as excess glutamate is converted into glutamine. Thus the toxicity of high levels of ammonia is thought to involve the depletion of α-ketoglutarate and ATP.
α-ketoglutarate + NADPH + H+ + NH3 --> glutamate + NADP+ glutamate + NH4+ + ATP --> glutamine + ADP + Pi + H+ |
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Review the urea cycle and make sure you undertand how nitrogen (ammonia) enters the cycle and how it is converted into urea (Failure to Thrive, Chp 5)
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Urea Cycle - method of removing nitrogen from the blood stream; urea is the major disposal form of amino groups derived from amino acids; location: in the mitochondria and cytosol or the liver
Nitrogen enters into the urea cycle through ammonia transported to the liver as glutamine via blood. glutamine is the non toxic form of NH3, glutamine synthase combines NH3 with glutamate in liver, flutamine is cleaved by glutaminase to produce glutamate and free ammonia 1st step of urea cycle - NH3 to CO2 + 2ATP -> carbamoyl phosphate via carbamoyl phosphate synthetase I Overview of Urea Cycle 1.) Form Carbamoyl Phosphate (2 ATP input) [NH3 = source of 1st N in Urea] 2.) Formation of Citrulline 3.) Formation of Argininosuccinate [This step: Aspartate = source of 2nd N in Urea] i. Catalyzed by arginosuccinate synthetase 4.) Cleavage of Argininosuccinate 5.) Cleavage of arginine to ornithine and urea |
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Understand biochemical, metabolic consequences of genetic defect in arginosuccinate synthetase (Failure to Thrive, Chp 5)
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arginosuccinate synthetase catalyzes citrulline to argininosuccinate
metabolic consequence - block the progression of urea cycle - cannot form urea -patient presents with high blood NH3 - hyperammonemia which causes neurological symptoms. - acute: ammonia intoxication - tremors, slurred speech, somnolence, vomiting, cerebral edema, blurring of vision -chronic - mental retardation -low blood urea |
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What is the short term treatment for a person with hyperammonemia? (Failure to Thrive, Chp 5)
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Hemodialysis is the immediate treatment because plasma NH4+ levels need to be reduced in order to prevent brain damage from occurring
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What is the long term treatment for a person with hyperammonemia?(Failure to Thrive, Chp 5)
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-restricting dietary protein intake to frequent small amounts to prevent the defective urea cycle from being overloaded
- medication: phenylacetate, arginine, benzoate; this gives an alternate route for excreting excess ammonia. excess citrulline will be excreted |
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Understand the rationale behind treating the patient with phenylactetate, arginine and benzoate.(Failure to Thrive, Chp 5)
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basis of all treatments = reduce ammonia content in blood by providing alternate pathways to excrete N from amino acids
-phenylacetate - binds glutamine; bound glutamine is excreted as phenylacetyleglutamine by kidneys -arginine - oral arginine is metabolized as far as citrulline, on the way it picks up NH4+ in the form of carbamoyl phosphate and accumulated citrulline can be excreted - benzoate - sodium benzoate conjegates with glycine and allows for rapid excretion by the kidneys |
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Aminotransferases employ a cofactor derived from what vitamin?
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Vitamin B6 - pyridoxine
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Most tissues transport ammonia to liver in the form of glutamine. In the liver, ammonia is liberated from glutamine by the action of which enzyme?
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glutaminase
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The urea cycle occurs in which cellular compartment(s)?
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A combination of the mitochondrial matrix and the cytosol
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Urea is liberated by hydrolysis of which compound?
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L-arginine
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Understand the two enzymes that require vitamin B12. (Acid Excretors, Chp 10)
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- homocysteine methyltransferase - catalyses methylation of homocysteine to methionine
- methylmalonyl- CoA mutase - catalyses methylamlonyl - CoA to succinyl-CoA |
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What metabolites will accumlate in a patient with insufficient vitamin B12?(Acid Excretors, Chp 10)
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- low vitamin b12 will lead to low homocysteine methyltransferase leading to high homocysteine and other intermediates
-low vitamin b12 can also cause low methylmalonyl coA mutase leading to high L-methylmalonyl coA |
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Understand the biochemical basis of the genetic lesion in patients whose mutations fall into groups A, B and C in this chapter (Acid Excretors, Chp 10)
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A- problem in handing or processing vitamin B12 into deoxyadenosylcobalamin
B- deficiency in the mutase itself or less commonly the racemase C - deficiency in both homocystein methyltransferase and methylmalonyl- coA mutase so the proble is a general problem with handing or processing vitamin B12 |
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Understand the metabolic block in phenylketonuria. (Chp 19, Amino Acid Overload)
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The conversion of phenylalanine to tyrosine is blocked. The accumulation of phenylalanine in blood is phenylalaninemia and its metabolites in the urine is PKU. This occurs in two ways: deficiency of BH4 cofactor or deficiency of phenylalanine hydroxylase
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How do you treat phenylketonuric patients? what must they avoid in their diet? (Chp 19, Amino Acid Overload)
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1) Low in phenylalanine
2) adequate tyrosine 3) neutral AA (valine, isoleucine, leucine) as supplement (they are transported into the brain by the same carrier protein that transports phenylalanine, so competitively inhibit the entry of phenylalanine into brain) |
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Should you put a patient of a diet with zero phenylalanine? (Chp 19, Amino Acid Overload)
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No, phenylalanine is needed in a small amount since it is an essential amino acid
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What about tyrosine in this patient? (Chp 19, Amino Acid Overload)
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Tyrosine should be given to the patient since he lacks tyrosine. The light pigmentation is due to a lack of melanine, which is synthesized from tyrosine via L-DOPA. The deficiency of tyrosine in this patient also affects the brain development since tyrosine is required for the synthesis in the brain of catacholomine neurotransmitters, dopamine and nor epinephrine.
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What important metaolites of phenylalanine/tyrosine will be deficient in an untreated PKU? (Amino Acid Overload, Chp 19)
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Tyrosine ->L-DOPA-> dopamine->norepinephrine (noradrenalin)
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Why should they avoid aspartame? (Amino Acid Overload, Chp 19)
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Aspartame can be metabolized into phenylalanine
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Amino acids whose carbon atoms are metabolized to acetyl coA or acetoacetate are said to be
glucogenic ketogenic neither glucogenic nor ketogenic teratogenic nonpolar |
ketogenic
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Which of the following statements about PKU are correct?
PKU patients need to avoid phenylalanine only until puberty PKU patients must reduce their phenylalanine intake to zero PKU can result from mutations in phenylalanine hydroxylase, BH2 synthetase or BH2 reductase PKU patients must avoid tyrosine in their diet PKU is autosomal dominant |
PKU can result from mutations in phenylalanine hydroxylase, BH2 synthetase or BH2 reductase
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Patients with maple syrup urine disease must limit their intake of which of these?
phenylalanine tyrosine aromatic amino acids branched-chain amino acids maple syrup |
branchedchain amino acids
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porphyrias are caused by genetic defects in which pathway?
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heme biosynthesis
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what is the correct pairing of a product with its amino acid precursor?
serotonin - serine serotonin - phenylalanine melanin - methionine histamine - proline catecholamines - tyrosine |
catecholamines - tyrosine
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Understand the biochemical bases for the anemias presented by Jane D. and Simon K. in this chapter (Thin Blood, Chp 6)
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Jane’s anemia is accounted for by a shortage of iron to complete the synthesis of heme for the hemoglobin. The enzyme ferrochelatase catalyses the incorporation of ferrous iron into protoporphyrin IX to form heme. Since the synthesis of globin chains is closely coupled to the availability of heme, hemoglobin synthesis is inadequate and the red cells released are small and deficient in hemoglobin. Women are more prone to anemia through menstruation, pregnancy and lactation, vegetarianism. IRON DEFICIENCY.
Simon on the other hand has decreased hemoglobin probably due to his occupation as a foundry worker. By being exposed to toxic metals and lead a block in his iron utilization could have occured blocking heme biosynthesis leads to a build of of porphyrin intermediates and their metabolites |
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What enzyme activities would be deficient in Simon K.? What about his occupation would cause this deficiency? (Thin Blood, Chp 6)
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In Simon, the failure to synthesize hemoglobin is not due to iron deficiency, but rather a block of iron utilization. He works in a foundry, which means he was probably exposed to toxic metals. Lead has an avidity for thiol groups for their catalytic activity are irreversibly inhibited. Among these are two enzymes involved in the heme biosynthesis pathway. One is ferrochelatase, which catalyzes the final step, the other is aminolavulinic acid dehydratase which catalyzes the formation of porphobilinogen. Blocks in this pathway lead to a buildup of porphyrin intermediates, which are part of the lead poisoning component. LEAD POISONING.
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How would you treat Simon K.? (Thin Blood, Chp 6)
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To treat Simon for ingested lead: Dimercaprol (EDTA, BAL), or other chelating agent would bind the metal and help him excrete it in the urine. When you are giving chelation therapy, you must keep it low because you can deplete calcium levels in the body.
Metallothioneins naturally protect the body against heavy metals by binding thiol groups, cysteines, if you buy heavy metals you are going to free up ferrochelatase and ALA-dehydratase to perform their regular duty of incorporating into the heme. |
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How would you treat Jane D.? Why give ascorbic acid (vitamin C) along with iron tablets to Jane? That is, what is the chemical/biochemical basis for this?
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Gastric HCl helps to release iron in vegetables, but for efficient absorption ferric iron, the usual dietary form, must be reduced to the ferrous state. In this respect, Vitamin C (ascorbic acid) is an important reducer. Jane should be treated initially with a course of ferrous sulfate and vitamin C tablets. Then adjust her diet to increase iron absorption.
Her iron level must be monitored because high iron allows infectious diseases to take over. Iron provides surfaces for nutrients necessary for infectious disease to establish itself, including the production of free radicals which are toxic to the blood. One way to test iron level is to look at transferrin saturation, and also the ferritin level. If the iron doesn’t help, Jane could be failing to absorb dietary iron in the jejunum. She could start eating meat, or get intravenous iron dextran or iron dextrose transfused into her to circumvent absorption issues. |
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Understand in very general terms how MPTP is processed into a neurotoxic chemical in vivo. (Designer Drug, Chp 21)
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Cathecholamines are synthesized in the adrenal medulla of the brain. Cathecholamines are synthesized in a series of steps from the precursor AA’s tyrosine and tryptophan. They cross the blood-brain barrier, enter their respective neurons, and complete their enzymatic steps for conversion.
MPTP is not in itself toxic, but oxidized via the intermediate MPDP+ to become toxic product MPP+ by MAO in glial cells surrounding neurons. MAO’s normal role is to inactivate monoamine NT’s after their uptake into glial cells. By shitty luck, MPP+ is a good substrate for pre-synaptic dopamine transporter molecule, making MPP+ severely toxic to dopaminergic neurons. |
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What does MPP+ damage? What does this lead to? (Designer Drug, Chp 21)
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MPP+ inhibits the ADP-stimulated oxidation of NAD+-linked substrates (respiration chain complex I), an inhibition of ATP synthesis that results in cell death. Oxidative radicals have also been linked in the neuronal death pathway.
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Randy B. was treated with L-DOPA, carbidopa and bromocryptine. What is the biochemical basis for the action of each of these drugs, and how would they help him? (Designer Drug, Chp 21)
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L-DOPA can travel through to the proper places before it is converted to dopamine. It is more effective than tyrosine precursor because tyrosine is involved in many other pathways that you do not want to upregulate. Tyrosine hydroxylase is a rate limiter in dopamine synthesis, which is why you combine DOPA with carbidopa so that DOPA is not metabolized to dopamine by DOPA decarboxylase in the liver and peripheral nerves. Bromocriptine potentiates L-DOPA by increasing the excitability of the dopamine targets, so that you can use lower doses of L-DOPA. L-DOPA treatment becomes less effective as time passes, which is why you want to start with as little as possible to make it work for years before being downregulated. Also, you can’t treat with simply dopamine because you want lasting excitability, and not immediate.
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Methotrexate is an anticancer drug in humans because it inhibits what?
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the conversion of folate to tetrahydrofolate
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Allopurinol is used to treat which medical conditions
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Gouty arthritis
Lesch-Nyhan syndrome |
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What do uricosuric agents do?
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the promote uric acid excretion
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A hereditary deficiency in adenosine deaminases causes what disorder?
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SCID
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Which condition is a consequence of autoimmune destruction of pancreatic Beta Cells
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Type I diabetes
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When insuline binds to its receptor, the most immediate response is what?
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Phosphorylation of tyrosine residues on proteins
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Osteomalacia is due to a deficiency in what?
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Vitamin D
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Understand the roles of parathyroid hormone (PTH) and the hormone form of vitamin D (1,25-dihydroxyvitamin D3) in calcium homeostasis: (Signal Failure, Chp 15)
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– Where are these hormones made?
o PTH: Parathyroid glands o Vitamin D: From diet (e.g., fatty fish, milk), endogenously produced from cholesterol precursor, which is in skin, with enough UV sunlight. It is converted to the hormone form (1,25-dihydroxyvitamin D3 ) in liver and kidney. – What controls their synthesis/release? o (low) serum calcium – What tissues do they act on? o Goal is to increase blood Ca levels. 1. increase absorption of calcium in the gut 2. reabsorption in kidneys 3. increase calcium mobilization from bone (increase osteoclast activity) – What is the phenotype of deficiencies in these hormones? o Children = Rickets o Adults = osteomalacia, osteoporosis The lower Ca levels explain the patient’s convulsions, cramps, short stature. |
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Understand, in general terms, how G-protein-coupled receptors work, and why this patient had a general failure in response to certain hormones (as well as diminished sense of smell, etc). (Signal Failure, Chp 15)
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– G protein are heterotrimetric. When activated G-protein receptors activate Adenylate cyclase to produce cAMP (and then protein kinase to have physiological effects).
– The patient has problem coupling the receptors to the adenylate cyclase effector system. – there will be an olfactory problem as well because smell is mediated by membrane receptor proteins that also work via AC. |
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Understand the biochemical basis for the differences between type I and type II diabetes (Lack of Cleavage, Chapter 18)
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Type I diabetes - insulin dependent: young <30, uncommon, no association with obesity, low blood insulin due to destruction of B cell, pancreatic beta cells are affected, sudden speed of onset, ketoacidosis
Type 2 diabetes - insulin resistant: in older people, >30, family history, a/w obesity, normal to high blood insulin, slow speed of onset |
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What is insulin resistance? which type of diabetes does it typically occur in? (Lack of Cleavage, Chapter 18)
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There is a failure to respond to insulin adequately even though the B cells are able to produce it. Occurs in Type II Diabetes.
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Why is this patient insulin resistant? (Lack of Cleavage, Chapter 18)
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A point mutation in her insulin receptor gene prevents the normal/important processing enzyme to cleave the insulin proreceptor protein into active alpha/beta subunits. Thus, her receptor exists as the less active proreceptor.
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What sort of signal does the insulin receptor transduce? (Lack of Cleavage, Chapter 18)
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Receptor tyrosine kinase
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What is the reason for at least partial remission of the immobility by L-DOPA? (Chapter 21 Designer Drug)
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It crosses the blood/brain barrier and is converted to dopamine and thence to noradrenaline in neurons that run from the substantia nigra to the corpus striatum, an area of the brain concerned with the smooth co-ordination of limb movements.
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What is the significance of the fact that membranes prepared from a sample of the patient's erythrocytes were treated with cholera toxin and radiolabeled NAD+, and that a single polypeptide of 45,000 molecular weight was radiolabeled but only to 40% of the level found in membranes from control subject? (Chp 15)
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The patient had a deficiency in a G protein that stimulates adenylate cyclase.
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