BRS: Biochem Nitrogen Metabolism ?s

7. The answer is C. Glutaminase acts on glutamine to release ammonia, which enters the urine and serves as a buffer by forming NH4+. The kidney produces guanidinoacetate, which travels to the liver to produce creatine. The muscle and brain then utilize the creatine to produce creatine phosphate. The kidney takes up glutamine and releases serine and alanine into the blood. Most of the urea that is excreted by the kidney is produced in the liver; the kidney has a limited ability to produce urea.

. Which one of the following best represents the kidney's utilization of amino acids? (A) Produces Urea from Amino Acid Nitrogen Produces Creatine Phosphate Creates Ammonia to Buffer Urine Uses Alanine to Produce Glutamate

1. The answer is A. Trypsin cleaves and thus activates the pancreatic zymogens, converting chymotrypsinogen to the active form, chymotrypsin, and the procarboxypeptidases to the active carboxypeptidases. If trypsin were inactive, the other proteases could not be activated because enteropeptidase is specific for trypsinogen. Pepsin is found in the stomach, whereas aminopeptidases are intestinal enzymes found on the brush border membrane, facing the lumen of the intestine.

1. A deficiency of which one of the following proteolytic enzymes would have the greatest effect on the digestion of proteins? (A) Trypsin (B) Chymotrypsin (C) Carboxypeptidase A (D) Pepsin (E) Aminopeptidase

10. The answer is E. Glycine reacts with succinyl-CoA in the first step of heme synthesis and with arginine in the first step of creatine synthesis. The entire glycine molecule is incorporated into the growing purine ring. Serine is not utilized for the biosynthesis of either heme, creatine, or purines. Aspartate is used for purine ring synthesis only (one nitrogen of the purine ring is derived from aspartate). Neither cysteine nor glutamate is directly involved in the synthesis of heme, creatine, or purines.

10. In the biosynthetic pathways for the synthesis of heme, creatine, and guanine, which one of the following amino acids directly provides carbon atoms that appear in the final product? (A) Serine (B) Aspartate (C) Cysteine (D) Glutamate (E) Glycine

11. The answer is C. The patient has a defect in argininosuccinate synthetase. Citrulline, the substrate for the reaction, accumulates and can be measured in the blood. A carbamoyl phosphate synthetase I deficiency would block carbamoyl phosphate formation, and citrulline would be neither synthesized nor accumulated. An ornithine transcarbamylase deficiency would lead to orotic acid accumulation (carbamoyl phosphate made in the mitochondria would diffuse into the cytoplasm, thereby activating pyrimidine synthesis and overproducing orotic acid). An argininosuccinate lyase deficiency would lead to elevated argininosuccinate, which is not observed, and an arginase deficiency would lead to elevated arginine, which was also not observed. Defects in argininosuccinate lyase and arginase also do not have as elevated ammonia levels as do defects in previous enzymes of the cycle because two nitrogens have been disposed of in the synthesis of argininosuccinate.

11. An infant who appeared normal at birth began to develop lethargy, hypothermia, and apnea within 24 hours. An analysis of blood components indicated high levels of ammonia and citrulline and low levels of urea. The most likely defective enzyme in this child is which one of the following? (A) Carbamoyl phosphate synthetase I (B) Ornithine transcarbamylase (C) Argininosuccinate synthetase (D) Argininosuccinate lyase (E) Arginase

12. The answer is D. The child has the symptoms of classic MSUD. In MSUD, the branched-chain amino acids (valine, leucine, and isoleucine) can be transaminated but not oxidatively decarboxylated because the α-keto acid dehydrogenase is defective. Therefore, these amino acids and their transamination products (the corresponding α-keto acids) will be elevated. Phenylalanine and phenylketones are elevated in PKU, but not in MSUD. The musky sweet odor of the urine strongly suggests MSUD. Dopa levels (dopa is derived from tyrosine) should be normal in MSUD because there is no mutation in the phenylalanine degradation pathway. Acetone, derived from acetoacetate, is exhaled and is not found in the blood. Depending on the feeding state of the child, ketosis could develop, but the acetone would still be exhaled, whereas blood levels of acetoacetate and β-hydroxybutyrate might be elevated.

12. A 5-day-old infant initially began feeding poorly, grew irritable, then very lethargic. The diaper, when changed, had a musky, sweet odor to it. At the emergency department of the local hospital, the child was suspected of having an inborn error of metabolism, and blood test was ordered. You would expect to see an elevation of which one of the following given the conditions of the child's case? (A) Phenylalanine (B) Phenylketones (C) Dopa (D) Isoleucine (E) Acetone

13. The answer is C. SAM synthesis requires methionine and ATP, and methionine can be regenerated from homocysteine in a reaction requiring N5-methyl-FH4. In the absence of N5-FH4 synthesis, homocysteine accumulates, and SAM levels will begin to drop. Folate is required for the incorporation of carbons 2 and 8 into all purine molecules. The synthesis of creatine phosphate and of phosphatidylcholine does not require folate. Folate deficiencies during pregnancy can lead to neural tube defects (e.g., spina bifida) in the fetus. Deoxyribonucleotide synthesis requires ribonucleotide reductase, which uses thioredoxin, and does not require a folate derivative.

13. A common polymorphism in the US population is a variant of N5,N10-methylene-FH4 reductase, which has a reduced activity at 37°C as compared to 32°C. A person expressing this variant enzyme would have difficulty producing which one of the following at the nonpermissive temperature? (A) Creatine phosphate from creatine (B) Pyrimidines required for RNA synthesis (C) SAM (D) Phosphatidylcholine from diacylglycerol and CDP-choline (E) All deoxyribonucleotides

14. The answer is C. The conversion of propionyl-CoA to methylmalonyl-CoA requires biotin, and the conversion of methylmalonyl-CoA to succinyl-CoA requires vitamin B12. The boy is consuming large amounts of avidin, which binds to biotin and inhibits biotin-containing enzymes, such as propionyl-CoA carboxylase. The hypoglycemia results from the inhibition of pyruvate carboxylase, blocking a key enzyme necessary for gluconeogenesis.

14. A young boy has been eating five to six raw eggs a day in an attempt to be like Rocky, the fictitious prize fighter. The boy, however, becomes tired between meals, and during one of these lethargic periods, he is taken to the emergency department. His blood glucose levels were 50 mg/dL. Which one of the following would be expected to be elevated in this boy's blood? (A) Methylmalonic acid (B) Malonic acid (C) Propionic acid (D) Succinate (E) Acetic acid

15. The answer is D. The patient has a deficiency of B12, caused by inadequate intrinsic factor production for the absorption of dietary vitamin B12, which is required for the conversion of methylmalonyl-CoA to succinyl-CoA and of homocysteine to methionine. A vitamin B12 deficiency results in the excretion of methylmalonic acid in the urine and an increased dietary requirement for methionine. The methyl group transferred from vitamin B12 to homocysteine to form methionine comes from N5-methyl-FH4, which accumulates in a vitamin B12 deficiency, causing a decrease in free folate levels and symptoms of folate deficiency, including increased levels of FIGLU and decreased purine biosynthesis. Both B12 and folate deficiencies will lead to anemia, but only a B12 deficiency will give rise to the mental status changes and tingling in the hands and feet. As individuals age, a variety of conditions can give rise to reduced intrinsic factor production by the stomach. Because intrinsic factor is low, B12 needs to be delivered by injection, not by the oral route of administration.

15. A 65-year-old man visits his primary physician because of tingling in his hands and feet, and a sense that he is forgetting things more than usual. A CBC indicates a mild anemia. The patient states that his diet has not changed, other than eating more red meat than before. This patient can be best treated by which one of the following? (A) Oral administration of vitamin B12 (B) Oral administration of folic acid (C) Oral administration of methionine (D) Injections of B12 (E) Injections of folic acid (F) Injections of methionine

16. The answer is D. The patient has diabetes-induced nephropathy. As the kidneys lose function, the ability of creatinine to be absorbed into the urine decreases, and its excretion would be low. Creatine is synthesized from glycine, arginine, and SAM. In muscle, creatine is converted to creatine phosphate, which is nonenzymatically cyclized to form creatinine. The amount of creatinine excreted by the kidneys each day depends on the body muscle mass. Weightlifting and increasing muscle mass would increase the levels of creatinine in the urine. A low-protein diet would not reduce the muscle mass, nor affect the creatinine excretion.

16. An individual who has been treated for type 2 diabetes for the past 24 years had, as part of his annual physical, a 24-hour urine collection. Reduced levels of creatinine were found, which is most likely because of which one of the following? (A) A decreased dietary intake of creatine (B) A higher-than-normal muscle mass resulting from weightlifting (C) A genetic defect in the enzyme that converts creatine phosphate to creatinine (D) Kidney failure (E) A lower-than-normal muscle mass owing to a low-protein diet

17. The answer is B. The child has nonclassical PKU, which is caused by a defect in the biosynthesis of tetrahydrobiopterin. Tetrahydrobiopterin is required for ring hydroxylation reactions, such as the conversion of phenylalanine to tyrosine, tyrosine to dopa, and tryptophan to serotonin. However, tetrahydrobiopterin is not required for the conversion of dopa to melanin, serotonin to melatonin, and norepinephrine to epinephrine, which is a methylation reaction. A deficiency of tetrahydrobiopterin would cause phenylalanine to be converted to phenylketones rather than to tyrosine.

17. A 3-year-old child from Russia, after immigrating to the United States, was found to have developmental delays and severe intellectual disability. Elevated levels of phenylalanine and phenylpyruvate were found in the blood. The child was placed on a low-phenylalanine diet, but there was no improvement in the child. Given this information, the child would be expected to have difficulty in undergoing which one of the following conversions? (A) Phenylalanine to phenylketones (B) Tyrosine to dopamine (C) Dopa to melanin (D) Serotonin to melatonin (E) Norepinephrine to epinephrine

18. The answer is B. 5-FU inhibits the thymidylate synthase reaction, which produces dTMP from dUMP. It does not inhibit FH2 reductase, which would block the production of FH4. Methotrexate inhibits FH2reductase. UMP is made via the de novo pyrimidine biosynthetic pathway, which is not inhibited by 5-FU. Methylcobalamin is produced from N5-methyl-FH4 and vitamin B12, and 5-FU does not block this activation of B12. CTP is produced from UTP, using glutamine as the nitrogen donor, and that reaction is also not affected by the presence of 5-FU.

18. A 42-year-old woman has been diagnosed with liver cancer and is being treated with 5-FU. 5-FU is successful in destroying the tumor cells because it blocks the production of which one of the following? (A) FH4 (B) dTMP (C) UMP (D) Methylcobalamin (E) CTP

19. The answer is D. The treatment for a positive PPD test (tuberculosis) is isoniazid, which can interfere with vitamin B6 (pyridoxine) function in cells. Pyridoxine is activated to PLP in cells (the active form of the vitamin), and isoniazid blocks this activation. A deficiency of B6 can lead to peripheral neuropathy because B6 is required for the conversion of tryptophan to niacin. In many cases, vitamin B6 is given along with isoniazid to prevent these side effects from occurring (by providing more substrate than the isoniazid can bind to). Isoniazid does not affect thiamine (B1), riboflavin (B2), niacin (B3), or cobalamin (B12) metabolism, although riboflavin is required to activate pyridoxine.

19. A medical student has been exposed to a patient with tuberculosis and developed a positive tuberculin test (PPD), but exhibited a normal chest X-ray. He is placed on a 6-month course of prophylactic treatment, but subsequently develops peripheral neuropathies. Which one of the following vitamins would be considered a treatment for the neurotoxicity? (A) B1 (B) B2 (C) B3 (D) B6 (E) B12

2. The answer is E. These transaminases convert amino acids to their corresponding α-keto acids in reactions that are readily reversible. α-Ketoglutarate and glutamate serve as the other α-keto acid/amino acid pair. Pyruvate (the end product of glycolysis) is the α-keto acid corresponding to alanine, and oxaloacetate (an intermediate of the TCA cycle) is the partner of aspartate. PLP is the cofactor. Thus, AST will convert aspartate and α-ketoglutarate to oxaloacetate and glutamate, and ALT will convert alanine and α-ketoglutarate to pyruvate and glutamate.

2. In liver disease, the enzymes AST and ALT leak into the blood from damaged liver cells. Both of these enzymes have which one of the following in common? (A) They both transfer ammonia to α-keto acids to form amino acids. (B) They both form intermediates of glycolysis from amino acids. (C) They both require thiamine pyrophosphate as a cofactor. (D) They both catalyze irreversible reactions. (E) They both convert α-ketoglutarate to glutamate.

s20. The answer is C. The excluded foods are all great dietary sources of vitamin B6 (pyridoxine). Vitamin B6 is water soluble so is easily excreted from the human body and is poorly stored by the body. At this time, the patient would have developed a B6 deficiency. B6 is essential in the production of PLP, which is the cofactor for the transamination reactions. Low PLP would greatly impair transaminations, along with glycogen phosphorylase activity. A lack of B6 would have no effect on absorption of amino acids, membrane-transport systems, or uric acid production. Ammonia is produced by bacteria in the gut in a B6-independent mechanism. The protein powder supplement will not provide B6 in sufficient quantity for the body's needs.

20. Over the past 2 months, a patient was on a nonscientific fad diet for weight loss which excluded all meats, eggs, legumes, nuts, and seeds. She takes a protein powder supplement, but not a vitamin supplement. Which one of the following will be greatly impaired in this patient? (A) Absorption of amino acids by the intestine (B) Membrane-transport systems for amino acids (C) Transamination reactions (D) Ammonia production by bacteria (E) Uric acid production

25. The answer is A. The patient has developed a vitamin B12 deficiency, causing a megaloblastic anemia. Intrinsic factor is produced by gastric parietal cells (bypassed by this operation), which are required for vitamin B12 absorption by the terminal ileum. Without intrinsic factor, vitamin B12 cannot be absorbed. Because vitamin B12 is stored and efficiently recycled by the body, it can take a year or more to show deficiency. Vitamin B12 is routinely supplemented after this operation for life. Iron deficiency and lead poisoning would give a microcytic, hypochromic anemia. Valine is an essential amino acid, but if the patient is eating appropriately, the levels of valine should be sufficient for protein synthesis. Gastrin deficiency would decrease acid production in the stomach, but not lead to an anemia (a reduction in red blood cell count).

25. An obese patient undergoes a gastric bypass procedure in order to lose weight but never returns for follow-up or continuing care. Three years later, he presents to an emergency room with fatigue, a glossy tongue, and a macrocytic and hyperchromic anemia. Which one of the following is deficient or malfunctioning in this patient, leading to this anemia? (A) Intrinsic factor (B) Gastrin (C) Iron (D) Lead (E) Valine

26. The answer is C. The patient is displaying megaloblastic anemia caused by a deficiency of vitamin B12. The use of omeprazole to reduce acid production in the stomach also reduces the ability of B12, bound to ingested proteins, to be released by the proteins to be bound by intrinsic factor for effective absorption into the blood. Providing injections of B12 will bypass the need for separation of B12 from its binding proteins and will allow B12 to circulate throughout the body and reach its intracellular targets and proteins. Oral B12 would also work under these conditions. The patient is unlikely to have an intrinsic factor problem (owing to his age), and intrinsic factor cannot be given orally or via injection (because it needs to work in the intestine). For lack of intrinsic factor, injections of B12 are also required. The patient has normal folate levels, so giving more folate will not help the anemia, and vitamin B6 is not involved in these reactions.

26. A 42-year-old male has fatigue, pale skin, and shortness of breath with exercise. Blood test shows a macrocytic, hyperchromic anemia with hypersegmented neutrophils and normal folate levels. The patient has been taking omeprazole for over 3 years to treat gastric reflux disease. One method to treat this patient is to do which one of the following? (A) Give injections of vitamin B6 (B) Give injections of intrinsic factor (C) Give injections of vitamin B12 (D) Give oral folic acid (E) Give oral intrinsic factor

27. The answer is D. Methotrexate targets and inhibits FH2 reductase, which catalyzes the reduction of FH2 to FH4. Thus, in the presence of methotrexate, FH4 cannot be regenerated, and the body becomes functionally folate deficient. Methotrexate does not interfere with the absorption or reactions of the other B vitamins listed as potential answers.

27. Methotrexate (an older cancer treatment medication) can be used as first-line therapy for rheumatologic and psoriatic diseases. One of the side effects of methotrexate usage mimics which one of the following vitamin deficiencies? (A) Pyridoxine (B6) (B) Biotin (B7) (C) Niacin (B2) (D) Folate (B9) (E) Thiamine (B1)

28. The answer is A. The patient has acute intermittent porphyria, which is a defect in one of the early steps leading to heme synthesis. The buildup of the intermediate that cannot continue along the pathway leads to the dark urine, and it turns darker when ultraviolet (UV) light interacts with the conjugated double bonds in the molecule. Erythromycin is metabolized through an induced P450 system, which requires increased heme synthesis. This leads to metabolite buildup to the level where the abdominal pain appears. The defect in heme synthesis does not affect creatine phosphate, cysteine, thymine, or methionine levels.

28. A 34-year-old female has a history of intermittent episodes of severe abdominal pain. She has had multiple abdominal surgeries and exploratory procedures with no abnormal findings. Her urine appears dark during an attack and gets even darker if exposed to sunlight. The attacks seem to peak after she takes erythromycin, because of her penicillin allergy. This patient most likely has difficulty in synthesizing which one of the following? (A) Heme (B) Creatine phosphate (C) Cysteine (D) Thymine (E) Methionine

3. The answer is D. Carbamoyl phosphate within the mitochondria is formed from NH4+, CO2, and ATP. Carbamoyl phosphate synthetase II catalyzes carbamoyl phosphate synthesis from glutamine for pyrimidine synthesis in the cytoplasm. Carbamoyl phosphate reacts with ornithine to form citrulline, which reacts with aspartate to form argininosuccinate. Fumarate is released from argininosuccinate, and arginine is formed. Urea is produced from the guanidinium group on the side chain of arginine, not from the amino group on the α-carbon. Ornithine is regenerated. N-Acetylglutamate is an allosteric activator of carbamoyl phosphate synthetase I. Ornithine transcarbamylase is not a regulated enzyme in mammals, and in bacteria, N-acetylglutamate is not an allosteric effector of ornithine transcarbamylase.

3. Which one of the following occurs in the urea cycle? (A) Carbamoyl phosphate is derived directly from glutamine and CO2. (B) Ornithine reacts with aspartate to generate argininosuccinate. (C) The α-amino group of arginine forms one of the nitrogens of urea. (D) Ornithine directly reacts with carbamoyl phosphate to form citrulline. (E) N-Acetylglutamate is a positive allosteric effector of ornithine transcarbamylase.

30. The answer is D. The child exhibits the symptoms of Lesch-Nyhan syndrome, which is a deficiency of HGPRT activity. HGPRT will convert the free bases hypoxanthine, or guanine, plus PRPP to the nucleotides IMP, or GMP, plus pyrophosphate. The reactions in answer choices A and C are part of the pyrimidine salvage pathways, using pyrimidine nucleoside phosphorylase, in which a nucleoside is formed from the free base and (deoxy)ribose-1-phosphate. The reaction in choice E is the IMP dehydrogenase step, the first step on the pathway to de novo GMP production. The reaction in the choice B is catalyzed by adenine phosphoribosyltransferase and is analogous to the HGPRT reaction, other than adenine is the substrate, and not hypoxanthine or guanine.

30. A 3-year-old child displays intellectual disability, poor muscle control, gout, chronic renal failure, facial grimacing, and lip and finger biting. This child has an inability to catalyze which one of the following reactions? (A) Thymine + deoxyribose-1-phosphate yields deoxythymidine + inorganic phosphate (B) Adenine + PRPP yields AMP + pyrophosphate (C) Uracil + ribose-1-phosphate yields uridine + phosphate (D) Guanine + PRPP yields GMP + pyrophosphate (E) IMP + NAD+ yields XMP + NADH

31. The answer is C. The child has von Gierke disease, a lack of glucose-6-phosphatase activity. The lack of glucose-6-phosphatase leads to glucose-6-phosphate accumulation under conditions of glucose export from the liver, and the excess glucose-6-phosphate has three potential fates—synthesize more glycogen (because of allosteric activation of phosphorylated glycogen synthase), produce lactate (glycolysis is forced to be active by high substrate concentrations and gives rise to lactate formation), and ribose-5-phosphate (through the oxidative reactions of the HMP shunt pathway). As ribose-5-phosphate accumulates, PRPP synthetase will convert the ribose-5-phosphate to PRPP, which then initiates the de novo purine biosynthetic pathway, and the purines are overproduced. With excess purines, they are then degraded to uric acid, which increases in concentration and leads to precipitation and gout.

31. A newborn infant develops its first cold and is fussy and cannot eat. After missing a few feedings, the child becomes quite lethargic, and the parents rush the child to the emergency department. Blood analysis indicates elevated levels of lactate and uric acid and significantly decreased levels of glucose. After stabilizing the child with glucose infusions, a glucagon challenge is given to the infant, and blood glucose levels do not increase, but decrease slightly. The accumulation of which metabolite in the liver is most responsible for the elevated uric acid seen in the circulation? (A) Glucose (B) Lactate (C) Ribose-5-phosphate (D) Thymidine (E) Acetoacetate

32. The answer is A. The girl has the disorder alkaptonuria, which is a defect in homogentisic acid oxidase, part of the phenylalanine/tyrosine degradative pathway. Homogentisic acid accumulates and is removed from the body in the urine. Upon contact with the atmosphere, homogentisic acid is oxidized and turns black. The constant presence of homogentisic acid in the circulation can lead to slow, but steady, deposits in the spine and joints, leading to arthritis in early adulthood. Calcification of the coronary arteries may also occur in these patients.

32. Parents of a newborn baby girl were concerned when they saw black spots in her diaper after the child had urinated. At their next meeting with the pediatrician, they were told that the disorder is one that can lead to arthritis in the spine and large joints, and the child may have heart problems and a propensity for kidney stones. The child has inherited an inborn error in the metabolism of which one of the following amino acids? (A) Phenylalanine (B) Tryptophan (C) Proline (D) Methionine (E) Histidine

33. The answer is B. Hartnup disease is a transport defect, manifest in both the kidney and intestinal epithelial cells. The transporter is for large, neutral amino acids, and even though many amino acid transport systems have overlapping specificities, tryptophan uptake can be limiting with this disorder. Under such conditions, the body may not produce sufficient NAD for its needs (the nicotinamide ring can be produced from dietary niacin, as well as tryptophan), and a pellagra-like illness can develop. Giving the child niacin will allow the NAD to be regenerated, and a high-protein diet may increase tryptophan levels such that the transporter can transport tryptophan from the intestinal lumen into the bloodstream. Cystinuria is a different transport defect that will not allow cystine to be absorbed from the diet, or removed from the urine and returned to the blood in the kidney (which can give rise to kidney stones). Myasthenia gravis is caused by autoantibodies directed against the acetylcholine receptor. Alkaptonuria is caused by a defect in homogentisic acid oxidase, and jaundice results from an inability to add glucuronic acid residues to bilirubin in the liver.

33. A 5-year-old boy has had episodic periods during which areas of his skin would develop a rash, which would spontaneously resolve in a week to 10 days. An astute pediatrician told the boy's parents to give him niacin the next time this occurred and a high-protein diet, and when they did, the rash resolved in a day or two. A likely disorder that this child has is which one of the following? (A) Cystinuria (B) Hartnup disease (C) Myasthenia gravis (D) Alkaptonuria (E) Jaundice

34. The answer is C. The child has inherited a mutation in each copy of the genes for adenosine deaminase and cannot convert adenosine to inosine (and deoxyadenosine to deoxyinosine). The deoxyadenosine is toxic and will accumulate in the blood cells, eventually forming dATP through salvage reactions. The dATP will, in part, inhibit ribonucleotide reductase, and the cells with the high dATP levels will not be able to proliferate when signaled to do so because of the lack of deoxyribonucleotide precursors. This is a form of SCID. Orotic acid builds up in hereditary orotic aciduria, but immune defects are not associated with that condition. Uric acid accumulation leads to gout without affecting the formation of the immune system. NADPH is required for the ribonucleotide reductase reaction, but its levels are not altered, nor is it secreted into the blood in an adenosine deaminase deficiency. dGTP levels do not increase with an adenosine deaminase deficiency.

34. A 9-month-old infant had been in and out of the hospital due to frequent infections. Blood test demonstrated the virtual lack of B and T cells and the almost complete absence of a thymic shadow on a chest X-ray. Measurement of metabolites in the blood would be expected to show elevated levels of which one of the following? (A) Uric acid (B) Orotic acid (C) Deoxyadenosine (D) NADPH (E) dGTP

35. The answer is D. Glycine metabolism involves a variety of pathways, one of which is a reversible transamination of glycine to form glyoxylic acid. The enzyme is glycine aminotransferase (also known as alanine-glyoxylate aminotransferase) and is defective in the disorder primary hyperoxaluria type 1. Glyoxylate can be produced from glycine by two different enzymes: the first is d-amino acid oxidase, and the second is the glycine aminotransferase. Glyoxylate is oxidized to oxalate, which forms calcium salts in the kidney and precipitates, forming kidney stones. A defect in any enzyme, which may lead to an accumulation of glyoxylate, will lead to kidney stone formation.

35. A 45-year-old man developed severe pain in his back, which, upon going to the emergency department, turned out to be because of kidney stones. A stone chemical analysis indicated a buildup of oxalic and glyoxalic acids. These compounds can accumulate due to a problem in the metabolism of which one of the following amino acids? (A) Alanine (B) Tryptophan (C) Isoleucine (D) Glycine (E) Glutamine

4. The answer is D. The formation of glutamate from glucose involves the TCA cycle intermediate α-ketoglutarate, which is formed from isocitrate in a reaction catalyzed by isocitrate dehydrogenase. α-Ketoglutarate is converted to glutamate either by glutamate dehydrogenase or by a transaminase. The formation of serine, alanine, aspartate, and cysteine from glucose does not require the activity of isocitrate dehydrogenase. Serine is derived from 3-phosphoglycerate, alanine from pyruvate, aspartate from oxaloacetate, and cysteine from methionine (only the sulfur) and serine (the carbon atoms). The oxaloacetate needed for aspartate synthesis can be generated from pyruvate via the pyruvate carboxylase reaction.

4. Starting with glucose, the synthesis of which one of the following would require the participation of isocitrate dehydrogenase? (A) Serine (B) Alanine (C) Aspartate (D) Glutamate (E) Cysteine

5. The answer is A. Glutamate cannot produce histidine because histidine is an essential amino acid in humans. Glutamate can fix ammonia to form glutamine in a reaction catalyzed by glutamine synthetase. Glutamate can be synthesized from α-ketoglutarate either through a transamination reaction or by glutamate dehydrogenase (which fixes ammonia into α-ketoglutarate). Glutamine donates nitrogens for purine ring synthesis, but glutamate does not. Glutamine is a nitrogen carrier in the blood, whereas glutamate is not.

5. The properties of glutamate are best represented by which one of the following? (yes, no) A Precursor for Histidine Synthesis in Humans? Is Produced from:Donates a Nitrogen to the Purine Ring Delivers Nitrogen to the Liver An Organic Compound That Can Fix Ammonia

6. The answer is C. Valine, isoleucine, and leucine (the branched-chain amino acids) are transaminated (which requires vitamin B6) and then oxidized by an α-keto acid dehydrogenase (that requires lipoic acid as well as vitamin B1 [thiamine], CoA, FAD, and NAD+). Four of the carbons of valine and isoleucine are converted to succinyl-CoA, which is a glucogenic product. Isoleucine also produces acetyl-CoA, a ketogenic product. Leucine is converted to hydroxymethylglutaryl-CoA (HMG-CoA), which is cleaved to acetoacetate and acetyl-CoA, and is strictly ketogenic. Branched-chain amino acid metabolism occurs primarily in the muscle because muscle contains the highest levels of the transaminase and dehydrogenase. Tetrahydrobiopterin is required for ring hydroxylations, which is not applicable to the metabolism of the branched-chain amino acids, which do not contain ring structures.

6. Which one of the following best represents the events that occur during the metabolism of the branched-chain amino acids? (yes, no) Requires Vitamin B1 Requires Vitamin B6 All Produce a Ketogenic Product Requires Tetrahydrobiopterin The Primary Tissue of Oxidation Is:

29. The answer is C. The man is experiencing gout attacks, cause by a buildup of uric acid. Uric acid is the end product of purine degradation. The liver contains larger levels of nucleic acids (DNA and RNA) than do the other foods listed as answers, and the intestinal epithelial cells will convert the purines in the food to uric acid and release it into the circulation. The alcohol the man has consumed leads to dehydration, which raises the uric acid concentration to the point where it will precipitate in the blood, leading to the painful episodes.

9. A 30-year-old male has had multiple episodes of sudden, severe pain, redness, and swelling of metatarsophalangeal joint of his great toes. These problems seem to occur after the man has had a night out on the town with his friends, when they go barhopping, and the night usually ends with a cab ride home for the group. This problem would also be exacerbated if the man eats which one of the following during his night out? (A) Hamburger (B) Chicago hot dog (C) Chopped liver (D) Nachos and salsa (E) Chicken wings

22. The answer is B. Tyrosine is a precursor of the catecholamines dopamine, epinephrine, and norepinephrine. The pathway for catecholamine production is normal in individuals with albinism because it is the melanocyte isozyme of tyrosinase that is mutated, not the form in the cells that produce the catecholamines.

A 20-year-old male is new to your practice, and you notice he has white hair, white skin, and nystagmus. 22. The amino acid(s) pathway that contained a mutation as indicated in the previous question is also a precursor for which one of the following? (A) Serotonin (B) Norepinephrine (C) Testosterone (D) Aldosterone (E) Histamine

21. The answer is D. The patient has the signs of albinism, a lack of melanin. Melanin is produced from tyrosine (tyrosine is hydroxylated in melanocytes to form dopa, which then enters the pathway for melanin production). The defective enzyme in oculocutaneous albinism (the type exhibited by this patient, as opposed to ocular albinism, which only affects the eyes) is tyrosinase. This is a melanocyte-specific genetic deficiency-neuronal cells also contain tyrosinase, which is needed to produce the catecholamines, and that isozyme is normal in patients with albinism. A defect in branched-chain amino acids would lead to MSUD; in phenylalanine, PKU; and in tryptophan, low serotonin levels. A defect in histidine metabolism may lead to reduced levels of histamine.

A 20-year-old male is new to your practice, and you notice he has white hair, white skin, and nystagmus. 21. A defect in the metabolism of which one of the following compounds is responsible for this presentation? (A) Branched-chain amino acids (B) Histidine (C) Tryptophan (D) Tyrosine (E) Methionine

24. The answer is B. Methionine, obtained from the diet, is activated by the reaction with ATP to form SAM, the universal methyl donor. After donating a methyl group, SAM is converted to S-adenosylhomocysteine. A hydrolase removes the adenosine, thereby generating homocysteine. Homocysteine then has two fates—it can react with N5-methyl-FH4 (with B12) to regenerate methionine, or it can react with serine (in the presence of B6) to form cystathionine, which goes on to form cysteine. A defect in either the enzyme that forms methionine (methionine synthase) or the enzyme that forms cystathionine (cystathionine β-synthase) will lead to elevated homocysteine levels.

A 45-year-old male is concerned about his risk of a heart attack because his brother just had a heart attack at the age of 46. His physician orders an HbA1c, lipid panel, and homocysteine level. 24. A reduction in the metabolism of which one of the following amino acids can lead to elevated homocysteine levels in the blood? (A) Alanine (B) Methionine (C) Phenylalanine (D) Glutamate (E) Cysteine

23. The answer is B. High homocysteine levels may be a risk factor for early atherosclerotic disease. The high levels appear to be associated with low B6, B12, and/or folate levels. Vitamin B12 is required for the methionine synthase reaction (homocysteine + N5-methyl-FH4 yields methionine and FH4), vitamin B6 is required for the cystathionine β-synthase reaction (homocysteine + serine yields cystathionine), and folate is required for the methionine synthase reaction. Vitamins B3 (niacin), C, E, and B1 (thiamin) are not required for homocysteine metabolism.

A 45-year-old male is concerned about his risk of a heart attack because his brother just had a heart attack at the age of 46. His physician orders an HbA1c, lipid panel, and homocysteine level. 23. A high homocysteine level could be associated with a deficiency of which one of the following vitamins? (A) B3 (B) B12 (C) C (D) E (E) B1

8. The answer is C. Pyrimidines are first built as a free base (orotic acid) before being converted to a nucleotide (OMP), which is the opposite of that of purine synthesis, in which the purine is built upon ribose-5-phosphate to first produce the nucleotide IMP. FH4 does not provide carbons for pyrimidine synthesis (the precursors are carbamoyl phosphate, derived from glutamine and carbon dioxide, and aspartic acid). Carbamoyl phosphate synthetase II, which produces carbamoyl phosphate in the cytoplasm for pyrimidine synthesis, does not fix ammonia into the product, but rather uses glutamine as the nitrogen donor. Aspartate is required to build the pyrimidine ring.

Which one of the following best represents de novo pyrimidine synthesis in a liver cell? (A) Synthesized as a Nucleotide, Not a Free Base Requires FH4 Requires an Enzyme That Fixes Ammonia Requires Aspartic Acid

9. The answer is D. Bilirubin is produced by the oxidation of heme after its iron is released; CO is produced in this reaction. Bilirubin diglucuronide, which contains two glucuronic acid (not glucose) residues, is excreted into the bile (not the urine) by the liver. The bilirubin is modified in the intestinal tract and eventually excreted in the feces.

Which one of the following best represents the metabolism of bilirubin? (A) Contains Iron Excreted in the Urine In the Formation of Bilirubin, a Carbon Is Lost as: Solubility Enhanced by: