KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Part I ● Biochemistry

9.A woman 7 months pregnant with her first child develops anemia. Laboratory evaluation indicates an increased mean cell volume (MVC), hypersegmented neutrophils, and altered morphology of several other cell types. The most likely underlying cause of this woman’s anemia is

A.folate deficiency

B.iron deficiency

C.glucose 6-phosphate dehydrogenase deficiency

D.cyanocobalamin (B12) deficiency

E.lead poisoning

Items 10 and 11

A 64-year-old woman is seen by a hematologist for evaluation of a macrocytic anemia. The woman was severely malnourished. Both homocysteine and methylmalonate were elevated in her blood and urine, and the transketolase level in her erythrocytes was below normal.

10.What is the best evidence cited that the anemia is due to a primary deficiency of cyanocobalamin (B12)?

A.Macrocytic anemia

B.Elevated methylmalonate

C.Low transketolase activity

D.Elevated homocysteine

E.Severe malnutrition

11.In response to a B12 deficiency, which of the additional conditions may develop in this patient if she is not treated?

A.Progressive peripheral neuropathy

B.Gout

C.Wernicke-Korsakoff

D.Destruction of parietal cells

E.Bleeding gums and loose teeth

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Chapter 17 ● Amino Acid Metabolism

Items 12–15

G

malate F succinate

Link the following to the letters in the cycle.

12.Obligate activator of hepatic pyruvate carboxylase in the postabsorptive state.

13.Product formed by argininosuccinate lyase during urea synthesis.

14.Substrate and energy source for synthesis of δ-aminolevulinate in the heme pathway.

15.Converted to glutamate in a reaction requiring the coenzyme form of pyridoxine (B6)

16.A 62-year-old man being treated for tuberculosis develops a microcytic, hypochromic anemia. Ferritin levels are increased, and marked sideroblastosis is present. A decrease in which of the following enzyme activities is most directly responsible for the anemia in this man?

A.Cytochrome oxidase

B.Cytochrome P450 oxidase

C.Pyruvate kinase

D.δ-Aminolevulinate synthase

E.Lysyl oxidase

17.A 48-year-old man developed abdominal colic, muscle pain, and fatigue. Following a 3-week hospitalization, acute intermittent porphyria was initially diagnosed based on a high level of urinary δ-aminolevulinic acid. Subsequent analysis of the patient’s circulating red blood cells revealed that 70% contained elevated levels of zinc protoporphyrin, and the diagnosis was corrected. The correct diagnosis is most likely to be

A.protoporphyria

B.congenital erythropoietic porphyria

C.lead poisoning

D.barbiturate addiction

E.iron deficiency

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Part I ● Biochemistry

18.A 3-week-old infant has been having intermittent vomiting and convulsions. She also has had episodes of screaming and hyperventilation. The infant has been lethargic between episodes. Tests reveal an expanded abdomen, and blood values show decreased citrulline amounts as well as a decreased BUN. What other clinical outcomes would be expected in this infant?

A.Decreased blood pH and uric acid crystals in urine

B.Decreased blood pH and increased lactic acid in blood

C.Increased blood glutamine and increased orotic acid in urine

D.Increased blood ammonia and increased urea in urine

E.Megaloblastic anemia and increased methylmalonic acid in blood

19.A 69-year-old male presents to his family physician with a complaint of recent onset difficulty in performing activities of daily living. He is a retired factory worker who last worked 4 years ago. Upon questioning, his spouse reveals that he “hasn’t been able to get around the way he used to.” Physical examination reveals a well-nourished 69-year-old man who walks with an exaggerated kyphosis. His gait appears to be quite slow and wide-based. He also appears to have a resting tremor. The appropriate management of his case would target which of the following?

A.Amino acid degradation

B.Catecholamine synthesis

C.Ganglioside degradation

D.Prostaglandin synthesis

E.Sphingolipid degradation

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Chapter 17 ● Amino Acid Metabolism

Answers

1.Answer: E. Aspartate is produced by AST and carbamoyl phosphate by CPS-I.

2.Answer: E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase.

3.Answer: A. Homocysteine, the substrate for the enzyme, accumulates increasing the risk of deep vein thrombosis and disrupting the normal crosslinking of fibrillin. Deficiency of homocysteine methyltransferase would cause homocystinuria, but would also predispose to megaloblastic anemia.

4.Answer: C. Only methionine is degraded via the homocysteine/ cystathionine pathway and would be elevated in the plasma of a cystathionine synthase–deficient patient via activation of homocysteine methyltransferase by excess substrate.

5.Answer: A. Adults with alcaptonuria show a high prevalence of ochronotic arthritis due to deficiency of homogentisate oxidase.

6.Answer: C. Maple syrup urine disease; substrates are branched chain α-ketoacids derived from the branched chain amino acids.

7.Answer: E. The child has PKU; aspartame contains phenylalanine. These children may be blond, blue-eyed, and pale complected because of deficient melanin production from tyrosine.

8.Answer: F. The only biotin-dependent reaction in the diagram. The enzyme is propionyl-CoA carboxylase.

9.Answer: A. Pregnant woman with megaloblastic anemia and elevated serum homocysteine strongly suggests folate deficiency. Iron deficiency presents as microcytic, hypochromic anemia and would not elevate homocysteine. B12 deficiency is not most likely in this presentation.

10.Answer: B. Methylmalonyl-CoA mutase requires B12 but not folate for activity. Macrocytic anemia, elevated homocysteine, and macrocytic anemia can be caused by B12 or folate deficiency.

11.Answer: A. Progressive peripheral neuropathy. A distractor may be D, but this would be the cause of a B12 deficiency, not a result of it.

12.Answer: B. Acetyl-CoA activates pyruvate carboxylase and gluconeogenesis during fasting.

13.Answer: F. Fumarate.

14.Answer: E. Succinyl-CoA.

15.Answer: D. Glutamate is produced by B6-dependent transamination of α-ketoglutarate.

16.Answer: D. Sideroblastic anemia in a person being treated for tuberculo-

sis (with isoniazid) is most likely due to vitamin B6 deficiency. δ-Aminolevulinate synthase, the first enzyme in heme synthesis, requires vitamin B6 (pyridoxine).

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Part I ● Biochemistry

17.Answer: C. Lead inhibits both ferrochelatase (increasing the zinc protoporphyrin) and ALA dehydrase (increasing δ-ALA).

18.Answer: C. The infant has a defect in the urea cycle, resulting from ornithine transcarbamylase (OTC) deficiency. OTC deficiency would result in decreased intermediates of the urea cycle, including decreased urea formation as indicated by the decreased BUN. OTC can be diagnosed by elevated orotic acid since carbamyl phosphate accumulates in the liver mitochondria and spills into the cytoplasm entering the pyrimidinesynthesis pathway.

Methylmalonic acid in blood (choice E) is seen in vitamin B12 disorders.

A decreased BUN would result in elevated ammonia in blood, raising the pH (choices A and B).

Decreased BUN means decreased blood urea, hence, decreased urea in urine (choice D).

19.Answer: B. The above case describes a patient with Parkinson’s disease, which is caused by degeneration of the substantia nigra. This leads to dopamine deficiency in the brain and results in resting tremors, bradykinesia, cog-wheeling of the hand joints, and rigidity of musculature. In addition, patients are often described as having “mask-like facies.” Dopamine is one of the catecholamines synthesized in a common pathway with norepinephrine and epinephrine.

The diseases involving amino acid degradation (choice A), ganglioside degradation (choice C), and sphingolipid degradation (choice E) do not match the presentation seen in the case.

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Purine and Pyrimidine Metabolism 18

Learning Objectives

Explain information related to pyrimidine synthesis

Explain information related to purine synthesis

Demonstrate understanding of purine catabolism and the salvage enzyme HGPRT

OVERVIEW

Nucleotides are needed for DNA and RNA synthesis (DNA replication and transcription) and for energy transfer. Nucleoside triphosphates (ATP and GTP) provide energy for reactions that would otherwise be extremely unfavorable in the cell.

Ribose 5-phosphate for nucleotide synthesis is derived from the hexose monophosphate shunt and is activated by the addition of pyrophosphate from ATP, forming phosphoribosyl pyrophosphate (PRPP) using PRPP synthetase. Cells synthesize nucleotides in 2 ways: de novo synthesis and salvage pathways.

•In de novo synthesis, which occurs predominantly in the liver, purines and pyrimidines are synthesized from smaller precursors, and PRPP is added to the pathway at some point.

•In the salvage pathways, preformed purine and pyrimidine bases can be converted into nucleotides by salvage enzymes distinct from those of de novo synthesis. Purine and pyrimidine bases for salvage enzymes may arise from:

–Synthesis in the liver and transport to other tissues

–Digestion of endogenous nucleic acids (cell death, RNA turnover)

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis.

In Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent or deficient. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation. Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. Patients also all have hyperuricemia because purines cannot be salvaged, causing gout.

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Part I ● Biochemistry

Purines

Pyrimidines

Figure I-18-1. Nucleotide Synthesis by Salvage and De Novo Pathways

PYRIMIDINE SYNTHESIS

Pyrimidines are synthesized de novo in the cytoplasm from aspartate, CO2, and glutamine. Synthesis involves a cytoplasmic carbamoyl phosphate synthetase that differs from the mitochondrial enzyme with the same name used in the urea cycle.

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