Clinical Correlates 9 Purine & Pyrimidine Metabolism

Question 1

Overactivity of PRPP synthetase, owing to a lack of ___, is an X-linked disorder resulting in overproduction of nucleotides. The condition leads to increased degradation as well, resulting in __ ___ ___.

Answer 1

feedback inhibition

hyperuricemia, gout, and kidney stones

Question 2

PRPP

Answer 2

5-phosphoribosyl-1-pyrophosphate, the activated substrate in the synthesis of purine and pyrimidine synthesis

Question 3

___ is a powerful immunosuppressant and a reversible inhibitor of IMP dehydrogenase. The drug limits the formation of nucleic acids in activated and proliferating immune cells and is used in treating autoimmune disease as well as to prevent ___ ___.

Answer 3

Mycophenolic acid

transplant rejection

Question 4

The antineoplastic agent hydroxyurea is an inhibitor of ___. It is used in the treatment of chronic myelogenous leukemia, polycythemia vera, and essential thrombocytosis.

Answer 4

ribonucleotide reductase

Question 5

____ syndrome, an X-linked recessive disorder, is caused by a defective HGPRT. Purine bases cannot be salvaged (i.e., reconverted to nucleotides). The purines are converted instead to uric acid, which increases in the blood. Mental retardation and____ are characteristics of the disease.

Answer 5

Lesch-Nyhan

self-mutilation

Question 6

HGPRT and APRT

Answer 6

The purine-salvage enzymes are hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT).

Question 7

Autosomal recessive mutations in APRT result in the inability of cells to salvage the purine base adenine. Patients develop ___ with renal colic, hematuria, recurrent urinary tract infections, and dysuria.

Answer 7

nephrolithiasis

Question 8

Deficiency of purine nucleoside phosphorylase (PNP) results in accumulation of both ___ ___ in lymphoid tissue, which is toxic to immune cells. Patients present with decreased numbers of ____ __. Neurologic symptoms, including mental retardation and muscle spasticity, and autoimmune disease are present.

Answer 8

dATP and dGTP

T cells and lymphopenia

Question 9

___ deficiency leads to severe combined immunodeficiency (SCID). As in PNP deficiency, both dATP and dGTP accumulate. ______ results in a T-, B-, and natural killer (NK)-cell deficiency with marked lymphopenia.

Answer 9

Adenosine deaminase (ADA)
ADA deficiency

Question 10

Allopurinol, an inhibitor of xanthine oxidase, is used in the treatment of gout. More recently, ____, a novel nonpurine analog inhibitor of xanthine oxidase, has been used.

Answer 10

febuxostat

Question 11

___, which is not very water soluble, is excreted by the kidneys

Answer 11

Uric acid

Question 12

___ results from accumulation of uric acid with the formation of uric acid crystals in the joints, especially the first metatarsophalangeal joint (podagra). This results in a painful arthritis that is treated with multiple agents like ___

Answer 12

Gout

allopurinol.

Question 13

In hereditary orotic aciduria, orotic acid is excreted in the urine because UMP synthase is defective. ___ cannot be synthesized, and therefore, growth retardation occurs. Oral administration of uridine bypasses the metabolic block and provides a source of ___.

Answer 13

Pyrimidines

pyrimidines

Question 14

____ is inhibited by the antineoplastic agent 5-fluorouracil (5-FU). 5-FU is converted by thymidylate synthase to 5-FdUMP, which remains bound to the enzyme, as a suicide inhibitor. 5-FU is an important agent in the treatment of cancers such as ___

Answer 14

Thymidylate synthase

breast and colon cancer.

Question 15

Aminolevulinic acid synthase (d-ALA) dehydrogenase is inhibited by heavy metal ions such as lead. This inhibition results in the ___ seen in patients with lead poisoning. Accumulation of lead leads to ___ and encephalopathy with cognitive and motor impairment.

Answer 15

anemia

abdominal pain

Question 16

Jaundice results from a deficiency in the liver’s ability to conjugate or transport ___. Jaundice refers to the yellow color of skin and eyes that results from the __ __. Causes include hemolytic anemia, primary liver disease, obstruction of the biliary system, and congenital deficiencies of the enzymes responsible for the ___ ___.

Answer 16

bilirubin
deposition of bilirubin
metabolism of bilirubin

Question 17

d-ALA dehydrogenase porphyria

Answer 17

Autosomal recessive disorder characterized by acute attacks of abdominal pain and neuropathy.

Question 18

Acute intermittent porphyria

Answer 18

Autosomal dominant disorder with periodic attacks of abdominal colic, peripheral neuropathy, psychiatric disorders, and tachycardia. Attacks are precipitated by drugs such as gonadal steroids, barbiturates, and
alcohol.

Question 19

Congenital erythropoietic porphyria

Answer 19

Autosomal recessive disorder with photosensitivity. Sometimes it is almost immediate and so severe that the infant may scream when put in sunlight, with erythema, swelling, and blistering occurring on exposed sites. The patient may also have hemolytic anemia and splenomegaly.

Question 20

Porphyria cutanea tarda

Answer 20

This autosomal dominant disorder is the most common porphyria. It results in photosensitivity with vesicles and bullae on skin of exposed areas.

Question 21

Hereditary coproporphyria

Answer 21

An autosomal dominant disorder that presents with photosensitivity and neurovisceral symptoms, like colic.

Question 22

Variegate porphyria

Answer 22

An autosomal dominant disorder that presents with photosensitivity along with neurologic symptoms and developmental delay in children.

Question 23

Erythropoietic protoporphyria

Answer 23

Autosomal dominant disorder characterized by photosensitivity with skin lesions after brief sun exposure. Patients may also have gallstones and mild liver dysfunction.

Question 24

___ ___results from a deficiency of bilirubin uridine diphosphate gluconyl transferase (UDP-GT). Type I results from a complete absence of the gene, with severe ___ that accumulates in the brain of affected newborns, causing a toxic encephalopathy (kernicterus). Type II, a benign form, results from a mutation causing a partial deficiency of the gene.

Answer 24

Crigler-Najjar syndrome

hyperbilirubinemia

Question 25

___syndrome is a relatively common and benign disorder (2% to 10% of the population) that results from decreased activity of UDP-GT. Occasional bouts of mild jaundice with increased physiologic stress occur during hemolysis or hepatocellular injury.

Answer 25

Gilbert

Question 26

1. A 56-year-old diabetic patient with end-stage renal disease receives a kidney transplant from his son. His nephrologist is concerned about the possibility of transplant rejection and puts the patient on mycophenolic acid, which inhibits which important enzyme in the synthesis of nucleotides?
(A) PRPP synthetase
(B) IMP dehydrogenase
(C) Adenylosuccinate synthetase
(D) Ribonucleotide reductase
(E) Adenylosuccinate lyase

Answer 26

B. Mycophenolic acid is a potent immunosuppressant and an inhibitor of IMP dehydrogenase, which normally converts IMP to xanthosine monophosphate. PRPP synthetase catalyses the initial step in nucleotide metabolism, forming PRPP from ATP and ribose. Adenylosuccinate synthetase and adenylosuccinate lyase are sequential enzymes in the synthesis of AMP and are not affected by mycophenolic acid.

Question 27

2. A physician evaluates a 42-year-old patient for fatigue. The patient is found to have an elevated white blood cell count and an enlarged spleen. A referral to an oncologist
   results in a diagnosis of chronic myelogenous leukemia. Treatment with hydroxyurea, a ribonucleotide reductase inhibitor, is begun. The normal function of ribonucleotide reductase is to catalyze which one of the following
   reactions?
   (A) Form PRPP from adenosine diphosphate (ADP) and ribose
   (B) Convert xanthine to uric acid
   (C) Form carbamoyl phosphate from glutamine, CO2, and two ATP molecules
   (D) Convert ADP to dADP
   (E) Convert guanosine to guanine and ribose 1-phosphate

Answer 27

D. Ribonucleotide reductase converts nucleoside diphosphates (NDPs) to deoxynucleoside diphosphates (dNDPs) for their use in DNA synthesis (an example is ADP to dADP). PRPP synthetase forms PRPP from ATP and ribose. Xanthine oxidase converts xanthine to uric acid. Carbamoyl phosphate is synthesized by carbamoyl phosphate synthetase II from glutamate, CO2, and two ATP molecules (carbamoyl phosphate synthetase I utilizes ammonia, carbon dioxide, and two ATP molecules as substrates). Purine nucleoside phosphorylase degrades
guanosine to guanine and ribose 1-phosphate (as well as inosine to hypoxanthine and ribose 1-phosphate).

Question 28

3. A 4-day-old infant develops severe jaundice and is transferred to the neonatal intensive care unit for aggressive phototherapy. He is found to have a complete loss of UDP-GT activity. The loss of this enzyme activity leads to which of the following disorders?
(A) Crigler-Najjar syndrome
(B) Gilbert syndrome
(C) Dubin-Johnson syndrome
(D) Hereditary orotic aciduria
(E) Gout

Answer 28

A. Crigler-Najjar syndrome, type I, results from a complete lack of UDP-GT activity and is a lethal condition. Gilbert syndrome is a mild defect in bilirubin conjugation that is usually asymptomatic, although it is due to a subtle defect in the same enzyme. Dubin-Johnson syndrome is a transport defect in bilirubin and does not involve its conjugation with glucuronic acid. Hereditary orotic aciduria results from a defect in pyrimidine synthesis. Gout results from hyperuricemia, not hyperbilirubinemia.

Question 29

4. A 3-year-old boy is brought to the emergency room with abdominal pain, mental status changes, and fatigue. On history, the physician finds that the patient lives in an older house and has been sucking on the paint chips that
   have crumbled in the windowsills, making the doctor suspicious for lead poisoning. Lead typically interferes with which of the following enzymes?
   (A) Cytochrome oxidase
   (B) Protoporphyrinogen oxidase
   (C) UMP synthase
   (D) d-ALA dehydratase
   (E) Porphobilinogen deaminase

Answer 29

D. Lead inhibits hemoglobin synthesis by inhibiting d-ALA dehydratase. Cytochrome oxidase is a component of complex IV of the electron transport chain, which is inhibited by cyanide and carbon monoxide, but not by lead. Protoporphyrinogen oxidase is deficient in variegate porphyria, and is not sensitive to lead. UMP synthase is defective in the genetic condition of hereditary orotic aciduria. UMP synthase is not sensitive to the presence of lead. Patients with acute intermittent porphyria have a deficiency of porphobilinogen deaminase. Lead has no effect on this enzyme.

Question 30

5. A child is noted to have recurrent respiratory infections that necessitate hospitalization. His laboratory tests demonstrate a decrease in T cells, B cells, and NK cells. He has decreased levels of circulating antibodies and is diagnosed with severe combined immunodeficiency. The
   enzyme that is defective in this disorder is important in which one of the following processes?
   (A) The conversion of ribonucleotides to deoxyribonucleotides
   (B) The de novo synthesis of AMP
   (C) The degradation of adenosine
   (D) The de novo synthesis of UMP
   (E) The conversion of dUMP to dTMP

Answer 30

C. The enzyme deficiency in severe combined immunodeficiency disease (SCID) is likely adenosine deaminase, which normally degrades adenosine to inosine. The conversion of ribonucleotides to deoxyribonucleotides is performed by ribonucleotide reductase. AMP is formed from IMP through the action of adenylosuccinate synthetase, followed by the action of
adenylosuccinate. UMP synthase is an important enzyme in the formation of UMP and, subsequently, cytidine triphosphate (CTP) and thymidine triphosphate (TTP). The conversion of dUMP to dTMP is mediated by thymidylate synthase. A second enzyme deficiency that can lead to SCID is the loss of a cytokine receptor subunit (the interleukin-2 receptor g-chain). This is an
X-linked form of SCID owing to the inability of immune cells to proliferate in response to interleukin-2.

Question 31

6. A 7-year-old boy suffers from mental retardation and self-mutilation (e.g., biting through lip) and has an increased susceptibility to gout. These symptoms are characteristic of Lesch-Nyhan syndrome, which is due to
   a mutation in which of the following pathways?
   (A) Salvage pathway for pyrimidines
   (B) De novo biosynthesis of purines
   (C) Pathway of uric acid synthesis
   (D) Salvage pathway for purines
   (E) De novo biosynthesis of pyrimidines

Answer 31

D. Lesch-Nyhan syndrome results from a defect in HGPRT, an enzyme involved in the purine salvage pathway. HGPRT catalyzes the conversion of the free base (hypoxanthine
of guanine) to a nucleotide (IMP or GMP). HGPRT is not required for de novo purine synthesis, or urate synthesis, or for either the de novo or salvage pathways of pyrimidine metabolism.

Question 32

7. A 58-year-old man is awakened by a throbbing ache in his great toe. He has suffered these symptoms before, usually after indulging in a rich meal. On examination, he is noted to have a greatly inflamed great toe; also of note are several small nodules on the antihelix of his ear. Inhibition of which of the following proteins might prevent further occurrences of this man’s ailments?
(A) Carbamoyl phosphate synthetase II
(B) HGPRT
(C) PRPP synthetase
(D) Xanthine oxidase
(E) Orotate phosphoribosyl transferase

Answer 32

D. Gout is caused by either the increased production or reduced excretion of uric acid, leading to the deposition of urate crystals. Allopurinol, a xanthine oxidase inhibitor, decreases the production of urate from hypoxanthine and xanthine. Carbamoyl phosphate synthetase II is an enzyme in pyrimidine biosynthesis and is not involved in urate formation. HGPRT is an enzyme in the pathway for purine salvage. Inhibition of HGPRT activity would increase urate production. Orotate phosphoribosyl transferase is important in the synthesis of pyrimidines. PRPP synthetase is an important enzyme in the biosynthesis of purines; loss of its activity would reduce urate production.

Question 33

8. An 8-year-old boy sees a dermatologist because he has developed vesicles and bullae on his face and arms that appeared after a week-long trip to Florida. His father has a similar condition. A diagnosis of porphyria cutanea tarda is confirmed by finding elevated levels of porphyrins in his serum, urine, and stool. His disease is due to a deficiency of which of the following enzymes?
(A) d-ALA dehydratase
(B) Porphobilinogen deaminase
(C) Uroporphyrinogen III cosynthase
(D) Ferrochelatase
(E) Uroporphyrinogen decarboxylase

Answer 33

E. Porphyria cutanea tarda is the most common of the porphyrias and results from a deficiency of uroporphyrinogen decarboxylase. Deficiency of d-ALA dehydratase results in d-ALA dehydratase porphyria. Acute intermittent porphyria is due to a deficiency of porphobilinogen deaminase (also known as hydroxymethylbilane synthase). Deficiency of uroporphyrinogen III cosynthase results in congenital erythropoietic porphyria. Finally, ferrochelatase deficiency results in erythropoietic protoporphyria.

Question 34

9. A 17-year-old woman who recently began taking birth control pills presents to the emergency room with cramping abdominal pain, anxiety, paranoia, and hallucinations. A surgical evaluation, including ultrasound and computed tomography scan, fails to demonstrate an acute abdominal process. A urinalysis reveals an increase in urine porphyrins. Which of the following is the most likely?
(A) Congenital erythropoietic porphyria
(B) Variegate porphyria
(C) Porphyria cutanea tarda
(D) Acute intermittent porphyria
(E) Erythropoietic protoporphyria

Answer 34

D. Acute intermittent porphyria is an autosomal dominant disease resulting from the deficiency of porphobilinogen deaminase (also known as hydroxymethylbilane synthase). Often these intermittent attacks are provoked by drugs such as gonadal steroids, barbiturates, or alcohol. These drugs are metabolized by cytochrome P-450 systems, which contain heme. The presence of these drugs induces cytochrome P-450 synthesis (which includes an increase in heme biosynthesis). The induction of heme biosynthesis is the event that leads to an accumulation of the toxic intermediate. The other choices, including congenital erythropoietic porphyria,
porphyria cutanea tarda, variegate porphyria, and erythropoietic protoporphyria, are considered erythropoietic porphyries, which are characterized by photosensitivity and rarely exhibit abdominal pain.

Question 35

10. An otherwise healthy 19-year-old man recovering from a respiratory infection sees his family physician. His examination is unremarkable except for a slight degree of yellow discoloration to his skin and eyes. Laboratory tests are ordered that reveal a mild increase in unconjugated bilirubin but no other abnormalities. Which of the following is the most likely diagnosis in this patient? 
(A) Crigler-Najjar syndrome, type I
(B) Crigler-Najjar syndrome, type II
(C) Gilbert syndrome
(D) Lead poisoning
(E) Erythropoietin deficiency

Answer 35

C. This patient has Gilbert syndrome, which is a common disorder that manifests with mild jaundice as a result of decreased bilirubin UDP-GT activity. Crigler-Najjar syndrome also results from a deficiency of the same enzyme, although it is far rarer and, in the case of type
I disease, is lethal. Lead poisoning would lead to anemia, not jaundice. Erythropoietin deficiency is seen in patients with renal failure because erythropoietin is normally produced by the kidney.