A young child who presents with megaloblastic anemia is found to have increased orotate in the urine due to a deficiency of orotate phosphoribosyl transferase. This enzyme deficiency decreases the synthesis of
A. GlycogenB. Purines
C. Pyrimidines
D. Sphingomyeli
Answer.
C. Pyrimidines
begins with the
conversion of glutamine to carbamoyl phosphate. This step, which is the
committed step in pyrimidine synthesis, is catalyzed by the enzyme carbamoyl
phosphate synthetase II (CPSII) and requires 2ATP and CO2. After
several biochemical steps orotate is formed; orotate is then converted to
orotidine 5′-monophosphate (OMP) by the enzyme orotate phosphoribosyl
transferase. Subsequently OMP is converted to uridine 5′-monophosphate (UMP) by
the enzyme OMP decarboxylase. A deficiency of either of these two enzymes leads
to a disorder called orotic aciduria, which is characterized by orotate in the
urine, abnormal growth, and megaloblastic anemia. Next UMP is converted to CTP, while dUMP is
converted by thymidylate synthase to dTMP. This latter step also involves
folate and is inhibited by the folate analogue methotrexate, while thymidylate
synthase is inhibited by the thymine analogue 5-flurouracil (5-FU). Finally,
the ribonucleoside diphosphates (ADP, GDP, CDP, and UDP) are converted to
deoxyribonucleoside diphosphates by ribonucleotide reductase, an enzyme that is
inhibited by increased levels of dATP, as seen in individuals with the autosomal recessive
(Swiss type) form of SCID, which is due to a deficiency of adenosine deaminase
(ADA).
