Orotic aciduria, presenting in infancy with megaloblastic anaemia unresponsive to B12 and folate, is caused by deficiency of which bifunctional enzyme of pyrimidine biosynthesis?
- A Dihydroorotase
- B CAD trifunctional protein (CPS-II, ATCase, dihydroorotase)
- C UMP synthase (OPRT + OMP decarboxylase) ✓
- D Orotic acid phosphoribosyl transferase only
Explanation
Hereditary orotic aciduria type I results from deficiency of UMP synthase, the bifunctional enzyme catalysing the last two steps of de novo pyrimidine synthesis: orotate phosphoribosyltransferase (OPRT, step 5) and OMP decarboxylase (step 6). Without UMP, CTP and thymidylate synthesis is impaired, causing megaloblastic anaemia; accumulated orotate is excreted. Treatment is uridine supplementation, which bypasses the block and also feeds back to reduce orotic acid accumulation. The CAD trifunctional protein catalyses the first three steps. Isolated dihydroorotase deficiency does not cause clinical orotic aciduria.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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