Orotic aciduria type 1 is caused by deficiency of UMP synthase (bifunctional enzyme). Which two enzymatic activities are absent, and what is the net metabolic consequence?

• A CPSII and ATCase; failure of carbamoyl phosphate synthesis
• B Dihydroorotase and CPSII; failure of ring closure in pyrimidine synthesis
• C CTP synthetase and UMP kinase; failure of CTP synthesis from UTP
• D Orotate phosphoribosyltransferase and OMP decarboxylase; failure to convert orotic acid to UMP ✓

Explanation

UMP synthase is a bifunctional enzyme in mammals possessing both orotate phosphoribosyltransferase (OPRT) and OMP decarboxylase activities encoded on a single polypeptide. Deficiency prevents conversion of orotic acid to orotidine-5'-monophosphate (OMP) and then to UMP. This blocks pyrimidine synthesis downstream of orotic acid, causing massive orotic acid accumulation and urinary excretion. Clinical features include megaloblastic anaemia (unresponsive to B12/folate), failure to thrive and crystalluria from orotic acid. CPSII and ATCase are involved in earlier steps. CTP synthetase acts on UTP to form CTP and is a separate enzyme.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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