Orotic acid is excreted in large amounts in a child who develops megaloblastic anemia not responding to B12 or folate. Deficiency of which enzyme is responsible?

• A Dihydroorotase (in the CAD multifunctional enzyme complex)
• B Adenylosuccinate lyase in the de novo purine pathway
• C UMP synthase (bifunctional enzyme with orotate phosphoribosyltransferase and OMP decarboxylase activity) ✓
• D PRPP synthetase with increased activity

Explanation

Hereditary orotic aciduria type I results from deficiency of UMP synthase, a bifunctional enzyme catalysing the last two steps of de novo pyrimidine synthesis: orotate phosphoribosyltransferase (orotic acid to OMP) and OMP decarboxylase (OMP to UMP). Deficiency causes orotic acid accumulation (excreted in urine) and pyrimidine depletion causing megaloblastic anemia unresponsive to B12/folate. Treatment is uridine supplementation, which bypasses the block. Adenylosuccinate lyase is in the purine pathway.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.