Orotic aciduria occurs in two distinct settings: UMP synthase deficiency (hereditary orotic aciduria) and treatment with allopurinol. The reason allopurinol causes orotic aciduria is:

• A Allopurinol's metabolite oxypurinol inhibits orotate phosphoribosyltransferase (OPRT) in the pyrimidine pathway
• B Reduced uric acid causes reduced inhibition of CPSII, increasing pyrimidine synthesis flux and orotate overflow
• C Allopurinol itself is a substrate competitor for OPRT, reducing orotic acid conversion to OMP ✓
• D Oxypurinol inhibits dihydroorotase in the CAD trifunctional enzyme, blocking pyrimidine ring closure

Explanation

Allopurinol is metabolized by HGPRT to allopurinol ribonucleotide (PRPP is consumed); this competes with orotic acid for OPRT. Additionally, allopurinol ribonucleotide can directly inhibit OMP decarboxylase (ODC), the second activity of UMP synthase, partially blocking conversion of orotic acid to UMP. The net effect is orotic acid accumulation and orotic aciduria. This is benign and not associated with megaloblastic anemia (unlike hereditary orotic aciduria), because carbamoyl phosphate synthetase II is feedback-inhibited by UMP that is still formed via alternate paths.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.