Effects of Allopurinol and Oxipurinol on Pyrimidine Biosynthesis in Man

Abstract

The final steps of pyrimidine biosynthesis de novo which are catalyzed by two sequential enzymes, orotate phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC), involve the PP-ribose-P dependent conversion of orotic acid to orotidine-5′-monophosphate (OMP) followed by decarboxylation at the 7 position to form uridine 5′-monophosphate (UMP) (Fig. 1). UMP is then utilized further in the synthesis of nucleic acids and co-enzymes. Defects at this site in this metabolic pathway are important for they can result in “pyrimidine starvation” from depletion of the intracellular pool of pyrimidine nucleotides. In man the rare genetic disease, orotic aciduria, involves a deficiency of both OPRT and ODC (Type 1) (Smith, Sullivan and Huguley, 1961) or, less commonly, only ODC (Type II) (Fox, O’Sullivan and Firken, 1969). The resultant clinical state is characterized by failure of growth and development, megaloblastic anemia, and the increased urinary excretion of orotic acid (Types I and II) and orotidine (Type II).