Inhibition by barbituric acid and its derivatives of the enzymes in rat brain which participate in the synthesis of pyrimidine ribotides

Barbituric acid competitively inhibits dihydro-orotate dehydrogenase, uridine phosphorylase, and (directly or indirectly) orotate phosphoribosyltransferase. In addition, the ribotide of barbituric acid, 6-hydroxyuridine-5′-monophosphate, inhibits uridine monophosphate kinase and is a powerful competitive inhibitor of orotidylate decarboxylase—the final enzyme in the sequence for the de novo synthesis of pyrimidine ribotides. Barbituric acid itself causes marked competitive inhibition of decarboxylase activity provided the reaction mixture contains 5-phosphoribosyl-1-pyrophosphate (PRPP). Another barbituric acid derivative, phenobarbital, is a weak non-competitive inhibitor (in the presence of PRPP) of the decarboxylase. One convulsant barbiturate, DMBB [5-(1,3-dimethylbutyl)-5-ethyl-barbituric acid], and bemegride—a stimulant structurally resembling the barbiturates—were found to inhibit rat brain uridine phosphorylase activity, and this same enzyme was also inhibited by isobarbituric acid.