Inhibitor Of Uridine Phosphorylase Research Articles

Inhibitory effects of 2-thiouracil and 2-thiouracil metabolites on enzymes involved in pyrimidine nucleotide biosynthesis

The inhibitory effects of thiouracil, thiouridine and thio-UMP on enzymes in the pyrimidine pathways leading to nucleic acid synthesis were studied. Thiouracil. but not thiouridine. was a potent competitive inhibitor of rat liver uridine phosphorylase. However, thiouridine was a potent competitive inhibitor of rat liver uridine kinase, whereas thiouracil and other antithyroid drugs produced no effect. Thio-UMP was a weak inhibitor of this enzyme but was less active than UMP. Thiouracil and thio-UMP produced little inhibition of bacterial UMP pyrophosphorylase, although thiouracil is a good substrate. Thiouracil and its analogs had no measurable effect on calf thymus or baker's yeast OMP pyrophosphorylase, but thio-UMP inhibition of rat liver OMP decarboxylase was comparable to that obtained with UMP. The results presented demonstrate that there are three sites in the pyrimidine pathways where thiouracil or its metabolites may exert substantial inhibition. The enzymes primarily affected are uridine phosphorylase and uridine kinase which are inhibited by thiouracil and thiouridine, respectively, and OMP decarboxylase which is inhibited by thio-UMP. These results support the hypothesis that some of the biological effects of thiouracil may be due to an alteration in pyrimidine nucleotide synthesis.

Effects of 2-thiouracil and related compounds on pyrimidine metabolism

The effects of 2-thiouracil and some related compounds on enzymatic reactions at the pyrimidine nucleotide level have been studied. Thiouracil and propylthiouracil depressed the incorporation of uracil-2- 14C into uridine, uridine nucleotides and RNA in rat liver slices without affecting uracil oxidation. Uridine-2- 14C degradation was also inhibited but incorporation into nucleotides and RNA was markedly enhanced. These alterations in the metabolism of uracil and uridine appeared to be due to an inhibition of uridine phosphorylase. Thiouracil, methylthiouracil, and propylthiouracil, but not methimazole, were potent inhibitors of uridine phosphorylase but were not utilized as substrates. Thiouracil inhibition of uridine phosphorylase appeared to be competitive. Thiouracil inhibition of uracil incorporation into nucleotides and RNA occurred only in those tissues in which uridine phosphorylase was rate limiting or was made rate limiting by inhibition. The thiourea derivatives had no effects on uridine kinase or OMP pyrophosphorylase and were not substrates for OMP pyrophosphorylase. Therefore none of these enzymes appear to serve as a site for thiouracil entrance into pathways leading to nucleotide and RNA synthesis. However, inhibition of uridine phosphorylase might explain the thiouracil produced inhibition of growth in some systems.