Effects of benzimidazole on the purine and pyrimidine metabolism of yeast

Abstract Yeast cells inhibited by benzimidazole accumulate hypoxanthine with an associated efflux of xanthine. Unlike control cells, inhibited cells contain no detectable free UMP and CMP. Benzimidazole decreases uptake of [8- 14 C]-hypoxanthine into the intracellular pool of hypoxanthine and xanthine but causes radioactive xanthine to accumulate in the medium. In inhibited cultures there is a threefold increase in incorporation of [8- 14 C]hypoxanthine into the total (intracellular plus extracellular) xanthine. Uptake of [8- 14 C]hypoxanthine into free nucleotides and into bound adenine and guanine was inhibited by 70%. Uptake of [U- 14 C]glycine into IMP, AMP, GMP, DNA and RNA was also substantially decreased. Incorporation of [2- 14 C]uracil into the intracellular uracil pool was inhibited by 30% and into free uridine and cytidine by over 90%. Benzimidazole inhibited incorporation of [8- 3 H]IMP into AMP and GMP, and decreased substantially the activity of glutamine-amidophosphoribosyltransferase (EC 2.4.2.14). Yeast cultures were shown to N -ribotylate benzimidazole. Results are consistent with benzimidazole inhibiting yeast growth by competing for P -rib- PP and so depriving other ribotylation processes such as the ‘salvage’ pathways and de novo synthesis of purines and pyrimidines.