Hypoxanthine Depletion Induced by Xanthine Oxidase Inhibits Malaria Parasite Growth in Vitro

Abstract

While Plasmodium falciparum, cause of the most virulent form of human malaria, synthesizes its pyrimidine requirements de novo, it lacks the ability to synthesize purines de novo, and depends on the erythrocyte host for its purine supply (1). Although ATP forms about 90% of the total erythrocyte purine pool, there is considerable evidence that the purine base, hypoxanthine, is the immediate purine precursor utilized by these parasites (2). Previous studies by ourselves (3) and others (4), have shown that the steady state concentration and nett rate of formation of hypoxanthine under physiological conditions is relatively low, and, apparently, inadequate to support parasite nucleic acid synthesis. We showed, however, that hypoxanthine formed in erythrocytes was recycled via a three component oxypurine cycle, comprising hypoxanthine, IMP and inosine, and that such recycling limited the rate of hypoxanthine release (5). Irreversible oxidation of hypoxanthine to uric acid by xanthine oxidase interrupted the cycle and enhanced the nett rate of ATP catabolism. During the course of these experiments, we noted that xanthine oxidase markedly decreased intracellular hypoxanthine levels. We therefore investigated whether xanthine oxidase could deplete intracellular hypoxanthine to the point where it could no longer sustain the growth and replication of malaria parasites in vitro.