Purine Metabolism in Parasites: Potential Targets for Chemotherapy

Abstract

This chapter discusses the broad aspects of the differences among the specificities of the transport, metabolic pathways, and enzymes involved in the metabolism of purines in parasites as compared to their mammalian host. Parasites differ from their host in various aspects of purine metabolism, including among other things: the lack of de novo purine biosynthesis, substrate specificity of various enzymes of the salvage pathway, the presence of special salvage enzymes exclusively in the parasites but not the host, nature and type of purine nucleobase and nucleoside transport, and insensitivity of purine transport to inhibitors of mammalian host purine transport inhibitors. These various differences in purine metabolism among parasites and/or parasite-infected cells and host cells present excellent targets for antiparasitic chemotherapeutic interventions as demonstrated by several studies. The importance of differences in transport and salvage metabolism of purine between the parasite and its hosts was highlighted by the discovery that potent nucleoside transport inhibitors of mammalian systems do not significantly inhibit the uptake of nucleosides in Schistosomes. Based on these findings, a successful antischistosomal chemotherapeutic regimen was developed. The highly toxic purine analogs, tubercidin (7-deazaadenosine) and nebularine were made selectively toxic against Schistosoma mansoni, S. japonicum and S. haematobium by simultaneous administration of a nucleoside transport inhibitor as an antidote for adverse toxic effects to the host but not the parasite.