MOLECULAR AND BIOCHEMICAL-STUDIES ON THE HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASES OF THE PATHOGENIC HEMOFLAGELLATES

All genera of protozoan parasites are auxotrophic for purines, and thu s, purine acquisition from the host is a nutritional necessity for the survival and growth of these pathogens. Many of these parasites, incl uding Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp., acces s host purines by phosphoribosylating purine bases via purine phosphor ibosyltransferase (PRT) enzymes. The trypanosomatid hypoxanthine-guani ne phosphoribosyltransferase (HGPRT) enzyme has been implicated as a c ritical enzyme of purine salvage in members of the Trypanosomatidae fa mily. Moreover, the HGPRT enzymes of Trypanosoma brucei, Trypanosoma c ruzi and Leishmania spp. can also initiate the metabolism of certain c ytotoxic purine base analogs that have little effect on the mammalian host. This implies that either inhibitors or substrates of HGPRT might serve as efficacious and selective agents for the treatment of diseas es for which trypanosomatids are the etiologic agent. The hgprt genes from Trypanosoma brucei, Trypanosoma cruzi and Leishmania donovani hav e all been cloned, sequenced and overexpressed in E. coli, and the rec ombinant proteins have all been purified to homogeneity and characteri zed with respect to kinetic parameters and physicochemical properties. This paper presents an overview of recent molecular and biochemical s tudies on trypanosomatid HGPRT proteins and future efforts to validate HGPRT as a rational target for the chemotherapeutic manipulation of A frican sleeping sickness, Chagas disease and leishmaniasis. (C) 1997 A ustralian Society for Parasitology. Published by Elsevier Science Ltd.