STRUCTURE OF TOXOPLASMA GONDII ADENOSINE KINASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Morbidity and mortality due to infections with Toxoplasma gondii are an increasing problem in the HIV-infected population. Management of toxoplasmosis in these patients is complicated by a high incidence of side effects with the most commonly used compounds and the inactivity of these compounds against the latent stage of the parasite. Hence, there is a continuing need to define novel therapeutic targets and develop new therapeutic agents for this pathogen. One feature of the basic metabolism of these organisms which has not been fully exploited for chemotherapy is the characteristics of their adenosine kinase and its unique specificity in the activation of "subversive" substrates". Results from a collaborator indicate that the parasite, but not the host, adenosine kinase can uniquely phosphorylate certain 6-substituted purine nucleosides as "subversive" substrates and thereby selectively kill T. gondii in vitro and extend the life span of infected mice. Therefore, T. gondii adenosine kinase (TgAK) was cloned, overexpressed and purified. Structure activity relationships as well as comparative metabolic and molecular studies indicate that T. gondii adenosine kinase is indeed substantially different from that of the host in substrate specificity, structure and other characteristics. In conjunction with our collaborator, we will characterize the TgAK and to use the information gained to develop potent and selective subversive substrates as potential anti-toxoplasmic agents. This approach may well apply to other opportunistic infections which share with toxoplasma this unique feature of purine analogue metabolism.