The long-term goal of this proposal is to characterize the reversible protein phosphorylation pathways in reference to biochemical and genetic regulation in the Apicomplexan group of parasites. Protozan Apicomplexan parasites are exemplified by deadly pathogens such as Plasmodium that causes malaria, and Toxoplasma and Cryptosporidium that cause opportunistic infections in AIDS patients. Malaria, transmitted by mosquitoes, alone kills between 1.5 and 2.5 million people worldwide, mostly young children. The resurgence of drug-resistant parasites as well as pesticide-resistant mosquitoes and the global transmission of the disease have produced an urgent need to understand the fundamental regulatory pathways of the parasite. Although our knowledge in this area is still rudimentary, a large body of evidence accumulated over the last two decades has shown that in higher animals a reversible protein phosphorylation provides a major mechanism of biochemical and genetic regulation. In this proposal, therefore, a combination of biochemistry and molecular biology will be employed to study selected Plasmodium protein phosphatases, key enzymes that are responsible for the dephosphorylation of specific phosphoproteins. The properties and regulation of these enzymes and their interactions with specific physiological inhibitors and drugs will be studied in- depth. The anti-parasitic drugs such as okadaic acid, a potent marine toxin, and cyclosporin, an immunosuppressant, will be used as tools in the analysis of the structure and function of specific protein phosphatases of the parasite. These results should form the cornerstone in the detailed elucidation of the regulatory pathways and possible drug-target interactions in Plasmodium in particular, and Apicomplexans in general.
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