Development ofenzyme inlulkar far infectious diseace including malaria and clarification ofthe inlubitor activity

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Tropical diseases such as human malaria, leishmaniasis, Chagas disease, human African trypanosomiasis, dengue fever and schistosomiasis continue to cause significant morbidity and mortality. In this project, we performed X-ray crystallographic studies of important enzymes from parasite concerning three these infectious disease to construct the structural basis for the drug development by the in-silica method. The important enzymes are (1) two kinds of enzymes concerning the de novo synthesis of pyrimidine nucleotide from human malaria, (2) prostaglandin (PG) F synthases from parasites of Chagas' disease and Leishmania.Recombinant enzymes of orotate phosphoribosyltransferase (pyr5) and Orotidine 5'-monophosphate decarboxylase (pyr6) were purified from E.coli and crystallized. As the result, the native and product UMP complex form of pyr6 were crystallized and carried out with the X-ray structural analyses. The 2.7 and 2.6 A resolutional structures of apo- and complex forms of pyr6 provided the details of the decarboxylation mechanism (J. Biochem., 2008). As for the PGF synthases from Trypanosoma cruzi and Leishmania mejor were also performed crystallization and the structure of PGF synthase from T. cruzi were determined at 1.7 A resolution (Acta Cryst. F, 2007). The complex structure of PGF sytnthase with indomethacin were also determined, providing the structural information for new inhibitor development.