Structural and Functional Studies of the Enzyme Glucose-6-phosphate dehydrogenase

Abstract

Trypanosomiasis and leishmanosis are infectious diseases caused by protozoan parasites from genus Trypanosoma and Leishmania, respectively. Such diseases are currently treated with low effective and highly toxic drugs. The research of novel compounds which inhibits validated metabolic targets might lead to the development of more efficient drugs to such neglected diseases. The enzyme glucose-6-phosphate dehydrogenase (G6PDH) was experimentally validated as a metabolic target in T. brucei bloodstream form. G6PDH catalyzes the first step of the pentose phosphate pathway (PPP), which supplies the cell with ribose-5-phosphate for synthesis of nucleotides and NADPH for biosynthesis of lipids, cholesterol and detoxification of reactive oxygen species. The steroid Dehydroepiandrosterone (DHEA) was recently characterized as a potent uncompetitive inhibitor of T. brucei G6PDH (Ki = 1.7 ¼M). It was also demonstrated that DHEA is toxic to cultured T. brucei bloodstream form (LD50 = 43.8 ¼M). Together these results suggest that DHEA derivatives must be explored as a novel anti parasite drug class. The actual project will establish a complex of trypanosomatids G6PDH and DHEA (and its derivatives) more suitable to crystallization. The structural characterization of such complex will permit the rational design of uncompetitive inhibitor of trypanosomatids G6PDHs, which must be effective in treatment of a broader spectrum of infectious diseases with reduced side effects to the mammalian host.