LEISHMANIA MEXICANA ALDOLASE INHIBITION STUDIES

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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. Third world countries are in a crisis situation because of parasitic diseases. A major disease is caused by trypanosomatids, unicellular organisms that rely solely on glycolysis to meet their metabolic energy demands. Our approach is to use inhibitors directed against glycolytic enzymes to stop glycolysis. The enzyme target is fructose-1,6-biphosphate aldolase because of its key-position in the glycolysis pathway. Our model enzyme is Leishmania mexicana aldolase whose structure is already solved. Its catalytic site differs by a critical alanine residue that replaces a glycine residue observed in mammalian aldolases. Studies on the mammalian enzyme places the putative alanine near one of the substrate (fructose-1,6-bisphosphate) phosphate binding sites alluding to binding differences between parasite and mammalian aldolases. The goal of our project is to solve the structure of Leishmania mexicana aldolase-ligand complexes and to compare the structure of these complexes with substrate/inhibitors bound in mammalian aldolases. Data collection at X29 using the ADSC 3x3 detector has allowed us to collect data to maximum resolution otherwise not possible because of a long unit cell dimension in our crystals. We propose to collect high resolution data on several reaction complexes from which to design mechanism based lead compounds that will be optimized through iterative rounds of crystal structure determination.