High-Resolution X-Ray Crystal Structures of Tritrichomonas Foetus Inosine Monophosphate Dehydrogenase as Lead Compound for Structure-Based Drug Design
Background: Trichomoniasis is a venereal disease of cattle caused by a protozoan parasite, Tritrichomonas foetus. The disease has been reported worldwide with an estimated economic loss to the U.S. beef industry exceeding $100 million annually due to reduced conception rates, lowered weaning weights and increased culling. Currently there is no treatment for T. foetus. Technology: University of California, Irvine researchers utilized high-resolution x-ray crystallography to study the structure of a key enzyme in purine metabolism, inosine monophosphate dehyrogenase (IMPDH). IMPDH has been isolated and characterized from many sources, including human, and is an essential enzyme in the life cycle of the parasite. A unique complex of T. foetus IMPDH with inhibitors such as ribavirin and mycophenolic acid was discovered. Application: The unique high resolution x-ray crystal structures of T. foetus IMPDH:inhibitor complexes identified could lead to novel inhibitors to control this devastating disease in cattle. Furthermore, since structural and catalytic differences exist between mammalian and bacterial IMPDH, specific inhibitors of the isoforms could lead to discovery of a new class of antibacterial agents. Specific inhibitors of human IMPDH may have beneficial immunosuppressive effects.
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