Inosine Monophosphate Dehydrogenase

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DESCRIPTION (provided by applicant): Inosine monophosphate dehydrogenase (IMPDH) enzyme catalyzes the rate-limiting step in guanine nucleotide biosynthesis: the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) with concomitant reduction of NAD. IMPDH controls the size of the guanine nucleotide pool, which in turn controls proliferation and many other important cellular processes. IMPDH inhibitors are antiproliferative, making the enzyme a drug target for virtually every disease; specific IMPDH inhibitors could be used as immunosuppressive, cancer, antiviral or antimicrobial chemotherapy. We have shown that IMPDH undergoes a large conformational change in mid-catalytic cycle that converts the enzyme from a dehydrogenase to a hydrolase, and thus presents a unique opportunity to investigate the role of conformational dynamics in catalysis. This conformational change also appears to be a major determinant of drug selectivity. This proposal outlines an investigation of the mechanism and function of IMPDH. We will delineate the structural features that account for the varied activities of IMPDH isozymes. In addition to being crucial for the design of isozyme-specific inhibitors of IMPDH, this work will be an important contribution to understanding the relationship between structure and function in enzyme catalysis.