The broad, long-term objectives of the proposed research are to understand geometric and electronic structure contributions to the function of pyranopterin molybdenum enzymes, with particular relevance to understanding the mechanism of activity in xanthine oxidase, aldehyde oxidase and sulfite oxidase as these are key enzymes found in humans.
The specific aims of the proposed research plan are to 1) develop a comprehensive understanding of the reductive half-reaction in xanthine oxidase (XO), 2) use small molecule analogues of the XO related carbon monoxide dehydrogenase (CODH) active site to understand electronic structure contributions to catalysis, 3) correlate electronic and geometric structure contributions to oxygen atom and electron transfer reactivity in sulfite oxidase (SO), and 4) determine how the DMSO reductase site symmetry contributes to enzymatic catalysis. Individuals suffering from molybdenum cofactor deficiency display severe neurological symptoms and early childhood death. The physiological function of XO appears to be quite complex, and is exemplified by the fact that XO has recently been suggested to play a central role in the function of the innate immune system, and in postischemic reperfusion injury. Both AO and XO have recently been implicated in pro-drug activation, drug metabolism and, under specific conditions, NO synthase activity. Compared to XO, very little is known concerning the full pathophysiological relevance of AO. However, AO catalyzes the reduction of sulfa drugs, the activation of anticancer prodrugs, and has recently been shown to metabolize famciclovir to the potent antiviral penciclovir, which has been found to be effective against such viral infections as herpes simplex, varicella zoster, Epstein-Barr, and hepatitis B. In vertebrates, SO is found in the mitochondria! intermembrane space where the physiologically important oxidation of sulfite represents the terminal step in the oxidative degradation of cysteine and methionine. The research plan will utilize a combined spectroscopic approach, complimented by computational studies, on both models and enzymes to develop a detailed electronic structure description of the active site and how this electronic structure contributes to their mechanism of activity. Molybdenum enzymes are of key importance to human health. Our emerging understanding of their role in drug metabolism, free-radical damage, and the immune system underscore their role in a variety of health related issues.
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