Models for nitrate reductases and related enzymes

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DESCRIPTION (provided by applicant): The pterin-containing molybdenum cofactor (Moco) is a remarkable metal center that lies at the catalytic heart of a variety of enzymes. The Moco has the same basic core structure in all mononuclear molybdenum enzymes (MMEs) and is found in all forms of life. The ability of this cofactor to mediate oxygen atom transfer and hydroxylation reactions, has given rise to the diverse family of MMEs. Similarly, constituted, MMEs include dehydrogenases (e.g., formate, ethylbenzene), oxidases (e.g., sulfite, xanthine, arsenite), and reductases (e.g., nitrate, arsenate, selenate). In humans, xanthine oxidase and sulfite oxidase fulfill crucial functions in redox reactions in purine and sulfur metabolism, respectively. Human molybdenum cofactor (MCD) deficiency is a pleiotropic autosomal recessive genetic disorder due to the loss of sulfite oxidase, xanthine oxidase and aldehyde oxidase. Patients show progressive neurological damage with early childhood death resulting in most cases. An experimental treatment with a precursor to the cofactor has shown significant promise in treating this disease for which no commercial treatment is currently available. A fundamental question in biology and medicine is how has the basic unit of Moco been tuned to fulfill the various functions. The ultimate goal of our program is to understand how the different components of Moco contribute to its overall reactivity. To address this goal we have devised three specific aims to synthesize and characterize several organic and inorganic molecules, and propose detailed investigation of their chemistry. Successful completion of this project will help better understand the reactivity of different components of the complex cofactor. In accordance with the guideline of R15 program we will continue to train next generation of scientists. PUBLIC HEALTH RELEVANCE: This proposal seeks to develop a fundamental understanding of an important class of enzymes by synthesizing new compounds.