Models for nitrate reductases and related enzymes

Duquesne University, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Redox reactions catalyzed by mononuclear molybdoenzymes (MMEs) can seriously impact human health. Not only do defects in the cofactor biosynthesis result in infant death, through sulfite oxidase (SO) and xanthine oxidase (XO) deficiencies, but XO has also been linked to tissue damage during reperfusion following ischemic conditions. In addition, the transformation of oxyanions by native bacterial flora can also lead to pathological conditions such as non-Hodgkin's lymphoma (nitrate reductase, NR) and arseniasis (arsenate reductase, arsenite oxidase). On a more global scale, mononuclear molybdoenzymes are involved in key reactions of biogeochemical cycles of carbon, nitrogen, sulfur and arsenic. The focus of this research program is to understand the factors that control the reactivity of the molybdenum center using analog systems to probe the structure function relationship in nitrate reductases and related enzymes. Our significant progress in the past three years with support from an NIH AREA grant (11 publications) includes developing procedures for the synthesis of novel molybdenum complexes including stable intermediates of oxygen atom transfer reactions, and the development of protocols for detailed kinetic analysis, and new generation of dithiolene ligands. With these tools in hand, we propose the following research goals: to design and synthesize new oxo-molybdenum complexes with conformationally strained dithiolene ligands; to understand details of OAT reactivity from dioxo-Mo(VI) center and to understand the OAT reactivity of the monooxo-Mo(VI) center and desoxo-Mo(IV) center. The results of the proposed research will make a significant contribution to the field of metalloenzymes (including MMEs) and their impact on human health.