Enzymes that contain a mononuclear molybdenum center at their active site, known as molybdoenzymes, are found in all forms of life and catalyze a wide range of oxidative transformations of key importance to human health. Many molybdoenzymes are critical in metabolizing purines, xanthine, and xenobiotic compounds. Human xanthine oxidoreductase is a useful drug target for hyperuricemia and gout, which affects 3-10% of the general population. For pathogenic bacteria like Mycobacterium tuberculosis and Campylobacter jejuni, the loss of some molybdoenzymes important for bacterial respiration and energy conversions are correlated with a loss of bacterial virulence. The long-term goal of my research program is to elucidate the fundamental aspects of structures and mechanisms of molybdoenzymes relevant to human health. Key to atom and electron transfer reactivity in molybdoenzymes is the transfer of protons and/or hydride between the active site and the substrate or water. However, the nature of these proton and hydride transfer questions is such that they are very difficult to study directly using enzymes. The central hypothesis of this proposal states that we can overcome this knowledge gap using small molecule molybdenum model compounds, and this will allow us to gain new chemical insight into reactivity patterns. The current research project seeks to reveal details of reaction mechanisms of oxo transfer and hydroxylation reactions mediated by molybdenum-oxo centers. The objective will be achieved by preparing, structurally characterizing, and mechanistically and spectroscopically studying small molecule molybdenum model compounds in the following specific aims.
Specific Aim 1. Reveal molecular-level mechanistic details of oxo-transfer reactions mediated by molybdenum(VI)-dioxo centers.
Specific Aim 2. Synthesize key cis-[MoVIO2], [MoIVO], and cis-[MoVIOS] complexes supported by biomimetic sulfur-rich thiosemicarbazone ligands, and study the hydroxylating reactivities. Achieving these aims will elucidate fundamental chemistry needed to enhance our understandings of the active sites and functions of molybdoenzymes. Potential longer-term applications of this basic research include rational design and development of mechanism-based inhibitors as drugs and therapeutic treatment. The Li research group at NMSU has the synthetic, mechanistic, and spectroscopic expertise, facilities, scientific environments, and motivation to complete this project, which will allow us to achieve our goal of emerging as a significant and regular contributor to molybdenum bioinorganic chemistry. 1
s: Our proposed project is relevant to NIH missions because molybdenum- containing enzymes catalyze a wide range of oxidative transformations of key physiological importance, are invoked as important drug targets in humans, and are correlated with virulence in pathogenic bacteria. Our project will test mechanistic hypotheses and reveal fundamental chemistry relevant to the active site features and oxidative functions of molybdoenzymes using molybdenum model compounds, which will guide better treatment for illness.