SYNTHETIC MODELS FOR MOLYBDOENZYMES ACTIVE SITES AND FUNCTIONS

项目摘要：活性部位含有单核钼中心的酶，称为 钼酶，存在于所有形式的生命中，催化关键的广泛的氧化转化 对人类健康的重要性。许多钼酶在代谢嘌呤、黄嘌呤和 异种生物化合物。人黄嘌呤氧化还原酶是治疗高尿酸血症和痛风的有用药物靶点， 这影响了3%-10%的总人口。对于结核分枝杆菌和 空肠弯曲杆菌，一些对细菌呼吸和能量至关重要的钼酶的丧失 转化与细菌毒力的丧失有关。我的研究计划的长期目标是 阐明与人类有关的钼酶的结构和机制的基本方面 健康。钼酶原子和电子转移活性的关键是质子和/或 活性中心与底物或水之间的氢化物。然而，这些质子和氢化物的性质 转移问题是这样的，它们很难直接用酶来研究。的中心假说 这一建议指出，我们可以利用小分子钼模型来克服这一认识差距。 化合物，这将使我们能够对反应模式有新的化学见解。当前的研究 该项目旨在揭示氧转移和羟基化反应的详细反应机理 通过钼氧中心。目标将通过准备、结构表征和 下列小分子钼模型化合物的机械和光谱研究 明确的目标。具体目标1.揭示分子水平上介导的氧转移反应的机理细节 由钼(VI)-二氧基中心组成。特定目标2.合成关键顺式[MoVIO2]、[MoIVO]和顺式-[MoVIOS] 以仿生富硫氨基硫脲为载体的配合物及其羟化反应的研究 反应性。实现这些目标将阐明增进我们理解所需的基础化学 钼酶的活性部位和功能。这项基础研究的潜在长期应用 包括合理设计和开发基于机理的抑制剂作为药物和治疗方法。 NMSU的LI研究小组拥有合成、机械和光谱专业知识，设施， 科学的环境和完成这个项目的动力，这将使我们能够实现我们的目标 成为钼生物无机化学的重要和经常性的贡献者。 1

Project Summary: 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