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中文摘要
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项目概述:在其活性部位含有单核钼中心的酶,称为 在所有形式的生命中都发现了这种酶,它们催化多种关键的氧化转化, 对人类健康的重要性。许多腺苷酸酶在代谢嘌呤、黄嘌呤和 异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效药物靶点, 影响了3-10%的总人口。对于像结核分枝杆菌和 空肠弯曲菌,一些对细菌呼吸和能量重要的脱氢酶的损失 转化与细菌毒力的丧失相关。我的研究计划的长期目标是 阐明与人类相关的辅酶A的结构和机制的基本方面, 健康辅酶中的原子和电子转移反应性的关键是质子和/或电子的转移。 氢化物在活性位点和底物或水之间。然而,这些质子和氢化物的性质 转移问题是这样的,它们很难直接使用酶来研究。的中心假设 该提案指出,我们可以利用小分子钼模型来克服这一知识差距, 化合物,这将使我们能够获得新的化学洞察反应模式。目前的研究 该项目旨在揭示氧代转移和羟基化反应介导的反应机制的细节 由氘代氧中心。这一目标将通过制备、结构表征和 机械和光谱研究小分子钼模型化合物在以下 具体目标。具体目标1。揭示氧代转移反应介导的分子水平机理细节 钼(VI)-二氧中心。具体目标2。合成关键的顺式-[MoVIO 2]、[MoIVO]和顺式-[MoVIOS] 仿生富硫缩氨基硫脲配体负载的配合物,并研究了 反应性实现这些目标将阐明基础化学需要加强我们的理解 的活性位点和功能。这项基础研究的潜在长期应用 包括基于机制抑制剂作为药物和治疗性治疗的合理设计和开发。 NMSU的Li研究小组拥有合成、机械和光谱方面的专业知识、设施, 科学环境和完成该项目的动力,这将使我们能够实现我们的目标 作为钼生物无机化学的一个重要的和经常的贡献者出现。 1
英文摘要
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
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