Spectroscopic Studies of Molybdoenzymes & Models

钼酶的光谱研究

• 批准号: 10162609
• 负责人: MARTIN L KIRK
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162609
• 关键词: Address; Aldehyde oxidase; Amino Acids; Anabolism; Apoenzymes; Area; Bacteria; Behavior; Binding Proteins; Catabolic Process; Catalysis; Chemicals; Combined molybdoflavoprotein enzyme deficiency; Complex; Cysteine; Data; Disease; Drug Metabolic Detoxication; Electron Transport; Environment; Enzyme Reactivation; Enzymes; Family; Future; Goals; Health; Human; Infant Mortality; Investigation; Knowledge; Life; Ligands; Ligation; Mediating; Membrane Proteins; Metabolic Pathway; Metabolism; Methionine; Mission; Modeling; Molybdenum; Nature; Organism; Outcome; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen; Pathway interactions; Post-Translational Protein Processing; Process; Prodrugs; Proteins; Public Health; Reaction; Reperfusion Injury; Research; Role; Structure; Sulfoxide; Sulfur; Sulfur Compounds; Surface; Testing; United States National Institutes of Health; Work; XDH gene; Xenobiotics; antimicrobial; base; burden of illness; carbon compound; cofactor; dimethyl sulfoxide reductase; drug metabolism; electronic structure; geometric structure; gut microbiome; innovation; insight; knowledge base; methionine sulfoxide; methionine sulfoxide reductase; molybdenum cofactor; nervous system disorder; nitrogen compounds; novel; oxidative damage; persulfides; protonation; pyranopterin; repaired; spectroscopic survey; trafficking

There exist fundamental gaps in the knowledge base regarding the final steps of molybdenum cofactor (Moco) biosynthesis and sulfuration, how the Mo methionine sulfoxide reductase utilizes the pyranopterin dithiolene component (MPT) of the cofactor in catalysis, and the role of non-MPT ligands in the catalytic cycles of dimethylsulfoxide reductase family enzymes. Our long-term goal is to understand geometric and electronic structure contributions to pyranopterin molybdenum enzyme reactivity and function in order to provide a positive impact on the quality of human health. Our primary objectives are to determine critical Moco maturation, transport and sulfuration steps, define the mechanism of MsrP and the role of the MPT in Msr mediated catalysis, and understand the electronic structure of key paramagnetic intermediates in DMSOR family enzymes using a combined spectroscopic approach augmented by detailed bonding, spectroscopic, and reaction coordinate calculations. The central hypothesis is that specific geometric and electronic structure modifications of protein- bound Moco define the unique reactions catalyzed. The rationale for this research is that a comprehensive understanding of Moco maturation and transport, the complex interplay between Mo the MPT in Msr catalysis, and the nature of paramagnetic DMSOR family intermediates will provide new insights into disease states and have a positive impact on human health. We will test our central hypothesis in order to accomplish the objectives of this proposal through the successful pursuit of three Specific Aims 1) Understand Moco maturation, transport, and sulfuration, 2) Determine electronic structure contributions to MsrP catalysis, 3) Determine the electronic and geometric structure of paramagnetic intermediates in DMSOR family enzymes. The proposed research is innovative in its approach because we have integrated structural, multicomponent spectroscopic, and computational investigations on models and enzymes to address critical questions concerning the final stages of Moco biosynthesis and sulfuration, Mo catalyzed repair mechanisms for oxidatively damaged proteins, and the synergistic interactions between MPT and amino acid ligation in pyranopterin Mo enzyme catalysis. This has led to new insight into long-standing questions in the molybdoenzyme field, effectively opening new horizons for future work in this area. The proposed research is significant since it will impact and advance our understanding of molybdate insertion and post-translational sulfuration processes, sulfur and Moco trafficking, molybdoenzyme mediated rescue of oxidatively damaged proteins, and the roles of amino acid and pyranopterin dithiolene ligands in molybdoenzyme catalysis.

关于钼辅因子（Moco）的最后步骤，知识库中存在根本性的空白 生物合成和硫化，钼蛋氨酸亚砜还原酶如何利用吡喃蝶呤二硫纶 在催化中的辅因子的组分（MPT），以及非MPT配体在催化循环中的作用。 二甲亚砜还原酶家族酶。我们的长期目标是了解几何和电子 结构对吡喃蝶呤钼酶的反应性和功能的贡献，以提供一个积极的 影响人类健康质量。我们的主要目标是确定关键的莫科成熟，运输 和硫化步骤，确定MsrP的机制和MPT在Msr介导的催化中的作用， 了解DMSOR家族酶中关键顺磁性中间体的电子结构， 通过详细的键合、光谱和反应坐标增强的组合光谱方法 计算。核心假设是蛋白质的特定几何和电子结构修饰- 结合的Moco定义了催化的独特反应。这项研究的基本原理是， 了解Moco成熟和运输，Msr催化中Mo与MPT之间的复杂相互作用， 顺磁性DMSOR家族中间体的性质将为疾病状态提供新的见解， 对人类健康有积极的影响。我们将测试我们的中心假设，以实现目标 通过三个具体目标的成功追求1）了解莫科成熟，运输， 2）确定电子结构对MsrP催化的贡献，3）确定电子结构对MsrP催化的贡献， 和DMSOR家族酶中顺磁性中间体的几何结构。拟议的研究是 创新的方法，因为我们已经整合了结构，多组分光谱， 对模型和酶的计算研究，以解决有关最后阶段的关键问题 在Moco生物合成和硫化中，Mo催化氧化损伤蛋白质的修复机制， 在吡喃蝶呤钼酶催化中MPT与氨基酸连接的协同作用。这 导致了对酶领域长期存在的问题的新见解，有效地为 未来在这一领域的工作。拟议的研究是重要的，因为它将影响和促进我们的理解 插入和翻译后硫化过程，硫和莫科运输， 介导的氧化损伤蛋白质的拯救，以及氨基酸和吡喃蝶呤二硫烯配体的作用 在酶催化中。