Models for nitrate reductases and related enzymes

硝酸还原酶和相关酶的模型

• 批准号: 7921704
• 负责人: PARTHA BASU
• 金额: $ 3.66万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921704
• 关键词: Academic Research Enhancement Awards; Active Sites; Address; Aerobic; Anabolism; Apoproteins; Arsenates; Arsenic; Arsenites; Benchmarking; Binding; Biology; Carbon; Catalysis; Cells; Cessation of life; Complex; Copper; Defect; Enzymes; Failure; Family; Formates; Goals; Guidelines; Health; Heart; Human; Hydroxylation; Individual; Life; Ligands; Link; Mass Spectrum Analysis; Mediating; Medicine; Metals; Modeling; Molecular Conformation; Molybdenum; Mononuclear; Natural regeneration; Nitrate Reductases; Nitrates; Nitrogen; Optics; Oxidases; Oxidation-Reduction; Oxidoreductase; Oxygen; Phase; Physiological; Play; Process; Property; Pyrans; Pyrazines; Pyrimidine; Pyrimidines; Raman Spectrum Analysis; Reaction; Research; Role; Scheme; Scientist; Spectrum Analysis; Structure; Sulfides; Sulfur; System; Testing; Training; Xanthine Oxidase; Xanthines; analog; base; cofactor; design; electron density; electronic structure; ethylbenzene; inorganic phosphate; interest; microbial; molybdenum cofactor; next generation; nitrate reductase; programs; purine metabolism; pyranopterin; selenate; sulfite oxidase

DESCRIPTION (provided by applicant): The molybdenum cofactor (Moco) is a remarkable metal center that lies at the catalytic heart of a variety of enzymes. The unique and `universal' Moco has the same core structure in all mononuclear molybdenum enzymes (MMEs) and is found in all forms of life. The ability of this cofactor to mediate oxygen atom transfer (OAT) and hydroxylation reactions, has given rise to the diverse family of MMEs. Similarly constituted, MMEs include dehydrogenases (e.g., formate, ethylbenzene), oxidases (e.g., sulfide, xanthine, arsenite), and reductases (e.g., nitrate, arsenate, selenate). In humans, xanthine oxidase and sulfite oxidase fulfill crucial functions in redox reactions in sulfur and purine metabolism. Microbial MMEs also indirectly impact human health through transformation of nitrate and arsenic. Defects in cofactor synthesis can result in severe physiological abnormalities leading to death. A fundamental question in biology and medicine is how has the basic unit of Moco been tuned to fulfill the various functions. The ultimate goal of our research is to better understand the reactivity of MMEs through an integrated program of inorganic, organic, physical, and reactivity studies. The broad questions that we are interested in answering are: What controls the reactivity in MMEs? How does the physical structure impose electronic structures that support the same substrate transformation with different active sites? How do these active sites influence the different phases of the catalytic cycle i.e., substrate binding, product formation, product releases and regeneration of the active site? These questions will be addressed by investigating the OAT reactivity and redox properties of molybdenum complexes and examining influence imposed by individual components of the cofactor. We will also synthesize and fully characterize oxo molybdenum complexes of dithione ligands, and investigate their properties. In addition, we conduct transmetallation reaction from copper to molybdenum, and complete the synthesis of the closest analog of pyranopterin cofactor. In accordance with the guideline of R15 program we will continue to train next generation of scientists. This proposal seeks to address fundamental questions relating to a class of enzymes that are important to human health though a hypothesis driven research.

描述(申请人提供)：钼辅助因子(MOCO)是一种重要的金属中心，位于各种酶的催化中心。独特而“通用”的MOCO在所有单核钼酶(MME)中具有相同的核心结构，在所有形式的生命中都存在。这种辅因子能够介导氧原子转移(OAT)和羟基化反应，从而产生了不同的MME家族。MME的构成类似，包括脱氢酶(例如甲酸盐、乙苯)、氧化酶(例如硫化物、黄嘌呤、亚砷酸盐)和还原酶(例如硝酸盐、砷酸盐、硒酸盐)。在人体内，黄嘌呤氧化酶和亚硫酸盐氧化酶在硫磺和嘌呤代谢的氧化还原反应中起着至关重要的作用。微生物微生态系统还通过硝酸盐和砷的转化间接影响人类健康。辅因子合成缺陷可导致严重的生理异常，导致死亡。生物学和医学中的一个基本问题是如何调整MOCO的基本单位以实现各种功能。我们研究的最终目标是通过无机、有机、物理和反应性研究的综合计划来更好地了解MME的反应性。我们有兴趣回答的广泛问题是：是什么控制了MME的反应性？物理结构如何施加电子结构来支持具有不同活性中心的相同底物的转化？这些活性中心如何影响催化循环的不同阶段，即底物结合、产物形成、产物释放和活性中心的再生？这些问题将通过研究钼络合物的燕麦活性和氧化还原性质以及考察辅因子的个别成分所造成的影响来解决。我们还将合成并充分表征二硫杂环氧钼配合物，并研究它们的性质。此外，我们还进行了铜到钼的过渡金属反应，完成了最接近的吡喃喋呤辅因子类似物的合成。按照R15计划的指导方针，我们将继续培养下一代科学家。这项提议寻求通过假设驱动的研究来解决与一类对人类健康重要的酶有关的基本问题。