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（由申请人提供）：钼辅因子（Moco）是一种非凡的金属中心，位于多种酶的催化核心。独特且“通用”的 Moco 在所有单核钼酶 (MME) 中具有相同的核心结构，并且存在于所有生命形式中。这种辅因子介导氧原子转移 (OAT) 和羟基化反应的能力，催生了多种 MME 家族。类似地，MME包括脱氢酶（例如甲酸、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）。在人类中，黄嘌呤氧化酶和亚硫酸盐氧化酶在硫和嘌呤代谢的氧化还原反应中发挥着至关重要的作用。微生物 MME 还通过硝酸盐和砷的转化间接影响人类健康。辅因子合成缺陷可能导致严重的生理异常，从而导致死亡。生物学和医学的一个基本问题是如何调整 Moco 的基本单位来实现各种功能。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更好地了解 MME 的反应性。我们有兴趣回答的广泛问题是：什么控制 MME 的反应性？物理结构如何强加电子结构来支持具有不同活性位点的相同基底转换？这些活性位点如何影响催化循环的不同阶段，即底物结合、产物形成、产物释放和活性位点再生？这些问题将通过研究钼络合物的 OAT 反应性和氧化还原性质并检查辅因子各个成分所施加的影响来解决。我们还将合成并充分表征二硫酮配体的氧代钼配合物，并研究其性质。此外，我们还进行了从铜到钼的金属转移反应，完成了吡喃蝶呤辅因子最接近类似物的合成。按照R15计划的指导方针，我们将继续培养下一代科学家。该提案旨在通过假设驱动的研究来解决与对人类健康重要的一类酶相关的基本问题。