Models for nitrate reductases and related enzymes

描述（由申请人提供）：钼辅因子（Moco）是一种显著的金属中心，位于多种酶的催化中心。独特和“普遍”的Moco在所有单核钼酶（MME）中具有相同的核心结构，并存在于所有形式的生命中。这种辅因子介导氧原子转移（OAT）和羟基化反应的能力，已经引起了不同的MME家族。类似地构成，MME包括内切酶（例如，甲酸盐，过氧化物酶），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重要作用。微生物MME还通过转化硝酸盐和砷间接影响人类健康。辅因子合成的缺陷可导致严重的生理异常，从而导致死亡。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更好地了解MMEs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？物理结构如何施加支持具有不同活性位点的相同底物转化的电子结构？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的再生？这些问题将通过调查钼络合物的OAT反应性和氧化还原特性，并检查辅因子的各个组成部分施加的影响来解决。我们也将合成并全面表征二硫代配体的氧代钼配合物，并研究其性质。此外，我们还进行了铜到钼的金属间化合物的转铁反应，完成了最接近的吡喃蝶呤辅因子类似物的合成。根据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一类对人类健康很重要的酶有关的基本问题。

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.