Models for nitrate reductases and related enzymes

描述(由申请人提供)： 含有蝶呤的钼辅助因子(MOCO)是一种重要的金属中心，位于多种酶的催化中心。MOCO在所有单核钼酶(MME)中具有相同的基本核心结构，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和羟化反应，从而产生了不同的MME家族。类似地，MME包括脱氢酶(例如，甲酸盐、乙苯)、氧化酶(例如，亚硫酸盐、黄嘌呤、亚砷酸盐)和还原酶(例如，硝酸盐、砷酸盐、亚硒酸盐)。在人体内，黄嘌呤氧化酶和亚硫酸盐氧化酶分别在嘌呤和硫代谢的氧化还原反应中发挥关键作用。人钼辅酶(MCD)缺乏症是一种常染色体隐性遗传疾病，由亚硫酸盐氧化酶、黄嘌呤氧化酶和乙醛氧化酶丢失所致。患者表现为进行性神经损害，大多数病例会导致儿童早期死亡。辅因子前体的实验性治疗在治疗这种目前尚无商业化治疗方法的疾病方面显示出巨大的前景。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。我们项目的最终目标是了解MOCO的不同成分是如何影响其整体反应性的。为了解决这一目标，我们设计了三个具体的目标来合成和表征几个有机和无机分子，并建议对它们的化学进行详细的研究。该项目的成功完成将有助于更好地了解复杂辅因子不同成分的反应性。按照R15计划的指导方针，我们将继续培养下一代科学家。 公共卫生相关性： 这项提议寻求通过合成新的化合物来发展对一类重要酶的基本理解。

DESCRIPTION (provided by applicant): The pterin-containing molybdenum cofactor (Moco) is a remarkable metal center that lies at the catalytic heart of a variety of enzymes. The Moco has the same basic 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 and hydroxylation reactions, has given rise to the diverse family of MMEs. Similarly, constituted, MMEs include dehydrogenases (e.g., formate, ethylbenzene), oxidases (e.g., sulfite, xanthine, arsenite), and reductases (e.g., nitrate, arsenate, selenate). In humans, xanthine oxidase and sulfite oxidase fulfill crucial functions in redox reactions in purine and sulfur metabolism, respectively. Human molybdenum cofactor (MCD) deficiency is a pleiotropic autosomal recessive genetic disorder due to the loss of sulfite oxidase, xanthine oxidase and aldehyde oxidase. Patients show progressive neurological damage with early childhood death resulting in most cases. An experimental treatment with a precursor to the cofactor has shown significant promise in treating this disease for which no commercial treatment is currently available. 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 program is to understand how the different components of Moco contribute to its overall reactivity. To address this goal we have devised three specific aims to synthesize and characterize several organic and inorganic molecules, and propose detailed investigation of their chemistry. Successful completion of this project will help better understand the reactivity of different components of the complex cofactor. In accordance with the guideline of R15 program we will continue to train next generation of scientists. PUBLIC HEALTH RELEVANCE: This proposal seeks to develop a fundamental understanding of an important class of enzymes by synthesizing new compounds.