Models for nitrate reductases and related enzymes

硝酸还原酶和相关酶的模型

• 批准号: 8182665
• 负责人: PARTHA BASU
• 金额: $ 33.82万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182665
• 关键词: Academic Research Enhancement Awards; Active Sites; Address; Affect; Aldehyde oxidase; Arsenates; Arsenic; Arsenites; Behavior; Biological; Biology; Catalysis; Cells; Cessation of life; Characteristics; Chemistry; Complement; Complex; Cysteine; Data; Development; Disease; Enzymes; Failure; Family; Formates; Goals; Guidelines; Health; Heart; Hereditary Disease; Human; Hydrogen Bonding; Hydroxylation; Individual; Inorganic Sulfates; Investigation; Life; Ligands; Ligation; Mediating; Medicine; Metals; Methionine; Methodology; Modeling; Modification; Molecular Structure; Molybdenum; Mononuclear; Nervous System Trauma; Nitrate Reductases; Nitrates; Nucleotides; Oxidases; Oxidation-Reduction; Oxidoreductase; Oxygen; Patients; Property; Pterins; Purines; Pyrans; Pyrazines; Raman Spectrum Analysis; Reaction; Reporting; Research; Role; Route; Scheme; Scientist; Solvents; Structure; Sulfides; Sulfites; Sulfur; Sulfur Metabolism Pathway; Testing; Training; Unspecified or Sulfate Ion Sulfates; Variant; Xanthine Oxidase; Xanthines; analog; cofactor; design; early childhood; electronic structure; ethylbenzene; inorganic phosphate; interest; microbial; molybdenum cofactor; next generation; nitrate reductase; programs; purine; purine metabolism; selenate; sulfite oxidase

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.

描述（由申请人提供）： 含蝶呤的钼辅因子（Moco）是一个显着的金属中心，位于各种酶的催化中心。Moco在所有单核钼酶（MMEs）中具有相同的基本核心结构，并存在于所有形式的生命中。这种辅助因子介导氧原子转移和羟基化反应的能力，已经引起了MME的多样性家族。类似地，构成的MME包括内切酶（例如，甲酸盐，过氧化物酶），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、硒酸盐）。在人类中，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重要作用。人类钼辅因子（MCD）缺乏症是由于亚硫酸氧化酶、黄嘌呤氧化酶和醛氧化酶的缺失而引起的一种多效常染色体隐性遗传病。患者表现出进行性神经损伤，在大多数情况下导致儿童早期死亡。用辅因子的前体进行的实验性治疗在治疗这种目前没有商业治疗的疾病方面显示出显著的前景。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。我们计划的最终目标是了解Moco的不同组成部分如何促进其整体反应性。为了实现这一目标，我们设计了三个具体的目标，合成和表征几种有机和无机分子，并提出详细的化学研究。这个项目的成功完成将有助于更好地了解复杂辅因子的不同组分的反应性。根据R15计划的指导方针，我们将继续培养下一代科学家。 公共卫生关系： 该提案旨在通过合成新化合物来发展对一类重要酶的基本理解。