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Enzymology of Sulfide Oxidation

硫化物氧化的酶学

基本信息

批准号：
9313289
负责人：
RUMA V BANERJEE
金额：
$ 29.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313289
关键词：
Address Aorta Apoptosis Ataxia Bacteria Biochemical Biogenesis Biological Blood Blood Vessels Catabolism Cell Respiration Cells Cellular Stress Response Clinical Colorectal Cancer Consumption Coupled Couples Cyanides Cystathionine Cysteine Cysteine Desulfhydrase Data Defect Developmental Delay Disorders Dioxygenases Disease Electron Transport Encephalopathies Enzymatic Biochemistry Enzymes Erythrocytes Event Excision Exhibits Failure Foundations Gases Generations Glutathione Goals Health Hemoglobin Hemorrhagic colitis Homeostasis Human Hydrogen Sulfide Hypoxia Inflammation Kinetics Laboratories Lead Literature Mammals Mediating Metabolic Metabolism Methemoglobin Methods Mitochondria Molecular Mutation NADP Neurologic Organism Oxidative Phosphorylation Oxidoreductase Oxygen Pathway interactions Petechiae Pharmacologic Substance Physiological Plasma Population Predisposition Process Production Proteins Quinones Reaction Reactive Oxygen Species Regulation Reporting Role Route Signal Transduction Signaling Molecule Sulfides Sulfites Sulfur Sulfur Metabolism Pathway TXN gene Therapeutic Thiosulfate Sulfurtransferase Tissues Toxic effect Twin Multiple Birth Ulcerative Colitis Uncertainty Unspecified or Sulfate Ion Sulfates Variant Width cellular targeting cytochrome c oxidase design enzyme pathway man neuroregulation novel oxidation persulfides public health relevance response sulfite oxidase sulfurtransferase thioredoxin reductase

项目摘要

DESCRIPTION (provided by applicant): Hydrogen sulfide (H2S), a signaling molecule that elicits profound physiological effects, is a product of mammalian sulfur metabolism and is synthesized at relatively high rates. Since H2S is highly toxic, cells avoid its build-up by an efficient oxidation pathway that is housed in mitochondria and coupled to the energy-generating electron transport chain. The constituent proteins include sulfide-quinone oxidoreductase (SQR), a persulfide dioxygenase (ETHE1) and rhodanese in addition to the well-studied sulfite oxidase that catalyzes the conversion of sulfite to sulfate in the terminal step in the pathway. In red blood cells on the other hand, which exhibit robust H2S production capacity but lack mitochondria and hence the classical route for sulfide oxidation, the mechanism of sulfide clearance is unknown. In this study, we propose to address fundamental gaps in our understanding of the oxygen-dependent steps catalyzed by SQR and ETHE1, which combine to maintain low steady-state levels of H2S (in the 10-30 nM range in most tissues) and to elucidate the role of rhodanese in the sulfide oxidation pathway. We also propose to elucidate the potential role of methemoglobin in sulfide removal in red blood cells. These goals will be realized by addressing the following specific aims. (i) Using a combination of spectroscopic and kinetic methods we will elucidate the reaction mechanisms of human SQR and ETHE1. (ii) We will assess the relative catalytic efficiencies with which rhodanese generates glutathione persulfide, thiosulfate and H2S and elucidate the biochemical differences between two common polymorphic rhodanese variants. (iii) We will elucidate the mechanism of methemoglobin-dependent sulfide oxidation and assess its contribution to sulfide clearance at physiologically relevant concentrations of H2S and methemoglobin. Our studies will address fundamental questions such as how the sulfide oxidation pathway is wired, elucidate the reaction mechanisms of key enzymes that are potentially important pharmaceutical targets for modulating H2S levels and assess a novel and previously unexplored role for human hemoglobin in maintaining low plasma H2S concentrations.

描述（由申请人提供）：硫化氢（H2S）是一种能引起深远生理效应的信号分子，是哺乳动物硫代谢的产物，合成速度相对较高。由于 H2S 具有剧毒，细胞通过位于线粒体中并与产生能量的电子传输链耦合的有效氧化途径来避免其积聚。组成蛋白包括硫化物醌氧化还原酶 (SQR)、过硫化物双加氧酶 (ETHE1) 和硫氰酸酶，以及经过充分研究的亚硫酸盐氧化酶，该酶在该途径的最终步骤中催化亚硫酸盐转化为硫酸盐。在另一方面，红细胞表现出强大的 H2S 生产能力，但缺乏线粒体，因此缺乏硫化物氧化的经典途径，因此硫化物清除机制尚不清楚。在这项研究中，我们建议解决我们对 SQR 和 ETHE1 催化的氧依赖性步骤的理解中的根本差距，这些步骤结合起来维持 H2S 的低稳态水平（在大多数组织中在 10-30 nM 范围内），并阐明硫氰酸酶在硫化物氧化途径中的作用。我们还建议阐明高铁血红蛋白在红细胞中硫化物去除中的潜在作用。这些目标将通过解决以下具体目标来实现。 (i) 结合光谱学和动力学方法，我们将阐明人类 SQR 和 ETHE1 的反应机制。 (ii) 我们将评估硫氰酸酶生成谷胱甘肽过硫化物、硫代硫酸盐和 H2S 的相对催化效率，并阐明两种常见多态性硫氰酸酶变体之间的生化差异。 (iii) 我们将阐明高铁血红蛋白依赖性硫化物氧化的机制，并评估其在生理相关浓度的 H2S 和高铁血红蛋白下对硫化物清除的贡献。我们的研究将解决诸如硫化物氧化途径如何连接等基本问题，阐明关键酶的反应机制（这些酶是调节 H2S 水平的潜在重要药物靶点），并评估人类血红蛋白在维持低血浆 H2S 浓度方面的新的且先前未探索的作用。