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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）是一种信号分子，具有深远的生理作用，是哺乳动物硫代谢的产物，合成速率相对较高。由于H2S是剧毒的，细胞通过一个有效的氧化途径来避免H2S的积累，这个氧化途径位于线粒体中，并与产生能量的电子传递链相结合。其组成蛋白包括硫化物-醌氧化还原酶（SQR）、过硫双加氧酶（ETHE1）和罗丹斯酶，以及在该途径的最后一步催化亚硫酸盐转化为硫酸盐的亚硫酸盐氧化酶。在