Hydrogen Sulfide Metabolism: From Mechanism to Application

硫化氢代谢：从机理到应用

• 批准号: 8731959
• 负责人: MARILYN S JORNS
• 金额: $ 29.09万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731959
• 关键词: Acetylation; Address; Animal Model; Atherosclerosis; Binding; Biological; Biological Assay; Biological Process; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cell physiology; Cells; Cellular biology; Chemicals; Clinical; Clinical Data; Collaborations; Collection; Competence; Complex; Defect; Dioxygenases; Disease; Drug Targeting; Electrons; Encephalopathies; Enzymes; Exhibits; Family; Future; Genetic; Glutathione; Goals; Homeostasis; Human; Hydrogen Sulfide; Hypertension; Inhibitory Concentration 50; Inner mitochondrial membrane; Integral Membrane Protein; Kinetics; Knowledge; Lead; Libraries; Life; Link; Liver; Lysine; Mammals; Metabolism; Methodology; Mitochondria; Mitochondrial Diseases; Modeling; Mutation; NAD(P)H dehydrogenase (quinone) 1, human; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Chemistry; Physiological; Physiological Processes; Play; Post-Translational Protein Processing; Property; Public Health; Reaction; Recombinants; Regulation; Role; Scientist; Signal Transduction; Signaling Molecule; Site; Structure; Structure-Activity Relationship; Sulfides; Sulfites; Sulfur; Techniques; Therapeutic; Toxic effect; Transferase; Ubiquinone; Ulcerative Colitis; United States; Volatile Fatty Acids; Work; base; data modeling; design; drug discovery; fatty acid metabolism; improved; in vivo; infancy; inhibitor/antagonist; leukemia; member; novel; novel therapeutics; oxidation; pharmacophore; scaffold; small molecule; structural biology; sulfite oxidase; tool

Hydrogen sulfide (H2S) is the newest member of a small family of gaseous, biological signaling molecules, termed gasotransmitters. H2S is the only gasotransmitter that is enzymatically metabolized. H2S signaling is involved in numerous cellular processes and plays an especially important role in the cardiovascular system. Despite its multiple life-supporting properties, H2S is a Janus-faced molecule that can exhibit toxic effects at higher concentrations. For example, a genetic defect in the mitochondrial metabolism of H2S is the cause of ethylmalonic encephalopathy (EE), a devastating, invariably fatal disorder of infancy that is characterized by extremely high (toxic) levels of the gasotransmitter and impaired metabolism of short-chain fatty acids. On the other hand, clinical data and animal model studies provide compelling evidence for a functional association between abnormally low levels of H2S and cardiovascular disease. The long-term goals of this project are to elucidate the pathways for and the possible regulation of the mitochondrial metabolism of H2S, to apply this knowledge to treat EE and other defects in H2S metabolism. Sulfide:quinone oxidoreductase (SQOR) is an integral membrane protein that catalyzes the first irreversible step in H2S metabolism and, as such, sits at a key potential regulatory point. We will elucidate the catalytic mechanism of this important enzyme and investigate its possible regulation by posttranslational modification. Our recent identification of the physiological acceptor of the sulfane sulfur (S0) produced in the SQOR reaction has necessitated a major revision of previously proposed pathways for H2S metabolism. To address important gaps in the current knowledge, we will characterize two postulated enzymes in the new model for H2S metabolism and evaluate the biological function of each enzyme in cells. Our discoveries in H2S metabolism allow us to design novel therapeutic strategies to treat EE and also suggest how a defect in H2S metabolism can interfere with fatty acid metabolism. This work will be conducted in close collaboration with basic and clinical scientists with expertise in mitochondrial disease, medicinal chemistry, drug discovery, cell biology, and structural biology.

硫化氢（H2S）是一个称为气态，生物信号分子的小家族的最新成员 燃气递质。 H2S是唯一酶代谢的杀高质递质。 H2S信号涉及 许多细胞过程和在心血管系统中起着特别重要的作用。尽管有它 H2S是多个生命支持的特性 浓度。例如，H2S的线粒体代谢中的遗传缺陷是乙基元素的原因 脑病（EE）是一种毁灭性的致命疾病，其特征是极高的特征 （有毒）焦虑剂的水平和短链脂肪酸的代谢受损。另一方面，临床 数据和动物模型研究为异常低较低的功能关联提供了令人信服的证据 H2S和心血管疾病的水平。该项目的长期目标是阐明和 H2S线粒体代谢的可能调节，以应用此知识来治疗EE和其他 H2S代谢缺陷。硫化物：喹酮氧化还原酶（SQOR）是一种催化催化的整体膜蛋白 H2S代谢，因此，第一个不可逆转的步骤是关键的潜在调节点。我们将阐明 这种重要酶的催化机制，并通过翻译后研究其可能的调节 修改。我们最近对SQOR中产生的硫硫硫（S0）生理受体的鉴定 反应需要对先前提出的H2S代谢途径进行重大修订。解决 当前知识中的重要差距，我们将在H2S的新模型中表征两个假定的酶 代谢并评估细胞中每种酶的生物学功能。我们在H2S代谢中的发现允许 我们设计新颖的治疗策略来治疗EE，并暗示H2S代谢中的缺陷如何干扰 脂肪酸代谢。这项工作将与基本和临床科学家密切合作与 线粒体疾病，药物化学，药物发现，细胞生物学和结构生物学方面的专业知识。