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）是气体生物信号分子小家族的最新成员，称为 气体变送器H2S是唯一被酶促代谢的气体递质。H2S信号传导参与了 许多细胞过程，并在心血管系统中发挥特别重要的作用。尽管 H2S具有多种生命支持特性，是一种两面神分子，在较高温度下可表现出毒性作用。 浓度的例如，H2S的线粒体代谢中的遗传缺陷是乙基丙二酸 脑病（EE），一种毁灭性的，总是致命的婴儿期疾病，其特征是极高的 （毒性）气体递质水平和短链脂肪酸代谢受损。另一方面，临床 数据和动物模型研究提供了令人信服的证据，表明异常低血糖和高脂血症之间存在功能性关联。 H2S水平与心血管疾病该项目的长期目标是阐明 H2S的线粒体代谢的可能调节，应用这些知识来治疗EE和其他疾病。 H2S代谢缺陷。硫化物：醌氧化还原酶（SQOR）是一种完整的膜蛋白，催化 H2S代谢的第一个不可逆步骤，因此，它位于关键的潜在调节点。我们将阐明 该酶催化机制，并探讨其可能的翻译后调节 改性我们最近鉴定了SQOR中产生的硫烷硫（S0）的生理受体 反应需要对先前提出的H2S代谢途径进行重大修订。解决 在目前的知识的重要差距，我们将描述两个假设的酶在新的模型H2S 代谢，并评估每种酶在细胞中的生物学功能。我们在硫化氢代谢方面的发现 我们设计新的治疗策略来治疗EE，并提出H2S代谢缺陷如何干扰EE 与脂肪酸代谢有关。这项工作将与基础和临床科学家密切合作进行， 在线粒体疾病、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。