Hydrogen Sulfide Metabolism: From Mechanism to Application

硫化氢代谢：从机理到应用

• 批准号: 8560708
• 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/8560708
• 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(H_2S)是一小类气体生物信号分子中的最新成员，称为 气体变送器。硫化氢是唯一被酶代谢的气体递质。H_2S信号转导参与 许多细胞过程，并在心血管系统中扮演着特别重要的角色。尽管它的 多种维持生命的性质，硫化氢是一种Janus面的分子，在较高的温度下可以显示出毒性效应 浓度。例如，硫化氢线粒体新陈代谢的遗传缺陷是乙基丙二酸的原因。 脑病(EE)，一种毁灭性的，总是致命的婴儿期疾病，特征是极高的 (有毒)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，证明异常低血压与 硫化氢水平和心血管疾病。这个项目的长期目标是阐明 H_2S线粒体代谢的可能调节，将这一知识应用于治疗EE和其他 硫化氢代谢缺陷。硫化物：苯醌氧化还原酶(SQOR)是一种完整的膜蛋白，它催化 硫化氢代谢的第一个不可逆转的步骤，因此处于一个关键的潜在调节点。我们会澄清 该重要酶的催化机制及翻译后对其可能的调控 修改。Sqor产生的硫烷硫(S0)的生理受体的最新鉴定 反应需要对以前提出的硫化氢代谢途径进行重大修改。致信地址 当前知识中的重要空白，我们将在新的硫化氢模型中描述两种假定的酶的特征 代谢和评价细胞中每种酶的生物学功能。我们在硫化氢代谢方面的发现使 美国将设计治疗EE的新治疗策略，并建议硫化氢代谢缺陷如何干扰 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， 擅长线粒体疾病、药物化学、药物发现、细胞生物学和结构生物学。