Enzymology of H2S Biogenesis

H2S 生物发生的酶学

• 批准号: 9064808
• 负责人: RUMA V BANERJEE
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064808
• 关键词: Address; Affect; Amino Acids; Anabolism; Androgens; Biochemistry; Biogenesis; Biology; Cardiovascular system; Catabolism; Cell Cycle; Cell Cycle Progression; Chemicals; Clinical; Communication; Cystathionine; Cysteine; Cysteine Desulfhydrase; Defect; Endocrine; Enzymatic Biochemistry; Enzymes; Exhibits; Fluorescence; Gases; Generations; Genitourinary system; Glutathione; Goals; Health; Heme; Homeostasis; Homocysteine; Homocystine; Homocystinuria; Human; Hydrogen Sulfide; Immune; In Vitro; Inherited; Investigation; Kinetics; Lead; Malignant neoplasm of prostate; Mammals; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mutagenesis; Mutation; Neural Tube Defects; Neuraxis; Neurodegenerative Disorders; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Physiological; Process; Production; Proteins; Pyridoxal Phosphate; Raman Spectrum Analysis; Rare Diseases; Reaction; Reducing Agents; Regulation; Research; Role; S-Adenosylmethionine; Signal Transduction; Signaling Molecule; Site; Spectrum Analysis; Stanolone; Structure; Substrate Specificity; Sulfur; Sulfur Metabolism Pathway; System; Testosterone; Therapeutic; Triad Acrylic Resin; base; cardiovascular risk factor; cell type; cofactor; gastrointestinal; high throughput screening; in vivo; inhibitor/antagonist; insight; interest; mercaptolactate-cysteine disulfiduria; neuroregulation; novel; operation; persulfides; prostate cancer cell line; response; screening; small molecule; small molecule libraries; sulfurtransferase

DESCRIPTION (provided by applicant): The discovery that endogenously produced H2S is a signaling molecule that mediates varied physiological effects in mammals ranging from neuromodulatory to cardioprotective, has spurred enormous recent interest in understanding its biology and in exploiting its pharmacological potential. Enzymes involved in sulfur metabolism catalyze the biogenesis of H2S and include: cystathionine -synthase (CBS), - cystathionase (CSE) and mercaptopyruvate sulfurtransferase (MST). However, despite the rising interest in H2S biochemistry, fundamental questions remain regarding regulation of its production, its mechanism of action and its destruction. In this study, we propose to address significant gaps in our understanding of the reaction mechanisms and regulation of H2S production by addressing the following specific aims. (i) Structure- function studies on H2S biogenesis will focus on elucidating the reaction mechanisms of CBS, CSE and MST and conducting a high throughput screen using a small molecule library as a platform for in vitro and ex vivo screening of activators and/or inhibitors of CBS and CSE. (ii) Regulation of CBS, CSE and MST by redox, androgens and sumoylation will be investigated to determine how these parameters modulate H2S production, affect transsulfuration flux and localization of glutathione pools during the cell cycle. The impact of the proposed studies is both fundamental (i.e., gaining insights into the operation and regulation of H2S-generating enzymes) and translational (i.e., informing therapeutic options for circumventing metabolic blockades, screening for activators/inhibitors of H2S production and characterizing testosterone regulation of the transsulfuration pathway in androgen-responsive prostate cancer).

描述（由申请人提供）：发现内源性产生的 H2S 是一种信号分子，可介导哺乳动物中从神经调节到心脏保护等各种生理效应，这一发现激发了人们最近对了解其生物学和开发其药理学潜力的巨大兴趣。参与硫代谢的酶催化 H2S 的生物合成，包括：胱硫醚合酶 (CBS)、胱硫醚酶 (CSE) 和巯基丙酮酸硫转移酶 (MST)。然而，尽管人们对硫化氢生物化学的兴趣日益浓厚，但有关其产生、作用机制和破坏的调节的基本问题仍然存在。在这项研究中，我们建议通过解决以下具体目标来解决我们对硫化氢产生的反应机制和调节的理解方面的重大差距。 (i) H2S生物发生的结构-功能研究将重点阐明CBS、CSE和MST的反应机制，并使用小分子库作为体外和离体筛选CBS和CSE激活剂和/或抑制剂的平台进行高通量筛选。 (ii) 将研究氧化还原、雄激素和苏酰化对 CBS、CSE 和 MST 的调节，以确定这些参数如何调节 H2S 的产生、影响细胞周期中的转硫通量和谷胱甘肽库的定位。拟议研究的影响既是基础性的（即，深入了解 H2S 生成酶的操作和调节），又是转化性的（即，为规避代谢阻断提供治疗选择、筛选 H2S 生成的激活剂/抑制剂以及表征雄激素响应性前列腺癌中睾酮转硫途径的调节）。