Heme and Protein Radical-Mediated Remote Enzyme Catalysis

血红素和蛋白质自由基介导的远程酶催化

• 批准号: 8761645
• 负责人: Aimin Liu
• 金额: $ 26.64万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761645
• 关键词: Aging; Anabolism; Biochemical Reaction; Biogenesis; Biological Process; Catalysis; Cellular Structures; Chemicals; Chemistry; Comprehension; Coupling; Disease; Electronics; Electrons; Enzymatic Biochemistry; Enzymes; Event; Free Radicals; Generations; Heme; Hemeproteins; Hydrogen Peroxide; Hydroxylation; Iron; Lead; Life; Mediating; Metabolic; Mitochondrial Diseases; Modification; Molecular; Mono-S; Nature; Oxidants; Oxidation-Reduction; Oxidative Stress; Post-Translational Protein Processing; Process; Production; Protein Precursors; Proteins; Protons; Reaction; Reactive Oxygen Species; Research; Role; Specificity; Tryptophan; absorption; base; biological systems; cell injury; chemical property; cofactor; crosslink; follow-up; insight; methylamine dehydrogenase; novel; oxidation; oxidative damage; public health relevance

DESCRIPTION (provided by applicant): Heme and Protein Radical-Mediated Remote Enzyme Catalysis Project Description Understanding how an enzyme specifically oxidizes a protein substrate that is much larger than the enzyme itself will illuminate the mechanism by which proteins mature through enzyme-mediated posttranslational modifications. Given the interconnectedness of protein posttranslational modification, metabolic chemistry, and diseases, the question of how enzymes preserve specificity for large protein substrates is fundamental to enzymology. We are studying the long-range remote enzyme catalysis mechanism required for the biogenesis of a protein-derived tryptophan tryptophylquinone (TTQ) cofactor. TTQ is the catalytic center of methylamine dehydrogenase. This proposal seeks to determine the chemical properties of two reactive intermediates, an unprecedented bis-FeIV state of a di-heme enzyme MauG and a novel tryptophan-based di-radical in the substrate protein preMADH. Both are critical catalytic intermediates that occur sequentially in the catalytic cycle of TTQ biogenesis. Characterization of these key intermediates will lead to comprehension of the TTQ biogenesis mechanism, which in turn will provide insight into long-range enzyme-mediated remote oxidative and oxygenation chemical modification strategies. These studies will begin with examining the nature of the electronic interactions between the two hemes and the chemical reactivity, stability, and spectroscopic signature of the high-valent bis-FeIV state of MauG. Then, we will follow up with spectroscopic, structural, and theoretical characterizations of the tryptophan-based di-radical intermediate in the substrate protein to elucidate the coupling nature of the di-radical species and the proton release mechanism necessary for cross-linking and subsequent oxidation reactions.

描述（由申请人提供）：血红素和蛋白质自由基介导的远程酶催化项目描述了解酶如何特异性氧化比酶本身大得多的蛋白质底物将阐明蛋白质通过酶介导的翻译后修饰成熟的机制。鉴于蛋白质翻译后修饰、代谢化学和疾病的相互关联性，酶如何保持对大蛋白质底物的特异性的问题是酶学的基础。我们正在研究蛋白质衍生的色氨酸色氨酸醌 (TTQ) 辅因子的生物合成所需的长程远程酶催化机制。 TTQ是甲胺脱氢酶的催化中心。该提案旨在确定两种反应中间体的化学性质，即二血红素酶 MauG 前所未有的双 FeIV 状态和底物蛋白 preMADH 中的新型色氨酸双自由基。两者都是关键的催化中间体，在 TTQ 生物发生的催化循环中依次发生。这些关键中间体的表征将有助于理解 TTQ 生物发生机制，进而深入了解长程酶介导的远程氧化和氧合化学修饰策略。这些研究将从检查两种血红素之间电子相互作用的性质以及 MauG 高价双 FeIV 态的化学反应性、稳定性和光谱特征开始。然后，我们将跟踪底物蛋白中基于色氨酸的双自由基中间体的光谱、结构和理论表征，以阐明双自由基物种的偶联性质以及交联和后续反应所需的质子释放机制。氧化反应。