Coupled Transfers of Electrons and Protons

电子和质子的耦合转移

• 批准号: 8725668
• 负责人: JAMES M MAYER
• 金额: $ 31.42万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725668
• 关键词: Acids; Active Sites; Address; Aerobic; Affect; Antioxidants; Area; Award; Biochemical; Biochemical Process; Biochemistry; Bioenergetics; Biological; Biological Models; Biological Process; Biology; Biomimetics; Catalysis; Cations; Chemicals; Chemistry; Chlorophyll; Clostridium perfringens epsilon toxin; Complex; Coupled; Coupling; Cytochrome P450; Cytochromes; Defect; Dependence; Disease; Distant; Electron Transport; Electron Transport Complex III; Electrons; Enzymes; Foundations; Goals; Heme Iron; Histidine; Hydrogen; Hydrogen Bonding; Hydroquinones; Hydroxide Ion; Hydroxides; Intuition; Iron; Kinetics; Knowledge; Lead; Light; Measures; Metabolism; Metalloproteins; Metals; Mitochondria; Modeling; Nitrogenase; One-Step dentin bonding system; Oxidases; Oxidation-Reduction; Oxidative Stress; Oxygenases; Pathway interactions; Peroxidases; Pharmaceutical Preparations; Phenols; Play; Porphyrins; Process; Property; Prostaglandin-Endoperoxide Synthase; Proton Pump; Protons; Reaction; Reactive Oxygen Species; Reagent; Research; Respiration; Respiratory Chain; Rest; Role; Ruthenium; Site; Sulfur; System; Testing; Travel; Tyrosine; Variant; Vitamin E; Work; abstracting; ascorbate; base; chemical reaction; cofactor; complex biological systems; cytochrome c oxidase; driving force; drug metabolism; enzyme mechanism; ferryl iron; heme a; hydroquinone; insight; metalloenzyme; oxidation; photosystem II; public health relevance; reaction rate; small molecule; theories

DESCRIPTION (provided by applicant): The proposed research will develop an accessible, intuitive, and quantitative under- standing of proton-coupled electron transfer (PCET) processes. The primary focus is on processes in which a proton and an electron transfer in a single kinetic step but go to or come from distinct, separated sites. These multiple-site concerted proton-electron transfer (MS-CPET) reactions are widespread across biology but are not well understood. They are key to bioenergetics, central to the catalytic cycles of numerous metalloenzymes, and are involved in the chemistry of reactive oxygen species. MS-CPET is important in metabolism and bioactivation of many drugs, and defects in MS-CPET processes can lead to disease, for instance malfunctioning of the Q-cycle in complex III of the electron transport chain in mitochondria. The proposed studies will examine a range of small molecule systems to develop the fundamentals of MS-CPET and to model specific biochemical processes. The systems to be examined include phenols, iron porphyrins, ruthenium complexes, and models for iron/sulfur cluster cofactors. The phenol studies, for instance, will shed light on the formation of tyrosyl radicals in enzymatic catalysis or under oxidative stress. Using a broad range of model systems will provide insights that can be confidently transferred to more complex biological systems. Studies under specific aim 1 will build an intuition about these processes, for instance testing our hypothesis that separation of the electron and proton often does not inhibit the rate of reaction. Systematic variation of the e-/H+ separation and other relevant parameters will help develop quantitative models of how each parameter affects the MS-CPET reactions (specific aim 2). These studies will provide tests of current theory, and will explore how to simplify these theories to capture the larger effects and to be more accessible to experimentalists. Specific aim 3 is to discover and understand the first examples of MS-CPET reactions involving C-H bonds, which could play an unappreciated role in biochemical processes. Together, the results from the different systems will build new intuition about MS-CPET and will provide the basis for new quantitative models. These will provide valuable understanding of a wide range of biological processes, and thus will be part of the foundation on which biomedical advances are built. The detailed knowledge available for electron transfer reactions has proven to be of great importance in biology. The work proposed aims to build a similarly valuable understanding for reactions that involve coupled transfers of electrons and protons.

描述（由申请人提供）：拟议的研究将开发出质子耦合电子传输（PCET）过程的可访问，直观和定量的理解。主要的重点是在单个动力学步骤中质子和电子传输的过程，但要转到或来自不同的分离位点。这些多地点协调的质子电子转移（MS-CPET）反应在生物学中广泛存在，但尚不清楚。它们是生物能学的关键，这是众多金属酶的催化循环的核心，并且参与了活性氧的化学。 MS-CPET在许多药物的代谢和生物活化中很重要，MS-CPET过程中的缺陷可能导致疾病，例如在线粒体电子传输链的复合物III中Q-Cycle的功能故障。拟议的研究将检查一系列小分子系统，以开发MS-CPET的基本原理并建模特定的生化过程。要检查的系统包括酚，铁卟啉，氟森复合物以及铁/硫簇辅因子的模型。例如，苯酚研究将阐明酪酶自由基在酶促催化或氧化应激下的形成。使用广泛的模型系统将提供可以自信地转移到更复杂的生物系统的见解。在特定目标1下的研究将建立有关这些过程的直觉，例如测试我们的假设，即电子和质子的分离通常不会抑制反应速率。 E-/H+分离和其他相关参数的系统变化将有助于开发每个参数如何影响MS-CPET反应的定量模型（特定目标2）。这些研究将提供当前理论的测试，并将探讨如何简化这些理论以捕获更大的影响并更容易被实验者使用。具体目的3是发现和理解涉及C-H键的MS-CPET反应的第一个例子，这些反应可能在生化过程中发挥了无可意识的作用。总之，不同系统的结果将建立有关MS-CPET的新直觉，并为新的定量模型提供基础。这些将为广泛的生物过程提供宝贵的理解，因此将成为建立生物医学进步的基础的一部分。事实证明，可用于电子传输反应的详细知识在生物学中非常重要。拟议的工作旨在为涉及电子和质子传输的反应建立类似的宝贵理解。