HYDROGEN ATOM TRANSFER REACTIONS OF METALLOENZYMES

金属酶的氢原子转移反应

• 批准号: 2188265
• 负责人: JAMES M MAYER
• 金额: $ 12.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 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 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2188265
• 关键词: X ray crystallography; active sites; chemical transfer reaction; enzyme activity; gas chromatography; heavy metals; hydrocarbons; hydrogen; imines; metal complex; metalloenzyme; nuclear magnetic resonance spectroscopy; oxidation reduction reaction; oximes

The study of metalloenzymes that oxidize C-H bonds is hampered by a lack of understanding of how transition metal centers oxidize organic substrates. The goal of this work is to provide new mechanistic paradigms for such reactions. A particular focus will be oxidation by hydrogen atom abstraction, which has been implicated as the key substrate-activating step for a number of important metalloenzymes, including cytochrome P-450, lipoxygenase, and dopamine Beta-hydroxylase. Hydrogen atom abstraction also appears to be a key step in C-H bond oxidation by permanganate and other reagents used in organic chemistry, and is involved in industrially important hydrocarbon oxidations. The current picture of these reactions is that there must be a radical at the active site -- such as an oxo-iron group with radical character at the oxygen as suggested for cytochrome P-450 and bleomycin. We propose a new approach to these reactions, based on the affinity of the active site for a hydrogen atom, in other words the O-H bond strength formed. The very extensive literature on hydrogen atom abstraction reactions is dominated by such discussions of bond strengths, not radical character. The affinity of an active site or reagent for a hydrogen atom can be calculated from its redox potential and pKa, adapting a procedure that is well developed for organic and organometallic compounds. Preliminary studies of oxidations by chromyl chloride and permanganate suggest that this perspective is not only qualitative, providing an explanation for why and how reactions occur, but also quantitative: the rate of hydrogen atom abstraction by CrO2Cl2 or MnO4- can be roughly predicted based on the strength of the O-H bond formed. This prediction is based on the Polanyi relation between the rate of radical reactions and their driving force, a simple treatment that is related to the Marcus theory of electron transfer rates. Further studies of chromium (VI) and permanganate oxidations are proposed to test this hypothesis. Related reactions that occur by initial hydride transfer will also be explored. We predict that a variety of coordination complexes should also be able to oxidize C-H bonds, and studies of copper, iron, nickel, manganese, and ruthenium compounds are described. We will begin with known copper(III) and iron(III) coordination complexes, which should be excellent functional models for the C-H activation step in dopamine Beta- hydroxylase and lipoxygenase. Preliminary results suggest that a copper(III) imine-oxime complex does oxidize substrates by hydrogen atom transfer. Confirmation of our hypothesis will facilitate preparation of better models for these oxidases, and will lead to better understanding and prediction of their selectivity.

氧化C-H键的金属酶的研究受到缺乏的阻碍 了解过渡金属中心如何氧化有机物 基材。 这项工作的目的是提供新的机械 此类反应的范例。 特定的重点将是氧化 氢原子抽象，已被视为钥匙 底物激活步骤，用于许多重要的金属酶， 包括细胞色素P-450，脂氧合酶和多巴胺β-羟化酶。 氢原子抽象似乎也是C-H键的关键步骤 锰酸盐和有机化学中使用的其他试剂的氧化， 并参与了工业上重要的烃氧化。 这 这些反应的当前图片是，必须有一个根本 主动部位 - 例如具有根本特征的氧铁群 如细胞色素P-450和博来霉素所建议的氧。 我们提出了一个新的 基于活动位点的亲和力对这些反应的方法 氢原子，换句话说，O-H键强度形成。 那是 关于氢原子抽象反应的广泛文献主导 通过对键强的讨论，而不是根本性的特征。 活性位点或试剂对氢原子的亲和力可以是 根据其氧化还原电位和PKA计算，适应一个程序 针对有机和有机金属化合物开发了。 初步的 氯化铬铁和高锰酸盐氧化的研究表明 这种观点不仅是定性的，还提供了解释 为什么以及如何发生反应，但也定量：氢的速率 可以根据CRO2CL2或MNO4-的原子抽象大致预测 O-H键的强度形成。 该预测基于 激进反应速度与其驾驶速度之间的波兰尼关系 力，一种与马库斯理论有关的简单处理 电子传输速率。 进一步研究铬（VI）和 提出了锰酸盐氧化以检验该假设。 有关的 还将探索初始氢化物转移发生的反应。 我们预测，各种协调络合物也应该能够 氧化C-H键，并研究铜，铁，镍，锰和 描述了芳族化合物。 我们将从已知的铜（III）开始 和铁（III）配位络合物，应该是极好的 多巴胺β-的C-H激活步骤的功能模型 羟化酶和脂氧酶。 初步结果表明 铜（iii）亚氨酸氧气复合物可通过氢原子氧化底物 转移。 确认我们的假设将有助于准备 这些氧化酶的更好模型，并将带来更好的理解 和预测其选择性。