Reactivity of Manganese and Iron Metalloenzyme Models

锰和铁金属酶模型的反应性

• 批准号: 8852634
• 负责人: David P Goldberg
• 金额: $ 29.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852634
• 关键词: Active Sites; Address; Benchmarking; Biological; Biological Process; Biomimetics; Cations; Chemistry; Complex; Contracts; Cytochrome P450; Cytochromes; Dioxygen; Disease; Distal; Electron Transport; Electronics; Enzymes; Event; Goals; Health; Heme; Hydrogen; Hydrogen Bonding; Hydrogen Peroxide; Investigation; Iron; Kinetics; Knowledge; Life; Ligands; Manganese; Measurement; Metals; Methods; Modeling; Nature; Nitric Oxide Synthase; Oxidases; Oxidation-Reduction; Oxygen; Oxygenases; Peroxidases; Play; Porphyrins; Process; Property; Reaction; Reporting; Research; Roentgen Rays; Role; Site; Spectrum Analysis; Structure; System; Techniques; Testing; Work; absorption; adduct; alkalinity; analog; biological systems; catalase; cold temperature; corrole; density; design; electronic structure; insight; interest; metalloenzyme; novel; novel diagnostics; novel therapeutics; oxidation; small molecule; theories

DESCRIPTION (provided by applicant): The goal of the proposed research is to investigate the reactivity of manganese and iron complexes as models of heme metalloenzymes that utilize dioxygen. Heme enzymes such as cytochrome P450, peroxidases, catalases, heme oxygenase, nitric oxide synthase and cytochrome C oxidase all rely upon Mn or Fe active sites to perform an impressive range of critical biological functions involving O2 or its derivatives. Although the functions of these enzymes are highly diverse, there are some mechanistic commonalities involving key intermediates that bring these systems together. These key intermediates involve high-valent metal-oxo (M=O) and metal-(hydro)peroxo (M-OO(H)) species. Understanding the reactivity and spectroscopic features of these species is critically important, yet many questions remain about these species in part because of challenges associated with studying what are unstable and often short-lived intermediates. We will address fundamental questions regarding high-valent M=O species and their precursors, M-OO(H), through a synthetic analog approach. We will utilize ligands known as corrolazines (Czs) and corroles (Cors) to carry out this research. These ligands are designed to stabilize high oxidation states (e.g. MVO). They also support lower-valent complexes such as MIII and MIV, which will be used to study O-O cleavage events. Aims of this proposal are 1) to synthesize novel high-valent (Cz)M(O) and (Cor)M(O) complexes, determine their structural and spectroscopic properties, and examine their reactivity in biologically relevant transformations and 2) to determine the reactivity of (Cz)M and (Cor)M toward O-O cleavage/O2 activation. Synthetic methods, including ligand design and coordination chemistry, will be used to construct new model complexes of interest. We will correlate the structural and electronic properties of the (Cz)M and (Cor)M (M = Mn, Fe) complexes with reactivity in reactions of direct biological relevance (e.g. hydrogen-atom-transfer (HAT), oxygen-atom-transfer (OAT), and electron-transfer (ET) processes). Reactivity and mechanism will be studied through analysis of products and kinetic measurements with a range of HAT substrates containing C-H and O-H bonds, O-atom acceptor substrates, and ET agents. Comparison of our Mn and Fe chemistry should yield insights regarding why Nature chooses Fe or Mn to perform specific functions. Fundamental information regarding the mechanisms of biomimetic HAT, OAT, ET and related reactions will be obtained.

描述（由申请人提供）：拟议的研究的目的是研究锰和铁配合物作为利用二恶英的血红素金属酶的模型。血红素酶，例如细胞色素P450，过氧化物酶，过氧化酶，血红素加氧酶，一氧化氮合酶和细胞色素C氧化酶都依赖于MN或Fe活性位点，以执行涉及O2或其衍生物的令人印象深刻的关键生物学功能。尽管这些酶的功能高度多样化，但仍有一些机械性共同点涉及将这些系统融合在一起的关键中间体。这些关键中间体涉及高价值金属氧（M = O）和金属（Hydro）Peroxo（M-OO（H））物种。了解这些物种的反应性和光谱特征至关重要，但是关于这些物种的许多问题部分是由于与研究不稳定和通常短暂的中间体有关的挑战。我们将通过合成的模拟方法解决有关高价值M = O物种及其前体M-OO（H）的基本问题。我们将利用称为Corrolazines（CZS）和Corroles（CORS）的配体进行这项研究。这些配体旨在稳定高氧化态（例如MVO）。它们还支持诸如MIII和MIV之类的低价配合物，这些复合物将用于研究O-O裂解事件。该提案的目的是1）合成新型的高价值（CZ）M（O）和（COR）M（O）复合物，确定它们的结构和光谱特性，并检查其在生物学上相关的转换中的反应性，以及2）以确定（CZ）M和（COR）M和（COR）M对O-O-O-O-O-O cleavage/O2 cleavage/O2 cleavage/o2的反应性。包括配体设计和配位化学在内的合成方法将用于构建新的感兴趣模型复合物。我们将将（Cz）M和（COR）M（M = MN，Fe）复合物的结构和电子性质与直接生物学相关性的反应（例如氢Atom-Transfer（HAT），氧气-ATOM-ATOM-TRANSFER（OAT）和电子转移（ETRON-TRANSFER（ET）过程）相关联。将通过分析包含C-H和O-H键，O-ATOM受体底物和ET代理的HAT底物的产品和动力学测量来研究反应性和机制。我们的MN和FE化学的比较应就为什么自然选择FE或MN执行特定功能的洞察力。将获得有关仿生帽，燕麦，ET和相关反应机制的基本信息。