Reactivity of Manganese and Iron Metalloenzyme Models

锰和铁金属酶模型的反应性

• 批准号: 9068158
• 负责人: David P Goldberg
• 金额: $ 29.33万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068158
• 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）：拟议研究的目标是研究锰和铁络合物作为利用双氧的血红素金属酶模型的反应性。血红素酶，如细胞色素 P450、过氧化物酶、过氧化氢酶、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 活性位点来执行涉及 O2 或其衍生物的一系列令人印象深刻的关键生物功能。尽管这些酶的功能高度多样化，但存在一些机制上的共性，涉及将这些系统结合在一起的关键中间体。这些关键中间体涉及高价金属-氧代 (M=O) 和金属-(氢)过氧代 (M-OO(H)) 物质。了解这些物种的反应性和光谱特征至关重要，但有关这些物种的许多问题仍然存在，部分原因是研究不稳定且通常寿命较短的中间体存在挑战。我们将通过合成模拟方法解决有关高价 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) 的配体来进行这项研究。这些配体旨在稳定高氧化态（例如 MVO）。它们还支持较低价的复合物，例如 MIII 和 MIV，这些复合物将用于研究 O-O 裂解事件。该提案的目的是 1) 合成新型高价 (Cz)M(O) 和 (Cor)M(O) 配合物，确定其结构和光谱特性，并检查其在生物学相关转化中的反应性，2) 确定(Cz)M 和 (Cor)M 对 O-O 裂解/O2 活化的反应性。合成方法，包括配体设计和配位化学，将用于构建感兴趣的新模型复合物。我们将把 (Cz)M 和 (Cor)M (M = Mn, Fe) 配合物的结构和电子性质与直接生物相关反应（例如氢原子转移 (HAT)、氧原子转移）的反应性联系起来。转移（OAT）和电子转移（ET）过程）。将通过对一系列含有 C-H 和 O-H 键的 HAT 底物、O 原子受体底物和 ET 试剂进行产物分析和动力学测量来研究反应性和机理。通过比较锰和铁的化学性质，应该可以了解为什么大自然选择铁或锰来执行特定功能。将获得有关仿生 HAT、OAT、ET 和相关反应机制的基本信息。