Reactivity of Manganese and Iron Metalloenzyme Models

锰和铁金属酶模型的反应性

• 批准号: 9766308
• 负责人: David P Goldberg
• 金额: $ 29.29万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766308
• 关键词: Acidity; Acids; Active Sites; Address; Benchmarking; Biological; Catalysis; Cations; Cell Nucleus; Chloride Peroxidase; Cleaved cell; Complex; Contracts; Coupled; Cytochrome P450; Data; Dependence; Development; Diagnostic; Dioxygen; Dioxygenases; Disease; Distal; Electron Transport; Environment; Enzymes; Event; Family; Funding; Generations; Goals; Heme; Hydrogen Bonding; Hydrogen Peroxide; Hydroxides; Iron; Isotopes; Kinetics; Knowledge; Life; Ligands; Manganese; Measures; Metals; Methods; Modeling; Oxidants; Oxidation-Reduction; Oxygen; Oxygenases; Pathway interactions; Peroxidases; Phenols; Play; Porphyrins; Process; Property; Protons; Reaction; Research; Series; Structure; System; Temperature; Therapeutic; Transition Elements; Tryptophan; X-Ray Crystallography; adduct; analog; catalase; catalyst; corrole; cytochrome c oxidase; design; driving force; electronic structure; enzyme structure; improved; indoleamine; knowledge base; metalloenzyme; novel; novel therapeutics; oxidation; scaffold; small molecule; success; tautomer

This proposal focuses on the synthesis and reactivity of transition metal porphyrinoid complexes that are designed to model key aspects of structure and function in heme enzymes. A subset of heme enzymes react with O2 and/or the related small molecules H2O2 and O2-, including Cytochrome P450 (CYP), dioxygenases such as tryptophan dioxygenase or indoleamine dioxygenase, peroxidases such as chloroperoxidase and myeloperoxidase, aromatic peroxygenase, catalases, heme oxygenases, and cytochrome c oxidase. Although these enzymes carry out a diverse array of critical functions, their proposed mechanisms of action have multiple intermediates in common. These intermediates include high-valent metal-oxo and metal-hydroxo species, such as FeIV(O)(porphyrin-radical-cation) (Compound-I) and FeIV(OH)(porphyrin) (protonated Compound-II) identified in CYP, as well as metal-dioxygen species such as FeIII(superoxo)(porphyrin). The factors that control the generation, stability, and reactivity of these species remains poorly understood in many cases, as do the overall mechanisms of action in which these species are proposed to play key roles. The proposed efforts focus on developing synthetic porphyrinoid analogs of M=O, M-OH, and M-O2 intermediates, and studying their reactivity in H-atom transfer (HAT), proton-coupled electron-transfer (PCET), O-atom transfer (OAT), and rebound processes. Catalytic oxidations of substrates with C-H bonds and O2 as oxidant will also be investigated. These analogs will also provide needed spectroscopic benchmarks (rR, Mössbauer, EPR, XAS) for comparison with, and identification of, the relevant biological species. A new series of Fe and Mn porphyrinoid complexes will be synthesized with corrole (Crl) and corrolazine (Cz) ligands. These porphyrinoid compounds are modified by ring contraction of the porphyrin nucleus, and are designed to stabilize metal-oxygen species such as high-valent M=O and M-OH complexes. In the previous funding period our group has shown that the Cz scaffold yields new M=O and M-OH complexes of biological relevance, and the study of these systems led to discoveries regarding the influence of oxidation state, spin state, coordination environment, and proximal and distal effects on HAT, PCET, and OAT reactivity. New corrole and corrolazine complexes will be prepared in this proposal that are designed to address two main goals 1) answer fundamental questions related to heme enzyme structure, function and mechanism and 2) gain fundamental knowledge regarding transition metal porphyrinoid complexes for the design and synthesis of new catalysts. Heme enzymes are of central importance to a range of disease states. The new knowledge to be gained regarding the mechanisms of action of these systems should help in the development of novel therapeutic and/or diagnostic strategies that target these enzymes.

该提案的重点是过渡金属卟啉配合物的合成和反应性，这些配合物是 旨在模拟血红素酶反应的结构和功能的关键方面。 与 O2 和/或相关小分子 H2O2 和 O2-，包括细胞色素 P450 (CYP)、双加氧酶 例如色氨酸双加氧酶或吲哚胺双加氧酶，过氧化物酶例如氯过氧化物酶和 髓过氧化物酶、芳香族过氧化酶、过氧化氢酶、血红素加氧酶和细胞色素c氧化酶。 这些酶执行多种关键功能，其拟议的作用机制已 多种中间体的共同点包括高价金属-氧代和金属-羟基。 种，例如 FeIV(O)（卟啉自由基阳离子）（化合物 I）和 FeIV(OH)（卟啉）（质子化 在 CYP 中鉴定出化合物-II)，以及金属双氧物质，例如 FeIII(超氧)(卟啉)。 许多人对控制这些物种的产生、稳定性和反应性的因素仍然知之甚少。 案例，以及建议这些物种发挥关键作用的总体作用机制。 建议重点开发 M=O、M-OH 和 M-O2 中间体的合成卟啉类似物， 并研究它们在氢原子转移（HAT）、质子耦合电子转移（PCET）、O原子中的反应性 以 C-H 键和 O2 作为氧化剂的底物的转移（OAT）和反弹过程。 这些类似物也将提供所需的光谱基准（rR、Mössbauer、 EPR、XAS），用于与相关生物物种进行比较和鉴定 一系列新的铁和元素。 锰卟啉配合物将与可咯 (Crl) 和可咯嗪 (Cz) 配体合成。 类卟啉化合物通过卟啉核的环收缩进行修饰，旨在 稳定金属氧物质，例如高价 M=O 和 M-OH 配合物。 我们的小组已经证明 Cz 支架产生具有生物相关性的新 M=O 和 M-OH 复合物，并且 对这些系统的研究导致了关于氧化态、自旋态、配位影响的发现 环境以及对 HAT、PCET 和 OAT 反应性的近端和远端影响。 本提案中将准备复合体，旨在实现两个主要目标 1) 答案 与血红素酶结构、功能和机制相关的基本问题以及 2) 增益 有关过渡金属卟啉配合物设计和制备的基础知识 新催化剂的合成对于一系列疾病状态至关重要。 获得有关这些系统的作用机制的知识应该有助于开发 针对这些酶的新型治疗和/或诊断策略。