Reactivity of Manganese and Iron Metalloenzyme Models

锰和铁金属酶模型的反应性

• 批准号: 9402926
• 负责人: David P Goldberg
• 金额: $ 29.34万
• 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/9402926
• 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; Light; Manganese; Measures; Metals; Methods; Modeling; Mono-S; 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.

该提议着重于过渡金属卟啉素络合物的合成和反应性 旨在模拟血红素酶中结构和功能的关键方面。血红素酶的一部分反应 与O2和/或相关的小分子H2O2和O2-，包括细胞色素P450（CYP），双加氧酶 例如色氨酸二加氧酶或吲哚胺二氧酶，过氧化物酶，例如氯仿酶和 虽然髓过氧化物酶，芳族过氧酶，过氧酶，血红素氧酶和细胞色素C氧化酶。 这些酶执行了一系列关键功能的潜水员，它们提出的作用机理已有 多个共同中间体。这些中间体包括高价值的金属氧和金属 - 羟基 物种，例如feiv（o）（卟啉 - 自由基）（化合物-I）和Feiv（OH）（卟啉）（质子化） CYP中鉴定出的化合物II以及金属二氧化物（例如FeIII（Superoxo）（卟啉））。 控制这些物种的产生，稳定性和反应性的因素在许多人中仍然对 案例，提出这些物种发挥关键作用的总体作用机制也是如此。 拟议的努力集中于开发M = O，M-OH和M-O2中间体的合成卟啉类似物， 并研究其在H原子转移（HAT），质子耦合电子转移（PCET），O-AMOM中的反应性 转移（燕麦）和反弹过程。具有C-H键和O2作为氧化剂的底物的催化氧化 它们的类似物还将提供所需的光谱基准（RR，Mössbauer， EPR，XAS），以与相关生物物种进行比较和鉴定。新系列的FE和 Mn卟啉复合物将与Corrol（CRL）和Corrolazine（CZ）配体合成。这些 卟啉化合物通过卟啉核的环收缩来改变，并设计为 稳定金属氧种类，例如高价值M = O和M-OH复合物。在上一期 我们的小组表明，CZ支架产生了新的M = O和M-OH复合物的生物学相关性，并且 这些系统的研究导致有关氧化状态，旋转状态，协调的影响的发现 环境以及对HAT，PCET和OAT反应性的近端和明显影响。新的科罗尔和科罗拉嗪 该提案将准备复合物，该提案旨在解决两个主要目标1）答案 与血红素酶结构，功能和机制有关的基本问题以及2） 关于设计和设计的基本知识 新催化剂的合成。血红素酶对各种疾病状态至关重要。新的 关于这些系统的作用机理的知识应有助于开发 针对这些酶的新型热和/或诊断策略。