Synthetic Nonheme Iron O2 Activation and S-Oxygenation

合成非血红素铁 O2 活化和 S 氧化

• 批准号: 10671670
• 负责人: David P Goldberg
• 金额: $ 35.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671670
• 关键词: Active Sites; Address; Alzheimer' s Disease; Arthritis; Binding; Binding Sites; Biochemical; Biological; Biology; Carbon; Chemicals; Cobalt; Complement; Complex; Cysteine dioxygenase; Dioxygen; Dioxygenases; Disease; Electron Spin Resonance Spectroscopy; Electronics; Encephalopathies; Enzymes; Family; Future; Genetic Diseases; Goals; Health; Human; Hydroxides; Iron; Iron Compounds; Kinetics; Knowledge; Ligands; Ligation; Malignant Neoplasms; Measurement; Mediating; Methods; Modeling; Mononuclear; Neurodegenerative Disorders; Outcome; Oxidants; Oxygen; Oxygenases; Parkinson Disease; Pathway interactions; Penicillins; Process; Property; Proteins; Reaction; Research Personnel; Roentgen Rays; Series; Signal Transduction; Spectrum Analysis; Structure; Sulfhydryl Compounds; Sulfinic Acids; Sulfites; Sulfoxide; Sulfur; Synthesis Chemistry; System; Thermodynamics; Transition Elements; Variant; Work; absorption; analog; catalyst; cold temperature; computer studies; design; enzyme mechanism; insight; isopenicillin N; novel; oxidation; persulfides; scaffold; small molecule; spectroscopic data

Project Summary This proposal focuses on the fundamental structural, functional, and mechanistic requirements for the activation of O2 by nonheme iron complexes and related enzymes. Dioxygen is processed by nonheme iron centers in biology as part of a range of critical functions, including the mono- and di-oxygenation of organic substrates, as well as the formation of C-S and C-halide bonds. The oxygenation of organic substrates is mediated by nonheme iron oxygenases, and an important subclass of these enzymes oxygenate sulfur sites bound to the iron center. This subclass includes the thiol dioxygenases (TDOs), such as mammalian cysteine dioxygenase (CDO), and the persulfide dioxygenases (PDOs), such as mammalian ethylmalonic encephalopathy protein (ETHE1). The mechanisms of action of the TDOs and PDOs are poorly understood, although several common iron/oxygen intermediates have been proposed. The sulfoxide synthases EgtB and OvoA are related mononuclear, nonheme Fe enzymes that utilize O2 to carry out both S-oxygenation and C-S bond formation, as does isopenicillin N synthase (IPNS), which employs Fe and O2 in the biosynthetic pathway of penicillin. The C-S bond formation in IPNS occurs via selective carbon radical addition to a sulfur bound to Fe, a process similar to what occurs in nonheme Fe α-KG halogenases. A number of fundamental mechanistic questions remain unanswered regarding these enzymes. This proposal describes the synthesis and study of synthetic nonheme iron compounds designed to model certain aspects of structure and function related to the TDO/PDOs, sulfoxide synthases, IPNS, and the α-KG halogenases. Proposed efforts also include select studies on the enzyme CDO, which parallel and complement the model compounds. A focus of the proposal is to characterize reactive, Fe/O2-derived species that are analogs of key intermediates thought to be important in nonheme iron-mediated O2 activation. Characterization of these species in structurally well-defined synthetic complexes will provide precedent and support for the analogous, proposed intermediates in the enzymatic systems. The feasibility of proposed, key bond-making/bond-breaking steps will be established. Methods designed to trap and/or characterize Fe/O2 species will be used, including low temperatures and a suite of advanced spectroscopies (low-temperature UV- vis, electron paramagnetic resonance, resonance Raman, Mössbauer, X-ray absorption). Computational studies will be employed to help interpret and predict structural and spectroscopic properties as well as reaction pathways. The selective reactivity of carbon radicals with iron-heteroatom bonds will also be assessed, taking advantage of a unique set of new, structurally characterized ferric hydroxide complexes. These studies should lead to significant advances in our fundamental knowledge regarding how nonheme Fe enzymes activate O2 and selectively oxidize substrates. This knowledge should also provide guidance for the design of future transition metal catalysts. The misfunctioning of these enzymes have been implicated in a variety of diseases, including neurodegenerative disorders (Alzheimer's, Parkinson's), arthritis, cancer, and genetic disorders.

项目摘要 该建议重点介绍激活的基本结构，功能和机械要求 非血红素铁复合物和相关酶的O2。二恶英由非血红素铁中心处理 生物学是一系列关键功能的一部分，包括有机底物的单氧和二氧化 以及C-S和C-Halide键的形成。有机底物的氧合作用是由非血红素介导的 铁氧酶和这些酶的重要亚类结合到铁心中心。 该亚类包括硫醇二氧酶（TDOS），例如哺乳动物半胱氨酸二氧酶（CDO）和 硫化二加氧酶（PDOS），例如哺乳动物乙基元素脑病蛋白（ETHE1）。 尽管有几种常见的铁/氧 已经提出了中间体。亚氧化氧化物合酶EGTB和OVOA是相关的单核，非血红素 利用O2同时进行S-氧和C-S键形成的Fe酶，等霉素N 合成酶（IPN），在青霉素的生物合成途径中雇员Fe和O2。 C-S键形成 IPN通过选择性碳自由基加成与Fe结合的硫的根本性，该过程类似于发生的过程 非血红素Feα-KG卤代酶。关于许多基本的机理问题仍未得到解决 这些酶。该建议描述了合成非血红素铁化合物的合成和研究 旨在建模与TDO/PDOS，亚氧化氧化物合酶，IPN，， 和α-kg卤代酶。拟议的努力还包括有关酶CDO的精选研究，该研究并行 补充模型化合物。该提案的重点是表征反应性，Fe/O2衍生的物种 这是关键中间体的类似物，认为在非血红素铁介导的O2激活中很重要。 这些物种在结构明确定义的合成复合物中的表征将提供先例，并且 支持酶系统中类似的，提出的中间体。提出的关键的可行性 将建立建立债券/债券的步骤。旨在捕获和/或表征Fe/O2的方法 将使用物种，包括低温和一套晚期光谱（低温紫外线） 计算研究（VIS，电子顺磁共振，共振拉曼，莫斯鲍尔，X射线抽象）。 将被用来解释和预测结构和光谱特性以及反应 途径。还将评估碳自由基与铁原子键的选择性反应性 一组独特的新结构表征氢氧化铁配合物的优势。这些研究应该 在我们关于非血红素FE酶如何激活O2的基本知识方面取得了重大进步 和有选择的氧化物底物。这些知识还应该为未来的设计提供指导 过渡金属催化剂。这些酶的功能错误已在多种疾病中隐含 包括神经退行性疾病（阿尔茨海默氏症，帕金森氏症），关节炎，癌症和遗传疾病。