Nonheme Iron(III)-Superoxo Compounds: Preparation and Characterization of Molecul

非血红素铁 (III)-超氧化合物：分子的制备和表征

• 批准号: 7908178
• 负责人: Katherine Marie Van Heuvelen
• 金额: $ 4.56万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908178
• 关键词: Anabolism; Basta; Binding; Borates; Chemicals; Complement; Complex; Computational Technique; Dioxygen; Dioxygenases; Electronics; Enzymes; Fosfomycin; Freedom; Herbicides; Iron; Keto Acids; Ligands; Methodology; Modeling; Mononuclear; Oxidants; Oxygen; Penicillins; Pesticides; Preparation; Production; Property; Reaction; Reporting; Roentgen Rays; Spectrum Analysis; Structure; Techniques; Time; Work; absorption; chemical reaction; clorobiocin; complex biological systems; density; electronic structure; inositol oxygenase; insight; isopenicillin N; novel; phosphinothricin; public health relevance; theories

DESCRIPTION (provided by applicant): Crucial steps in the biosynthesis of clinically important antibiotics (penicillin, fosfomycin, and chlorobiocin) and pesticides (phosphinothricin, a component of the herbicides Basta and Liberty) involve the reaction of dioxygen with nonheme iron enzymes, including the mononuclear enzymes isopenicillin N synthase and hydroxyethylphosphonate dioxygenase and the diiron enzyme myo-inositol oxygenase. The catalytic cycles of these enzymes are thought to involve a highly reactive Fe(III)-superoxo intermediate that acts as an oxidant, though such a species has proven difficult to isolate and characterize. The preparation and characterization of synthetic compounds that mimic the structure (both geometric and electronic) of putative enzymatic intermediates can provide significant insight into complex biological systems. Herein is proposed a new methodology for the preparation and thorough characterization of novel mononuclear iron-superoxo compounds. Initial studies will focus on trapping the putative Fe(III)-superoxo species through the reaction of dioxygen with [TpFeIIX] (Tp = hydrotris(pyrazolyl)borate, X = a-keto acids, RC(O)CO2-, or alkoxides, RO-). The steric and electronic properties of both the Tp supporting ligand and of the cosubstrate X are readily tuned to prolong the lifetime of the Fe(III)-superoxo species. The relevant intermediate will be characterized by a variety of spectroscopic (electronic absorption, resonance Raman, Mossbauer, and X-ray absorption spectroscopies) and computational (density functional theory and time-dependent density functional theory) techniques in order to generate a complete, experimentally-validated electronic structure description. Subsequent reactivity studies will quantify the oxidizing power of the Fe(III)-superoxo species toward the bound cosubstrate X and toward external organic substrates. In addition, only two synthetic diiron-superoxo species have been reported, and the electronic structures of both compounds are poorly understood. Therefore, the diiron-superoxo compound formed upon reaction of [Fe2(u-OH)2(6-Me3- TPA)2](OTf)2 with dioxygen (Shan, X. and Que, L. Proc. Nat. Acad. Sci. 2005, 102, 5340) will be thoroughly characterized. The previously reported electronic absorption and resonance Raman spectroscopic studies will be complemented by Mossbauer, and X-ray absorption spectroscopies, as well as the computational techniques described above. Finally, the experimentally-validated electronic structure descriptions obtained for the mononuclear and dinuclear model compounds described above will be used to critically evaluate the proposed catalytic cycles that invoke Fe(III)-superoxo intermediates. PUBLIC HEALTH RELEVANCE: It is of critical importance to understand the fundamental chemical reactions that are necessary for the production of widely used antibiotics (penicillin, fosfomycin, and chlorobiocin) and pesticides (phosphinothricin, a component of the herbicides Basta and Liberty). The biosynthesis of each of these compounds relies on the interaction of oxygen with iron-containing enzymes in complex biological systems, and the relevant chemical details are poorly understood. In this work, we propose to prepare and thoroughly characterize synthetic complexes that model the structures and reactivities of these enzymes in order to gain insight into the biosynthesis of these clinically- and environmentally-significant compounds.

描述（由申请人提供）：临床上重要的抗生素（青霉素、磷霉素和氯生霉素）和杀虫剂（膦丝菌素，除草剂Basta和Liberty的组分）生物合成的关键步骤涉及分子氧与非血红素铁酶的反应，包括单核酶异青霉素N合酶和羟乙基膦酸酯双加氧酶以及双铁酶肌醇加氧酶。这些酶的催化循环被认为涉及作为氧化剂的高反应性Fe（III）-superoxo中间体，尽管这样的物种已被证明难以分离和表征。模拟推定的酶中间体的结构（几何和电子）的合成化合物的制备和表征可以为复杂的生物系统提供重要的见解。本文提出了一种新的单核铁超氧化合物的制备和彻底表征的方法。最初的研究将集中在通过分子氧与[TpFeIIX]（Tp =氢化三（吡唑基）硼酸盐，X = α-酮酸，RC（O）CO2-，或醇盐，RO-）的反应捕获推定的Fe（III）-超氧物种。TP支持配体和共基质X的空间和电子性质很容易调整，以延长寿命的Fe（III）-superoxo物种。相关中间体将通过各种光谱（电子吸收、共振拉曼、穆斯堡尔和X射线吸收光谱）和计算（密度泛函理论和含时密度泛函理论）技术进行表征，以生成完整的、经实验验证的电子结构描述。随后的反应性研究将量化的Fe（III）-superoxo物种的氧化能力对绑定cosubstrate X和对外部有机基板。此外，只有两个合成的二铁-超氧物种已被报道，这两种化合物的电子结构知之甚少。因此，在[Fe 2（u-OH）2（6-Me 3- TPA）2]（OTf）2与分子氧反应时形成的二铁-超氧化合物（Shan，X.和Que，L.美国国家科学院学报Sci. 2005，102，5340）将被彻底表征。以前报道的电子吸收和共振拉曼光谱研究将补充穆斯堡尔谱，X射线吸收光谱，以及上述的计算技术。最后，上述单核和双核模型化合物获得的实验验证的电子结构描述将用于严格评估所提出的催化循环，调用Fe（III）-superoxo中间体。 公共卫生相关性：了解生产广泛使用的抗生素（青霉素、磷霉素和氯霉素）和杀虫剂（草丁膦，除草剂Basta和Liberty的一种成分）所必需的基本化学反应至关重要。这些化合物的生物合成依赖于氧与含铁酶在复杂的生物系统中的相互作用，相关的化学细节知之甚少。在这项工作中，我们建议制备和彻底表征合成复合物，模拟这些酶的结构和反应性，以深入了解这些临床和环境重要化合物的生物合成。