Modeling the Organometallic Chemistry of Radical S-adenosylmethionine Enzymes

自由基 S-腺苷甲硫氨酸酶的有机金属化学建模

• 批准号: 10579212
• 负责人: Daniel Leif Migdow Suess
• 金额: $ 29.26万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579212
• 关键词: Active Sites; Address; Affect; Alkylation; Binding; Biological Assay; Biology; Catalysis; Chlorides; Complex; Coupling; Data; Disease; Electron Nuclear Double Resonance; Ensure; Enzymes; Equilibrium; Generations; Goals; Health; Human; Iron; Isotopes; Kinetics; Label; Life; Ligands; Ligation; Measures; Metabolism; Methionine; Modeling; Molecular; Mossbauer Spectroscopy; Nature; Organometallic Chemistry; Oxidation-Reduction; Pathway interactions; Physiologic pulse; Play; Preparation; Property; Reaction; Reagent; Research; Role; Route; S-Adenosylhomocysteine; S-Adenosylmethionine; Site; Solubility; Solvents; Spectrum Analysis; Structural Models; Structure; Study Subject; Sulfur; Techniques; Testing; Work; X-Ray Crystallography; alkyl group; carbene; carboxylate; carboxylation; chelation; design; electronic structure; geometric structure; inhibitor; insight; member; spectroscopic survey

Project Summary/Abstract Iron-sulfur enzymes perform some of the most challenging transformations in biology. Of these, [Fe4S4] enzymes are the most ubiquitous and catalyze dozens of known transformations (and likely many more) that play direct and indirect roles in human health and disease. This proposal concerns the mechanisms of the > 100,000 members of the radical S-adenosyl-L-methionine (SAM) superfamily of enzymes. Understanding their reaction mechanisms on a molecular level is critical for identifying disease targets and designing mechanism- based inhibitors. An emerging theme in mechanistic studies of these enzymes is the intermediacy of species containing Fe–alkyl bonds whereby generation of the reactive 5’-deoxyadenosyl radical may proceed by homolytic Fe–C bond cleavage. However, the exact electronic and geometric structure of this intermediate, its function in catalysis, the strength of its Fe–C bond, and the mechanisms by which these steps might occur are not clear, and there is no precedent in synthetic Fe–S clusters for this structure type or reactivity. We therefore propose to address these questions using structurally and functionally faithful synthetic [Fe4S4]–alkyl complexes. We will prepare [Fe4S4]–alkyl complexes with rationally tunable properties and formulate and test hypotheses concerning the geometric and electronic structure requirements for achieving Fe–C bond homolysis. These requirements will be elucidated through systematic kinetic and spectroscopic studies. Overall, this work will reveal the role of organometallic chemistry in catalysis by radical SAM enzymes and yield insights into how Nature utilizes reactive Fe–C bonds in human health and disease.

项目摘要/摘要 铁硫酶在生物学中执行一些最挑战的转化。其中，[Fe4s4] 酶是最普遍和最催化的数十种已知转换（可能是更多） 在人类健康和疾病中发挥直接和间接作用。该提议涉及>的机制 酶的100,000个自由基S-腺苷-l-甲硫代（SAM）超家族成员。了解他们 分子水平上的反应机制对于鉴定疾病靶标和设计机制至关重要 - 基于抑制剂。这些酶的机械研究中的一个新兴主题是物种的中间体 包含Fe-烷基键，从而产生反应性的5'-脱氧丁糖基自由基可以通过 同型Fe – c键裂解。但是，该中间体的确切电子和几何结构 在催化中的功能，其Fe -C键的强度以及可能发生这些步骤的机制 尚不清楚，对于这种结构类型或反应性，合成Fe -S簇中没有先例。因此，我们 提议使用结构和功能忠实的合成[FE4S4] - 烷基解决这些问题 复合物。我们将准备具有合理可调特性的[FE4S4] - 烷基复合物并进行配方和测试 关于实现Fe – C键的几何和电子结构要求的假设 同型。这些要求将通过系统的动力学和光谱研究来阐明。 总体而言，这项工作将揭示有机化学在根治性SAM酶催化和 对大自然如何利用人类健康和疾病中的反应性Fe -C键产生见解。