Modeling the Organometallic Chemistry of Radical S-adenosylmethionine Enzymes

项目总结/摘要 铁硫酶在生物学中执行一些最具挑战性的转化。其中，[Fe 4S 4] 酶是最普遍存在的，催化数十种已知的转化（可能更多）， 在人类健康和疾病中起着直接和间接的作用。该提案涉及的机制> 自由基S-腺苷-L-甲硫氨酸（SAM）酶超家族的100，000名成员。了解他们的 分子水平上的反应机制对于识别疾病靶点和设计机制至关重要， 的抑制剂。在这些酶的机理研究中，一个新兴的主题是物种的中介性 含有Fe-烷基键，由此反应性5 ′-脱氧腺苷自由基的产生可以通过 均裂Fe-C键断裂。然而，该中间体的确切电子和几何结构，其 在催化中的作用，其Fe-C键的强度，以及这些步骤可能发生的机制是 这种结构类型或反应活性在合成Fe-S簇合物中尚无先例。因此我们 建议使用结构和功能上忠实的合成[Fe 4S 4]-烷基来解决这些问题 配合物我们将制备具有合理可调性质的[Fe 4S 4]-烷基络合物，并配制和测试 关于实现Fe-C键的几何和电子结构要求的假设 均裂这些要求将通过系统的动力学和光谱研究阐明。 总之，这项工作将揭示有机金属化学在自由基SAM酶催化中的作用， 深入了解自然界如何利用人类健康和疾病中的反应性Fe-C键。

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.