Modeling the Organometallic Chemistry of Radical S-adenosylmethionine Enzymes

项目摘要/摘要 铁硫磺酶在生物学中执行一些最具挑战性的转化。其中，[Fe4S4] 酶是最普遍存在的，它催化了数十种已知的转化(可能还有更多) 对人类健康和疾病起着直接和间接的作用。这项建议涉及到&gt； 100,000个成员是自由基酶S-腺苷-L-蛋氨酸超家族成员。了解他们的 分子水平上的反应机制对于确定疾病靶点和设计机制至关重要-- 基于抑制剂的。这些酶的机理研究中的一个新兴主题是物种的中介作用。 含有铁烷基键的，由此反应性5‘-脱氧腺苷自由基的生成可以通过 均溶Fe-C键断裂。然而，这种中间体的确切电子结构和几何结构，其 在催化中的作用，它的Fe-C键的强度，以及这些步骤可能发生的机制是 不清楚，而且在合成的铁-S簇合物中没有这种结构类型或反应性的先例。因此，我们 建议使用结构和功能上忠实的合成[Fe4S4]-烷基来解决这些问题 复合体。我们将制备性能合理可调的[Fe4S4]-烷基配合物，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 同种溶血。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金属化学在自由基SAM酶和 深入了解大自然如何在人类健康和疾病中利用活性铁-碳键。

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.