Biologically Related Iron-Sulfur Chemistry

本申请旨在继续支持生物无机化学中已建立的研究项目，该项目旨在对生物相关的铁硫簇进行详细的分子理解，各种类型的铁硫簇存在于生命的各个层面。除了它们作为电子载体的经典作用外，这些簇现在被认为是作为底物氧化还原和非氧化还原转化的催化位点，并作为某些细胞过程的传感器和调节剂。虽然对两种最普遍的簇类型（Fe2S2, Fe4S4）有了很好的了解，但簇的形成，相互转化和反应性仍然存在问题，需要进一步研究。研究更复杂的簇，其中一些含有异质金属，如钼，钒和镍，也强调。在酶氮酶、亚硫酸盐还原酶和一氧化碳脱氢酶中，催化位点是由两个离散片段由蛋白质结构在空间上排列并通过一个或多个共价键连接而成的桥接组合。本研究旨在利用合成模拟方法阐明簇和桥接组件的形成途径、几何结构、电子特征和反应性，其目标是蛋白质结合簇位点的结构和功能表征。在最近的倡议，肽被用作配体在合成和稳定复杂的金属位点。提出的研究问题包括：[Fe3S4]0氧化态在氮酶铁蛋白中的稳定性、立方体[Fe3S4]0簇对金属离子的结合特性、簇间转化以及作为反应物的Fe4S4簇在生物素合成酶催化机制中的作用、氮酶Fe8S7和MFe7S9 （M = Mo， V, Fe）簇的合成和性质，以及基于肽的一氧化碳脱氢酶和亚硫酸盐氧化酶类似物的合成。设计的肽可以作为支架或模板用于合成和稳定蛋白质结合金属位点的类似物的命题将被测试。提出的研究的很大一部分旨在通过展示在缺乏或存在肽和较大蛋白质的情况下，哪些合成路线对于簇构建是可行的，从而为金属中心合成和生物合成的发展领域做出贡献。

This application seeks continued support for an established research program in bioinorganic chemistry directed at a detailed molecular understanding of biologically relevant iron-sulfur clusters, various types of which are found at all levels of life. In addition to their classical role as electron carriers, these clusters are now known to function as catalytic sites for redox and non-redox transformations of substrates, and to act as sensors and regulators for certain cell processes. While a general understanding of the two most pervasive cluster types (Fe2S2, Fe4S4) is well developed, there remains issues of cluster formation, interconversion, and reactivity that require further investigation. Research on more complex clusters, some of which contain heterometals such as molybdenum, vanadium, and nickel, is also emphasized. In the enzymes nitrogenase, sulfite reductase, and carbon monoxide dehydrogenase, the catalytic sites are bridged assemblies in which two discrete fragments are spatially disposed by protein structure and linked by one or more covalent bonds. This research seeks elucidation of the pathways of formation, geometrical structures, electronic features, and reactivity properties of clusters and bridged assemblies using the synthetic analogue approach, whose objectives are structural and functional representations of protein-bound cluster sites. In a recent initiative, peptides are utilized as ligands in the synthesis and stabilization of complex metal sites. Among the problems proposed for investigation are the stability of the [Fe4S4]0 oxidation state in the iron protein of nitrogenase, binding properties of cuboidal [Fe3S4]0 clusters toward metal ions, cluster interconversion and the Fe4S4 cluster as a reactant in the catalytic mechanism of biotin synthase, the synthesis and properties of analogues of the Fe8S7 and MFe7S9 (M = Mo, V, Fe) clusters of nitrogenase, and peptide-based analogues of carbon monoxide dehydrogenase and sulfite oxidase. The proposition that designed peptides can be used as scaffolds or templates in the synthesis and stabilization of protein-bound metal sites of their close analogues will be tested. A significant portion of the proposed research is intended to contribute to the developing area of metallocenter synthesis and biosynthesis by showing what synthetic routes are feasible for cluster construction in the absence and presence of peptides and larger proteins.