Biologically Related Iron-Sulfur Chemistry

该申请寻求对生物无机化学的既定研究计划的持续支持，该计划旨在详细了解生物相关的铁硫簇的分子，其中各种类型的铁硫簇存在于生活的各个层面。 除了作为电子载体的经典作用外，这些簇现在已知作为底物的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器。虽然两个最普遍的簇类型（Fe2S2，Fe4S4）的一般理解是发达的，仍然存在的问题，簇的形成，相互转化，和反应，需要进一步的调查。 更复杂的集群，其中一些包含杂金属，如钼，钒和镍的研究也受到重视。 在固氮酶、亚硫酸盐还原酶和一氧化碳脱氢酶中，催化位点是桥接的组装体，其中两个离散的片段通过蛋白质结构在空间上布置并通过一个或多个共价键连接。 本研究旨在阐明的形成途径，几何结构，电子功能，和反应性能的集群和桥接组件使用的合成类似物的方法，其目标是蛋白质结合的集群网站的结构和功能表示。在最近的倡议中，肽被用作合成和稳定复杂金属位点的配体。 本文对固氮酶铁蛋白中[Fe_4S_4]_0氧化态的稳定性、[Fe_3S_4]_0簇合物与金属离子的结合性质、簇合物的相互转化和Fe_4S_4簇合物在生物素合成酶催化机制中的反应物、Fe_8S_7和Fe_7S_9类似物的合成和性质等问题进行了研究（M = Mo，V，Fe）固氮酶簇，以及一氧化碳脱氢酶和亚硫酸盐氧化酶的基于肽的类似物。 设计的肽可以用作支架或模板在合成和稳定的蛋白质结合的金属网站的密切类似物的命题将被测试。 拟议的研究的一个重要部分是为了促进发展领域的多肽合成和生物合成，显示什么合成路线是可行的集群建设的情况下和存在的肽和较大的蛋白质。

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.