Biologically Related Iron-Sulfur Chemistry

这项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，这些簇合物现在还被认为是底物的氧化还原和非氧化还原转化的催化中心，并作为某些细胞过程的传感器和调节器。虽然对两种最普遍的团簇类型(Fe2S2和Fe4S4)的总体理解已经很好，但仍然存在需要进一步研究的团簇形成、相互转化和反应性问题。此外，还强调了对更复杂的团簇的研究，其中一些团簇含有钼、钒和镍等异质金属。在固氮酶、亚硫酸盐还原酶和一氧化碳脱氢酶中，催化部位是桥接的组件，其中两个离散的片段通过蛋白质结构在空间上排列并通过一个或多个共价键连接。这项研究试图用合成模拟的方法来阐明簇合物和桥联组合物的形成途径、几何结构、电子特征和反应性性质，其目的是表示蛋白质结合的簇合物的结构和功能。在最近的一项倡议中，多肽被用作合成和稳定复杂金属中心的配体。提出要研究的问题包括固氮酶铁蛋白中[Fe4S4]0氧化态的稳定性，立方体[Fe3S4]0团簇与金属离子的结合性能，簇间相互转化和作为生物素合成酶催化机理中反应物的Fe4S4簇，固氮酶的Fe8S7和MFe7S9(M=Mo，V，Fe)簇的类似物的合成和性质，以及一氧化碳脱氢酶和亚硫酸盐氧化酶的多肽类似物。所设计的多肽可以作为支架或模板用于合成和稳定其紧密类似物的蛋白结合的金属中心的命题将得到验证。拟议研究的很大一部分旨在通过展示在没有和存在多肽和更大的蛋白质的情况下，哪些合成路线对于构建簇是可行的，从而为金属分配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.