Biologically Related Iron-Sulfur Chemistry

生物学相关的铁硫化学

• 批准号: 6606936
• 负责人: RICHARD Hadley HOLM
• 金额: $ 49.19万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606936
• 关键词: X ray crystallography; active sites; bicyclic compound; chemical kinetics; chemical structure function; chemical transfer reaction; covalent bond; cyclic compound; electron spin resonance spectroscopy; electronic spectra; enzyme inhibitors; high performance liquid chromatography; iron sulfur protein; mass spectrometry; matrix assisted laser desorption ionization; metal complex; metalloenzyme; molecular site; nitrogenase; organometallic compounds; oxidation reduction reaction; oxidoreductase; peptide chemical synthesis; stereochemistry; sulfite reductase

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.

该申请寻求对已建立的生物无机化学研究项目的持续支持，该项目旨在对生物学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。 除了作为电子载体的经典作用外，这些簇现在还可以作为底物氧化还原和非氧化还原转化的催化位点，并充当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、Fe4S4）的总体了解已经得到很好的发展，但团簇形成、相互转化和反应性等问题仍然需要进一步研究。 还强调了对更复杂簇的研究，其中一些簇含有钼、钒和镍等异金属。 在固氮酶、亚硫酸还原酶和一氧化碳脱氢酶中，催化位点是桥接组件，其中两个离散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。 本研究旨在使用合成模拟方法阐明簇和桥接组件的形成途径、几何结构、电子特征和反应特性，其目标是蛋白质结合簇位点的结构和功能表示。在最近的一项举措中，肽被用作复合金属位点的合成和稳定的配体。 提出研究的问题包括固氮酶铁蛋白中[Fe4S4]0氧化态的稳定性、立方形[Fe3S4]0簇与金属离子的结合特性、簇互变和Fe4S4簇作为生物素合酶催化机制中的反应物、Fe8S7和MFe7S9类似物的合成和性质（M = Mo、V、Fe) 固氮酶簇，以及一氧化碳脱氢酶和亚硫酸氧化酶的肽类似物。 设计的肽可以用作合成和稳定其密切类似物的蛋白质结合金属位点的支架或模板的主张将得到测试。 拟议研究的很大一部分旨在通过展示在不存在和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。