Biologically Related Iron-Sulfur Chemistry

这项申请寻求对生物无机化学方面已建立的研究计划的持续支持，该计划旨在对含有铁、硫和其他金属的生物相关簇合物进行详细的分子理解，这些簇合物的各种类型在生命的各个层面都有发现。除了它们作为电子加速器载体的经典作用外，这些簇现在还被认为是氧化还原和非氧化还原转化的催化中心，以及某些细胞过程的传感器和调节器。随着对三种最普遍的团簇类型([2Fe-2S]，[3Fe-4S]，[4Fe-4S])的大体了解，人们的注意力也集中在含有钼、钒和镍等异质金属的更复杂的团簇上。在固氮酶和一氧化碳脱氢酶/乙酰辅酶A合成酶中，电子转移和催化位置是桥接的组件，其中离散的片段通过两个或多个共价键连接。这项研究试图用合成模拟方法阐明簇合物和桥联组合物的形成途径、几何结构和反应性性质，其目的是以高分辨率研究活性中心的结构和功能表示。建议调查的问题包括固氮酶中发现的全铁[4Fe-4S]氧化态，S-腺苷蛋氨酸裂解的活性类似物，腺苷蛋氨酸是硫磺转化的来源 脱硫生物素为生物素，固氮酶的电子转移和催化辅因子簇以及一氧化碳脱氢酶的催化簇的类似物的合成。在整个过程中，非常强调原始的合成化学，目的是获得有意义的类似物或与酶位点相同的弱场簇。拟议研究的很大一部分旨在通过展示哪些合成路线对形成簇合物是可行的，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 clusters containing iron, sulfur, and other metals, various types of which are found at all levels of life. In addition to their classical role as lectron carriers, these clusters are now known to function as catalytic centers for redox and non-redox transformations, and as sensors and regulators for certain cellular processes. With a general understanding of the three most pervasive cluster types ([2Fe-2S], [3Fe-4S], [4Fe-4S]) in hand, attention is also focused on more complex clusters which contain heterometals such as molybenum, vanadium, and nickel. In the enzymes nitrogenase and carbon monoxide dehyrogenase/acetylcoenzyme A synthase, the electron transfer and catalytic sites are bridged assemblies in which discrete fragments are linked by two or more covalent bonds. This research seeks elucidation of the pathways of formation, geometrical structures, and reactivity properties of clusters and bridged assemblies using the synthetic analogue approach, whose objectives are structural and functional representations of active sites that can be examined at high resolution. Among the problems proposed for investigation are the all-ferrous [4Fe-4S] oxidation state found in nitrogenase, reactivity analogues for the cleavage of S-adenosylmethionine, the source of sulfur for the conversion of dethiobiotin to biotin, synthesis of analogues of the electron-transfer and catalytic cofactor clusters of nitrogenase and the catalytic clusters of carbon monoxide dehydrogenase. Throughout there is much emphasis on original synthetic chemistry aimed toward the attainment of weak-field clusters that are meaningful analogues, or are the same as, enzymes sites. 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 formation.