Biologically Related Iron-Sulfur Chemistry

该申请寻求对生物无机化学中已建立的研究计划的持续支持，该研究计划旨在详细了解含有铁，硫和其他金属的生物相关簇的分子，其中各种类型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氧化还原和非氧化还原转化的催化中心，以及作为某些细胞过程的传感器和调节器。随着对三种最普遍的簇类型（[2Fe-2S]，[3Fe-4S]，[4Fe-4S]）的一般理解，注意力也集中在更复杂的簇中，这些簇包含杂金属，如铌，钒和镍。在固氮酶和一氧化碳脱氢酶/乙酰辅酶A合酶中，电子转移和催化位点是桥接的组装体，其中离散的片段通过两个或更多个共价键连接。本研究旨在阐明的途径的形成，几何结构和反应性能的集群和桥接组件使用的合成类似物的方法，其目标是结构和功能的代表性的活性位点，可以在高分辨率下进行检查。提出的研究问题包括固氮酶中发现的全铁[4Fe-4S]氧化态，S-腺苷甲硫氨酸裂解的反应性类似物， 脱硫生物素转化为生物素，合成固氮酶的电子转移和催化辅因子簇和一氧化碳脱氢酶的催化簇的类似物。在整个过程中，都非常强调原始的合成化学，旨在实现弱场簇，这些簇是有意义的类似物，或者与酶位点相同。拟议的研究的一个重要部分是为了促进发展领域的双中心合成和生物合成，显示什么合成路线是可行的集群形成。

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.