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.
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