Functional models of the polynuclear nitrogen-fixing enzyme cofactors Nitrogen entry into the biosphere is the rate-limiting step for all biological processes, and therefore, life itself. Dinitrogen reduction occurs at polynuclear metalloenzymes called nitrogenase. The reaction center of the Molybdenum-containing enzyme consists of a cysteine ligated MoFe7S7 cofactor (FeMoco) where dinitrogen fixation takes place. Despite good structural information about the cofactor, many questions regarding substrate uptake and the overall chemical action of the cofactor during turnover remain. Specifically, the redox flexibility of Mo point to its likely involvement in substrate activation, which has been vetted by functional model studies. However, site-mutagenesis studies and theoretical models indicate a polynuclear Fe-face of FeMoco to participate in substrate activation. Synthetic structural analogues have been fashioned to reproduce the cofactor composition and elucidate structural details that mimic the cofactor. However, no synthetic models exist that would permit probing of the interaction between nitrogenase substrates and a polynuclear reaction site reminiscent of those present in FeMo/FeV/Feco. Using synthetic methodology developed in our laboratories to reliably synthesize polynuclear clusters, the goal of the proposed research is to both functionally and structurally model the active site of FeMoco. Polyamide and polyamide/sulfide ligand systems permit the isolation and study of well-defined tri- and hexanuclear iron complexes. The molecular tri-iron units will allow systematic examination of the reaction chemistry of nitrogenase substrates with an iron-only reaction site. Furthermore, bimolecular coupling of tri-iron units will permit the synthesis and characterization of various structural mimics of the cofactor featuring different interstitial atom components (e.g., C, N, O, S). The proposed research will permit the testing of several hypotheses concerning interaction of nitrogenase substrates with polynuclear reaction sites prevalent in the native enzyme: how do substrates bind; how is redox distributed throughout the cluster reaction site; how do surface hydrides gate dinitrogen or substrate binding; can we authenticate mechanistic proposal for the enzyme by observation of abiological models? The viability of the synthetic analogues to mimic nitrogenase activity will be probed by profiling the reactivity of the synthetic clusters towards nitrogenase substrates.
Nitrogen entry into the biosphere is mediated by the action of the enzyme nitrogenase, making biological nitrogen fixation essential to all life processes. Our goal is to use model polynuclear iron complexes to test key mechanistic hypotheses about the chemical action of nitrogenase, and cluster cofactors at large, as well as aid the development of new catalytic systems for dinitrogen reduction.
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