Polynuclear iron complexes as functional mimics of the nitrogenase FeMo-cofactor

描述（由申请人提供）：多核固氮酶辅助因子的功能模型氮进入生物圈是所有生物过程的限速步骤，因此也是生命本身的限速步骤。二氮还原发生在称为固氮酶的多核金属酶上。含钼酶的反应中心由半胱氨酸连接的 MoFe7S7 辅因子 (FeMoco) 组成，其中发生二氮固定。尽管有关辅因子的结构信息良好，但有关底物吸收和周转期间辅因子的整体化学作用的许多问题仍然存在。具体来说，Mo 的氧化还原灵活性表明它可能参与底物活化，这已经通过功能模型研究进行了审查。然而，位点诱变研究和理论模型表明 FeMoco 的多核 Fe 面参与底物激活。合成的结构类似物已被设计用来重现辅因子的组成并阐明模仿辅因子的结构细节。然而，不存在能够探测固氮酶底物与多核反应位点（类似于 FeMoco 中存在的多核反应位点）之间相互作用的合成模型。使用我们实验室开发的合成方法来可靠地合成多核簇，拟议研究的目标是对 FeMoco 的活性位点进行功能和结构建模。聚酰胺和聚酰胺/硫化物配体系统允许分离和研究明确的三核和六核铁配合物。分子三铁单元将允许系统地检查具有仅铁反应位点的固氮酶底物的反应化学。此外，三铁单元的双分子偶联将允许合成和表征具有不同间隙原子成分的辅因子的各种结构模拟物。拟议的研究将允许测试有关固氮酶底物与 FeMoco 中普遍存在的多核反应位点相互作用的几个假设。

DESCRIPTION (provided by applicant): 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 FeMoco. 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. The proposed research will permit the testing of several hypotheses concerning interaction of nitrogenase substrates with polynuclear reaction sites prevalent in FeMoco.