Designing Polymetallic Clusters to Model the Active site of the FeMo-Cofactor

描述(申请人提供)：多金属金属酶门自然界中的许多反应，这些反应包含氧、氮和许多其他对地球上的生命至关重要的元素。氮素还原在自然界中是通过多核金属酶固氮酶实现的。底物还原的位置由MoFe7S7辅因子组成。尽管关于辅因子的结构信息很好，但许多关于底物结合和辅因子在周转期间的整体化学作用的问题仍然很大程度上没有答案。固氮酶的功能模型通常在配基环境中使用单一的过渡金属离子，这些配基环境不能忠实地复制自然产生的酶位点。利用新的方法来可靠地合成多金属团簇，我们寻求使用定义良好的三金属团簇作为构建块来组装辅助因子核心模拟。利用天然酶中发现的化学功能，多胺/硫化物配体体系被建议作为支架来支撑三铁核心。更重要的是，定义明确的分子三铁单元将使我们能够系统地研究具有仅铁反应位点的固氮酶底物的反应化学，以及合成具有不同间隙原子成分的辅因子的结构模拟物。这项建议寻求开发多金属团簇来在结构和功能上模拟固氮酶的FEMO辅因子。 与公众健康相关：多金属金属酶可以控制自然界中的许多反应，这些反应含有氧、氮和许多其他对地球上的生命至关重要的元素。使用合成生物无机化学对这些过程进行建模为我们理解它们的结构和功能提供了一个强大的工具--最终产生了对生物学的化学见解。这项建议寻求发展多金属团簇，以在结构和功能上模拟一个这样的反应中心-固氮酶的FeMo辅因子。

DESCRIPTION (provided by applicant): Polymetallic metalloenzymes gate many of the reactions in nature which incorporate oxygen, nitrogen and many other elements essential for life on this planet. Dinitrogen reduction is achieved in nature by the polynuclear metalloenzyme nitrogenase. The site for substrate reduction consists of the MoFe7S7-cofactor. Despite good structural information about the cofactor, many questions regarding substrate binding and the overall chemical action of the cofactor during turnover remain largely unanswered. Functional models for nitrogenase often employ single transition metal ions in ligand environments that do not faithfully reproduce the naturally occurring enzyme sites. Utilizing new methodology to reliably synthesize polymetallic clusters, we seek to employ well-defined trimetallic clusters as building blocks to assemble a cofactor core mimic. Using chemical functionalities found within the native enzyme, polyamine/sulfide ligand systems are proposed as scaffolds to support the tri-iron cores. More importantly, the well-defined molecular tri-iron units will allow us to systematically examine the reaction chemistry of nitrogenase substrates with an iron-only reaction site, as well as synthesize structural mimics of the cofactor with differing interstitial atom components. This proposal seeks to develop polymetallic clusters to both structurally and functionally model the FeMo-cofactor of nitrogenase. PUBLIC HEALTH RELEVANCE: Polymetallic metalloenzymes gate many of the reactions in nature which incorporate oxygen, nitrogen and many other elements essential for life on this planet. Modeling these processes using synthetic bioinorganic chemistry provides us a powerful tool for understanding their structure and function - ultimately yielding chemical insights into biology. This proposal seeks to develop polymetallic clusters to both structurally and functionally model one such reaction center - the FeMo-cofactor of nitrogenase.