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

多核铁配合物作为固氮酶 FeMo 辅因子的功能模拟物

基本信息

批准号：
8474791
负责人：
Theodore A Betley
金额：
$ 29.83万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8474791
关键词：
Active Sites Address Amines Binding Biological Biological Process Chemical Actions Chemicals Chemistry Coenzymes Complex Coupling Cysteine Development Electronics Electrons Environment Enzymes Evaluation Face Faculty Family Characteristics Funding Generations Goals Hydrogen In Situ Ions Iron Laboratories Life Ligands Light Magnetism Mediating Metals Methodology Modeling Molecular Molybdenum Molybdoferredoxin Monitor Mutagenesis Nature Nitrogen Nitrogen Fixation Nitrogenase Nylons Oxidation-Reduction Polyamines Process Property Reaction Research Series Site Structure Study models Substrate Interaction Sulfides System Techniques Testing Theoretical model Thermodynamics Transition Elements analog chemical reduction cofactor electronic structure flexibility functional mimics interstitial metalloenzyme oxidation sample fixation scaffold self assembly solid state uptake

项目摘要

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.

描述（由申请人提供）：多核氮固定酶辅助因子的功能模型是所有生物过程的速率限制步骤，因此是生命本身的限制步骤。减少二氮的发生在称为氮酶的多核金属酶。含钼的酶的反应中心由发生二氮固定的半胱氨酸连接的MOFE7S7辅因子（Femoco）组成。尽管关于辅助因子的良好结构信息，但在营业额期间，有关底物摄取和辅因子的整体化学作用的许多问题仍然存在。具体而言，MO指向其可能参与底物激活的氧化还原灵活性，该氧化还可以通过功能模型研究审查。然而，位点 - 毒素研究和理论模型表明，Femoco的多核Fe面参与底物激活。合成结构类似物已被造成复制辅因子组成并阐明模仿辅因子的结构细节。但是，没有合成模型可以探讨氮酶底物与多核反应位点之间的相互作用，让人联想到Femoco中存在的氮。使用在实验室中开发的合成方法来可靠地合成多核簇，该研究的目的是在功能和结构上对Femoco的活性位点进行建模。聚酰胺和聚酰胺/硫化物配体系统允许分离和研究明确定义的三核铁络合物。分子三铁单元将允许系统地检查氮酶底物与仅铁反应位点的反应化学。此外，三铁单元的双分子耦合将允许综合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几种关于氮酶底物与多核反应位点相互作用的假设。