Bioorganometallic Iron-Sulfide Assemblies Related to the Hydrogenases

描述(由申请人提供)： 该项目的目标是为处理氢的两种主要金属酶--[FeFe]-氢酶和[NiFe]-氢酶--的活性部位制备和表征功能和光谱模型。这些模型将提供对这些酶的机械性见解，并将支持其他进展：(1)确定还原铁在生物系统中的作用；(2)抗击由利用氢进行新陈代谢的生物体引起的疾病的机会；以及(2)导致与许多药物的合成有关的利用氢的新试剂和催化剂。这项工作主要集中在[FeFe]-氢酶上，利用我们在模拟这种酶的还原和氧化状态方面的进展。一项新的努力建立在与[NiFe]-氢酶相关的最近突破的基础上，[NiFe]-氢酶特别广泛。许多工作都集中在[FeFe]-氢酶的混合价HOx状态上，从最近发现H2被仿生HOx模型激活开始。这一进展的关键是将氮杂硫酸酯辅助因子引入到合成类似物中。这些功能合格的模型将通过光谱学和同位素标记进行表征。对于这种酶作用的另一个方向-氢气的产生-我们将检查简化的仿生系统的质子化，阐明控制氢化物的区域化学和氧化还原的因素。最后，在组装[NiFe]-氢酶的仿生模型中描述了一种积木方法。初步研究证实了一个几乎完整的活性中心模型的组装和表征。总体而言，这项工作有望阐明大自然利用和产生氢气的途径。生物化学和潜在的无机化学是非常不寻常的。由于氢对结晶学的不可见性和干扰发色团的存在，这些问题中的许多不能用蛋白质完全解决。这项工作为涉及氢和氢化物配体的新生物无机化学奠定了基础。 公共卫生相关性： 以氢为基础的代谢支持幽门螺杆菌的病原体，据估计，幽门螺杆菌导致了所有胃癌和十二指肠癌的80%-90%。这种细菌感染了世界上一半的人口和5000万美国人。氢是人体肠道中大气的一种成分。

DESCRIPTION (provided by applicant): The goal of this project is to prepare and characterize functional and spectroscopic models for the active sites of the two main metalloenzymes that process hydrogen, the [FeFe]- and [NiFe]-hydrogenases. Such models will provide mechanistic insights into these enzymes and will underpin other advances: (i) define the roles for reduced iron in biological systems, (ii) opportunities for combating diseases caused by organisms that utilize hydrogen in their metabolism, and (ii) lead to new reagents and catalysts for using hydrogen, relevant to the synthesis of many pharmaceuticals. The work focuses mainly on the [FeFe]-hydrogenases, exploiting advances in our modeling both the reduced and oxidized states of this enzyme. An emerging effort builds on a recent breakthrough relevant to the [NiFe]-hydrogenases, which are particularly widespread. Much of the work focuses on the mixed valence Hox state of [FeFe]-hydrogenases, beginning with a recent discovery that H2 is activated by a biomimetic Hox model. The key to this advance is the incorporation of the azadithiolate cofactor into the synthetic analogues. These functionally competent models will be characterized spectroscopically and through isotopical labeling. For the other direction of this enzyme's action - H2 production - we will examine the protonation of reduced biomimetic systems, elucidating factors that control the regiochemistry and redox of the hydrides. Finally, a building block approach is described in the assembly of biomimetic models for the [NiFe]-hydrogenases. Preliminary studies demonstrate the assembly and characterization of a nearly complete active site model. Overall the work promises to clarify the pathways by which nature uses and produces hydrogen. The biochemistry and the underlying inorganic chemistry are highly unusual. Many of these questions cannot be fully addressed with the protein due to the invisibility of hydrogen to crystallography and the presence of interfering chromophores. The work underpins new bioinorganic chemistry involving H2 and hydride ligands. PUBLIC HEALTH RELEVANCE: An H2-based metabolism supports the pathogen H. pylori, estimated to be responsible for 80-90% of all gastric and duodenal cancers. This bacterium infects half of the world's population and 50M Americans. Hydrogen is a constituent of the atmosphere in the human gut.