Bioorganometallic Iron-Sulfide Assemblies Related to the Hydrogenases

描述（由申请人提供）： 该项目的目标是制备和表征两种主要金属酶的活性位点的功能和光谱模型，所述金属酶处理氢，[FeFe]-和[NiFe]-氢化酶。这些模型将提供对这些酶的机理见解，并将支持其他进展：（i）定义还原铁在生物系统中的作用，（ii）对抗由在其代谢中利用氢的生物体引起的疾病的机会，以及（ii）导致使用氢的新试剂和催化剂，与许多药物的合成有关。这项工作主要集中在[FeFe]-氢化酶，利用我们的模型的还原和氧化状态的这种酶的进展。一个新兴的努力建立在最近的突破有关的[NiFe]-氢化酶，这是特别普遍的。大部分的工作集中在混合价态Hox状态的[FeFe]-氢化酶，开始与最近的发现，H2被激活的仿生Hox模型。这一进展的关键是将azadithiolate辅因子纳入合成类似物中。这些功能胜任的模型将通过光谱和同位素标记进行表征。对于这种酶的行动的另一个方向- H2生产-我们将研究还原仿生系统的质子化，阐明控制的区域化学和氧化还原的酶的因素。最后，一个积木式的方法中所描述的[NiFe]-氢化酶的仿生模型的组装。初步研究表明，组装和表征一个几乎完整的活性位点模型。 总的来说，这项工作有望澄清自然界使用和生产氢的途径。生物化学和基本的无机化学是非常不寻常的。由于氢对晶体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H2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H2为基础的代谢支持病原体H。幽门螺杆菌，估计是负责80-90%的所有胃癌和十二指肠癌。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.