Nitric oxide reactivity with synthetic iron-sulfur clusters

说明书(申请人提供)：一氧化氮是一种重要的病原体和信号转导因子，与许多重要的生理功能有关。拟议的研究计划的过度目标是通过研究一氧化氮与具有生物相关性的铁部位的相互作用来促进对一氧化氮的理解。生物化学和生理学领域的研究表明，一氧化氮在铁-硫团簇的分解中起着重要作用。这些簇在各种蛋白质中充当电子转移剂，因此对酶的正常功能和生物体(包括人类)的整体健康至关重要。这项拟议的研究将通过仔细研究一氧化氮遇到铁硫簇合物的合成类似物时发生的基本步骤，集中在簇合物降解的化学方面。通过这种方式，可以比以前更深入地研究发生在生物学上的过程。这项研究的具体目标如下：(1)合成并探索合成的[2Fe-2S]簇合物与一氧化氮的反应性，(2)将这些发现推广到较大的[3Fe-4S]和[4Fe-4S]簇合物的研究，以及(3)同时探索带有非硫键连接的修饰簇合物的反应性。目标铁硫化合物的制备将涉及新的合成方法以及制备铁硫簇合物的现有方案。这项工作将集中在识别新的中间体，并应用生物无机技术，如红外光谱，电子顺磁共振光谱和X射线结晶学来监测化学反应。通过这些调查，拟议的研究计划将寻求开发一种一氧化氮与铁硫簇合物反应的连贯机制。相关性：人类的健康和福祉在很大程度上取决于人体内发生的无数化学反应。当这些反应未能以预期的方式进行时，可能会出现问题，最终可能导致疾病。与正常生物功能密切相关的一种化合物是一氧化氮。这项拟议研究的目标是了解一氧化氮在其与生物相关化合物相互作用中的作用。通过这种理解，拟议的工作将寻求确定当适当的一氧化氮功能受到干扰时会发生什么化学过程，并最终确定这些过程可能如何逆转。

DESCRIPTION (provided by applicant): Nitric oxide is an important pathogen and signaling agent that has been implicated in a number of important physiological functions. The overreaching goal of the proposed research plan is to forward the understanding of nitric oxide by examining its interaction with iron sites of biological relevance. Work from the biochemical and physiological fields have implicated the role of nitric oxide in the breakdown of iron- sulfur clusters. These clusters serve as electron transfer agents in a variety of proteins and are therefore critical to the proper function of enzymes and the overall health of the organism (including humans). The proposed research will focus on the chemical aspects of cluster degradation by scrutinizing the elementary steps that take place when nitric oxide encounters synthetic analogs of iron-sulfur clusters. In this way, the processes that take place biologically may be examined in greater depth than previously possible. The specific aims of the proposed research are as follows: (1) to synthesize and explore the reactivity of synthetic [2Fe-2S] clusters with nitric oxide, (2) to extend these findings to the examination of larger [3Fe- 4S] and [4Fe-4S] clusters, and (3) to concurrently explore the reactivity of modified clusters bearing non- thiolate ligation. Preparation of the target iron-sulfur compounds will involve new synthetic methodologies as well as existing protocols for the preparation of iron-sulfur clusters. The work will focus on identifying new intermediates, and on applying bioinorganic techniques such as infrared spectroscopy, EPR spectroscopy, and X-ray crystallography to monitor chemical reactions. Through these investigations, the proposed research plan will seek to develop a coherent mechanism for nitric oxide reactivity with iron-sulfur clusters. RELEVANCE: The health and well being of humans depends critically upon a myriad of chemical reactions that take place within the human body. When these reactions fail to proceed in the intended way, problems can arise that may ultimately lead to disease. One compound of great relevance to proper biological function is nitric oxide. The goal of the proposed research is to understand the role of nitric oxide in the context of its interaction with biologically relevant compounds. Through this understanding, the proposed work will seek to identify what chemical processes take place when proper nitric oxide function is disturbed, and ultimately, how these processes may be reversed.