Nitric oxide reactivity with synthetic iron-sulfur clusters

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

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.