Reactions of N-Nitroso Compounds with Heme
Biography
Overview
Nitric oxide (NO) is now one of the most studied small molecules in bioinorganic chemistry, and new discoveries of the consequence of NO binding to the metal center in heme continue to be made. N -nitroso compounds are also very important in the field of nitric oxide chemistry. Not only can they serve as sources of NO for metal-NO bond formation, but they are also associated with incidences of cancer after biochemical activation of nitrosmines and related compounds by the heme-containing cytochrome P450 enzyme. The iron center in cytochrome P450 has been implicated in some metabolic reactions of N -nitroso compounds. Surprisingly, however, metalloporphyrin-nitrosamine chemistry is an unexplored area of research. The biological and environmental occurrence of N -nitroso compounds, and the fact that they are metabolized by the heme-containing cytochrome P450 enzymes, underscores the necessity to examine their (N -nitroso) interactions with heme models and with heme-containing proteins as a means of better understanding their fundamental chemistry.In this proposal, we hypothesize that the bio-related chemistry of various organic N -nitroso compounds is interwoven with the chemistry of NO, and that heme iron is an important contributor in the biological NO-to-XNO conversion. Thus, a detailed knowledge of iron porphyrin-nitrosamine chemistry and subsequent Fe-NO bond formation will provide the necessary information needed to help elucidate some of the important metabolic pathways that involve nitrosamine interactions with heme biomolecules such as cytochrome P450.We have previously reported the preparation and reactions of a number of nitrosyl and nitroso (nitrosamine, nitrosoarene, nitrosothiol, etc.) complexes of metalloporphyrins. We are now entering the second major phase of our study to develop the representative reaction chemistry of these nitrosyl and nitroso metalloporphyrins. We propose to examine the interactions of nitrosamines and related compounds with heme models and with cytochrome P450 BM3 (both the heme domain and the full-length protein), and elucidate the reaction pathways of these heme-nitrosamine complexes. This planned research is fundamental to the understanding of the heme-dependent bloinorganic chemistry of NO.
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