Reactions of N-Nitroso Compounds with Heme

N-亚硝基化合物与血红素的反应

• 批准号: 6608014
• 负责人: George Bannerman Richter-Addo
• 金额: $ 26.19万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608014
• 关键词: X ray crystallography; chemical binding; chemical bond; chemical reaction; chemical synthesis; cytochrome P450; gas chromatography mass spectrometry; heme; high performance liquid chromatography; metalloporphyrins; nitric oxide; nitrosamines; nitroso compounds; organic chemicals; protein protein interaction

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：一氧化氮(NO)现在是生物无机化学中研究最多的小分子之一，关于NO与血红素中金属中心结合的后果不断有新的发现。N-亚硝基化合物在一氧化氮化学领域也是非常重要的。它们不仅可以作为金属-NO键形成的NO来源，而且在亚硝胺和相关化合物被含血红素的细胞色素P450酶生化激活后，它们还与癌症的发生有关。细胞色素P450中的铁中心参与了N-亚硝基化合物的某些代谢反应。然而，令人惊讶的是，金属卟啉-亚硝胺化学是一个未被探索的研究领域。N-亚硝基化合物在生物和环境中的存在，以及它们被含有血红素的细胞色素P450酶代谢的事实，强调了研究它们(N-亚硝基)与血红素模型和含血红素蛋白质的相互作用以更好地了解它们的基本化学的必要性。在这个建议中，我们假设各种有机N-亚硝基化合物的生物相关化学与NO的化学相互交织，并且血红素铁是生物NO转化为XNO的重要贡献者。因此，对亚硝胺-铁卟啉化学和随后的Fe-NO键形成的详细了解将提供必要的信息，以帮助阐明一些涉及亚硝胺与细胞色素P450等血红素生物分子相互作用的重要代谢途径。我们以前已经报道了一些亚硝酰基和亚硝基(亚硝胺、亚硝芳烃、亚硝硫醇等)的制备和反应。金属卟啉络合物。我们现在正在进入第二个主要阶段的研究，以发展这些亚硝酰基和亚硝基金属卟啉的代表性反应化学。我们建议研究亚硝胺及其相关化合物与血红素模型和细胞色素P450 BM3(血红素结构域和全长蛋白)的相互作用，并阐明这些亚硝胺络合物的反应途径。这项计划中的研究对于理解NO的依赖于血红素的血液无机化学是基础的。