MECHANISMS THAT REGULATE ENZYMES THAT METABOLIZE CIS UNSATURATED FATTY ACIDS

调节顺式不饱和脂肪酸代谢酶的机制

• 批准号: 6290022
• 负责人: Thomas Eling
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290022
• 关键词: animal genetic material tag; enzyme activity; enzyme mechanism; fatty acid metabolism; gene expression; human genetic material tag; human tissue; laboratory rat; ligands; lipopolysaccharides; messenger RNA; nitric oxide; oxygenases; peroxidases; phorbols; prostaglandins; tissue /cell culture; unsaturated fatty acids

Summary of Work: The goal is to develop an understanding of the biochemical mechanisms responsible for the metabolism of arachidonic acid and linoleic acid. Studies with PGHS-1 indicate that a tyrosyl radical is formed which could be the reactive intermediate that initiates arachidonic acid oxygenation. Recently, we have shown that NO reacts with the tyrosyl radical converting the radical to a new radical characterized by ESR analysis as an iminoxyl radical. The iminoxyl radical decays to nitrotyrosine resulting in the nitration of the tyrosine moiety on PHS. In addition, its formation of nitrotyrosine is often used as an indicator of oxidative stress. We have identified the specific tyrosine moiety in PHS nitrated by the reaction of NO with tyrosyl radical as Tyrosine-385. This indicates that tyrosine-385 is oxidized to tyrosyl radical during catalysis and suggests this residue is a likely active site or is the site of enzyme inactivation. Future studies will focus on understanding the interaction of Cox tyrosine radical with NO and its effect on Cox activity. In addition, we are currently testing the hypothesis that measurement of nitrotyrosine, a marked for oxidative stress, occur mainly by the interaction of metabolically active Cox-2 and NO formed by iNOS. Understanding the biochemical mechanisms which regulate the activities and expression of these enzymes will provide new insights into potentially controlling or preventing these disease conditions. - Prostaglandin-H-synthase, COX-1, COX-2, tyrosyl radical

工作总结：目的是了解花生四烯酸和亚油酸代谢的生化机制。对PGHS-1的研究表明，形成酪氨酰基自由基，其可能是引发花生四烯酸氧化的反应性中间体。最近，我们已经表明，NO与酪氨酰基自由基反应，将自由基转化为一个新的自由基，其特征在于通过ESR分析作为亚氨氧基自由基。亚氨氧基自由基衰变为硝基酪氨酸，导致PHS上酪氨酸部分的硝化。此外，它的硝基酪氨酸的形成通常被用作氧化应激的指标。我们已经确定了特定的酪氨酸部分在PHS硝化的NO与酪氨酰自由基作为酪氨酸-385。这表明酪氨酸-385在催化过程中被氧化为酪氨酰自由基，并表明该残基可能是活性位点或酶失活位点。未来的研究将集中在了解考克斯酪氨酸自由基与NO的相互作用及其对考克斯活性的影响。此外，我们目前正在测试的假设，硝基酪氨酸，氧化应激的标志，测量主要发生的代谢活性考克斯-2和NO的相互作用，形成的iNOS。了解调节这些酶的活性和表达的生化机制将为潜在地控制或预防这些疾病提供新的见解。- 前列腺素-H-合酶，考克斯-1，考克斯-2，酪氨酰自由基