Antioxidants and oxidative damage in mitochondria

描述（由申请人提供）：本项目的重点在于小抗氧化分子在线粒体中预防和/或修复硝化蛋白的作用。蛋白质硝化发生在暴露于一氧化氮的生物系统中。在酪氨酸残基上添加硝基，产生3-硝基酪氨酸，被认为是翻译后修饰，信号转导途径的一部分，或“正常”氧化应激的结果。 在这项研究中，我们将表征一氧化氮产生线粒体中蛋白质硝化的机制，因为这些细胞器在维持细胞ATP，β-氧化，血红素合成和其他功能方面发挥着重要作用。我们的研究旨在了解硝化作用引起的动力学和结构变化，以及水果和蔬菜中天然存在的抗氧化剂如何预防/逆转这种影响。黄酮类化合物，香豆素类化合物和儿茶素类化合物的抗氧化作用将在羟基取代，共轭环，和O-甲基化的羟基基团，以阐明结构和功能之间的关联方面进行研究。为此，本提案的具体目标如下： 1.研究线粒体蛋白质硝化的分子机制 2.阐明线粒体中蛋白质硝化的生物学意义 3.天然存在的类黄酮在蛋白质硝化的废除中的结构-活性关联，以及 4.硝化胁迫下含黄酮日粮的生物利用率。

DESCRIPTION (provided by applicant): The focus of this project resides on the role of small antioxidant molecules on the prevention and/or repair of nitrated proteins in mitochondria. Protein nitration occurs in biological systems exposed to nitric oxide. The addition of a nitro group to a tyrosine residue, yielding 3-nitrotyrosine, has been claimed to be a posttranslational modification, part of signal transduction pathways, or a result of "normal" oxidative stress. In this study, we will characterize the mechanism underlying the nitration of proteins in nitric oxide-producing mitochondria, given the important role that these organelles have in the maintenance of cellular ATP, beta-oxidation, heme synthesis, and other functions. Our studies will be aimed at understanding the kinetic and structural changes caused by nitration, and how naturally occurring antioxidants -- present in fruits and vegetables may prevent/reverse this effect. The antioxidant effect of flavonoids, coumarins, and catechins will be studied in terms of hydroxyl substitution, conjugation of rings, and o-methylation of hydroxyl groups to elucidate an association between structure and function. To this end, the specific aims of this proposal are the following: 1. Investigate the molecular mechanisms of mitochondrial protein nitration 2. Elucidate the biological relevance of protein nitration in mitochondria 3. Structure-activity association of naturally occurring flavonoids in the abrogation of protein nitration, and 4. Bioavailability of flavonoids containing diets in nitrative stress.