BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS

碳自由基的生物化学和肝毒性

• 批准号: 2176606
• 负责人: Paul R Ortiz De Montellano
• 金额: $ 22.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2176606
• 关键词: carbon; cytochrome P450; electronic spectra; enzyme activity; enzyme inhibitors; enzyme structure; free radical oxygen; hepatotoxin; high performance liquid chromatography; horseradish peroxidase; laboratory rat; mass spectrometry; myeloperoxidase; nuclear magnetic resonance spectroscopy; oxidation reduction reaction; oxygenases; peroxidases; protein structure function; toxin metabolism; ultraviolet spectrometry

The biochemistry of carbon radicals remains poorly understood despite its direct relevance to oxygen radical pathology and the unique value of carbon radicals as mechanistic probes. The work proposed here builds on key advances made during the expiring period of support, particularly (a) validation of a rationale for the fact that radicals are almost invariably produced by peroxidases but only under certain conditions by monooxygenases, (b) successful expression of catalytically active horseradish peroxidase in a baculovirus system, and (c) development of novel free radical probes. The first goal is to continue to elucidate the function of peroxidases, with initial emphasis on the structural features that determine the location of unpaired electrons in the protein, the mechanism of free radical generation, and the possible catalysis of monooxygenase reactions. The second goal is to extend our growing understanding of plant and fungal peroxidases to the physiologically relevant mammalian enzymes, particularly myeloperoxidase and thyroid peroxidase. The third goal is to construct new radical probes and to employ them to characterize biological radicals. The fourth goal is to explore the biological fates of carbon radicals, particularly their oxidation to cations and reactions with proteins. The collective intent of these studies is to advance our understanding of the biochemistry of carbon radicals, particularly the mechanisms by which they are formed and quenched, and to clarify their toxicological potential.

碳自由基的生物化学仍然知之甚少， 与氧自由基病理学的直接相关性和碳的独特价值 自由基作为机械探针。 这里提出的工作建立在关键的 在支助期结束时支付的预付款，特别是（a） 事实证明，激进分子几乎总是 由过氧化物酶产生，但仅在某些条件下， 单加氧酶，（B）催化活性的 杆状病毒系统中辣根过氧化物酶，和（c） 新型自由基探针。 第一个目标是继续阐明 过氧化物酶的功能，首先强调结构特征 决定蛋白质中未配对电子的位置， 自由基产生的机制，以及可能的催化作用， 单加氧酶反应 第二个目标是扩大我们不断增长的 了解植物和真菌过氧化物酶的生理 相关的哺乳动物酶，特别是髓过氧化物酶和甲状腺 过氧化物酶。 第三个目标是构建新的自由基探针， 用来描述生物基的特征 第四个目标是 探索碳自由基的生物命运，特别是它们的 氧化成阳离子和与蛋白质反应。 的集体意图 这些研究是为了增进我们对碳的生物化学的理解 自由基，特别是它们形成的机制， 淬灭，并阐明其毒理学潜力。