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BIOCHEMISTRY AND HEPATIC TOXICITY OF CARBON RADICALS

碳自由基的生物化学和肝毒性

基本信息

批准号：
7634077
负责人：
Paul R Ortiz De Montellano
金额：
$ 10.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-07-01 至 2009-06-30
项目状态：
已结题

项目摘要

Free radical processes have been implicated in a growing range of pathologies, including major health problems such as cancer and atherosclerosis. Nevertheless, despite impressive progress in the past few years, the basic biochemistry of protein radicals continues to be incompletely understood. The work proposed in this application rests on key advances made in the expiring period of support, including (a) identification of the residues in autocatalytic covalent binding of the heme group in lactoperoxidase, (b) Identification of specific residues in lactoperoxidase that are converted to free radicals centers upon reaction of the enzyme with H202, (c) mutation of horseradish peroxidase into an enzyme that mimics the mammalian peroxidases in its ability to bind its heme covalently, and (d) demonstration in a metmyoglobin system that the oxidation of tyrosines to radicals depends on factors other than distance from the oxidizing center. The present project focuses on two aspects of protein radical biochemistry: (a) the possible formation and role of carboxylate radicals, a highly neglected species, in peroxidase function, and (b) the mechanism of formation of unusual intramolecular cross-links and their functional consequences. The first aim of the present project is to define the role of the carboxylate group in the heme-protein cross-linking reaction through studies of the horseradish peroxidase model system. The second aim is to use the same model to clarify the role of radicals in formation of the methionine-vinyl bond of myeloperoxidase. The third aim is to clarify why covalent heme binding is important for mammalian peroxidase function. The fourth aim is to examine the role of the active site carboxylate group and the mechanism(s) by which the unusual cross-links in catalase-peroxidase enzymes are formed. A final goal is to employ a metmyoglobin model system with appended phenols to explore the relationships which determine which tyrosines are oxidized in a protein. These studies should shed light on the generation and fates of peroxidatively generated carbon radicals in physiological and pathological processes and provide insights into approaches for the modulation or suppression of such processes.

自由基过程与越来越多的病理学有关，包括主要的健康问题。癌症和动脉粥样硬化等问题。然而，尽管过去几年取得了令人印象深刻的进展，蛋白质自由基的基本生物化学仍然没有完全理解。在此提出的工作申请取决于在支助期即将结束时取得的关键进展，包括（a）确定乳过氧化物酶中血红素基团的自催化共价结合中的残基，（B）特异性乳过氧化物酶中转化为自由基的残基集中在酶与H2 O2反应时， (c)辣根过氧化物酶突变成一种在其能力上模仿哺乳动物过氧化物酶的酶共价结合其血红素，以及（d）在高铁肌红蛋白系统中证明酪氨酸的氧化与自由基的接触取决于除离氧化中心的距离以外的因素。本项目的重点是蛋白质自由基生物化学的两个方面：（a）羧酸根的可能形成和作用，高度被忽视的物种，在过氧化物酶的功能，和（B）的机制，形成不寻常的分子内交联及其功能后果。本项目的第一个目标是确定羧酸基团在血红素-蛋白质交联反应中的作用过氧化物酶模型系统第二个目的是使用相同的模型来阐明游离基在形成中的作用髓过氧化物酶的甲硫氨酸-乙烯基键。第三个目的是澄清为什么共价血红素结合是对哺乳动物过氧化物酶功能很重要。第四个目的是研究活性位点的作用羧酸基团和过氧化氢酶-过氧化物酶中不寻常的交联的机制，形成了最后一个目标是采用附加酚的高铁肌红蛋白模型系统来探索肌红蛋白的功能。确定蛋白质中哪些酪氨酸被氧化的关系。这些研究应该有助于了解过氧化碳自由基在生理和病理中的产生和转归过程，并提供了深入了解的方法，用于调制或抑制这种过程。