Modification of proteins by isoketal-containing oxidized phospholipids
Modification of proteins by isoketal-containing oxidized phospholipids
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DOI：
10.1074/jbc.m313349200
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发表时间：
2004-04-02
影响因子：
4.8
通讯作者：
Roberts, LJ
中科院分区：
文献类型：
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作者：
Brame, CJ;Boutaud, O;Roberts, LJ
氧化应激经常导致膜蛋白功能改变。异酮缩醇是自由基诱导的脂质过氧化的异前列烷途径的高反应性产物，可快速形成共价蛋白质加合物，并在体外表现出形成蛋白质交联的显着倾向。对氧化损伤动物模型的异缩酮加合物的检查表明，最初的加合物是由磷脂中酯化的异缩酮形成的，代表了磷脂对蛋白质的一种新的与氧化损伤相关的修饰。加合物的成熟涉及磷脂的裂解以及加合物转化为可以长时间检测的更稳定的化学形式。由于初始加合物是由磷脂酯化的异缩酮形成的，因此使用模型膜蛋白（心脏 K+ 通道）检查异缩酮加合的功能结果。这些研究表明，异缩酮加合深刻改变了蛋白质功能，以剂量依赖性方式抑制钾电流。这些发现表明，磷脂酯化的异缩酮快速加合膜蛋白，并且这种修饰可以改变蛋白质功能，这表明氧化应激导致膜功能改变的普遍细胞机制。
Oxidative stress frequently leads to altered function of membrane proteins. Isoketals are highly reactive products of the isoprostane pathway of free radical-induced lipid peroxidation that rapidly form covalent protein adducts and exhibit a remarkable proclivity to form protein cross links in vitro. Examination of isoketal adducts from an animal model of oxidative injury revealed that initial adducts were formed by isoketals esterified in phospholipids, representing a novel oxidative injury-associated modification of proteins by phospholipids. Maturation of adducts involved cleavage from phospholipids and conversion of adducts to a more stable chemical form that can be detected for extended periods. Because initial adducts were formed by phospholipid-esterified isoketals, the functional consequence of isoketal adduction was examined using a model membrane protein ( a cardiac K+ channel). These studies revealed that isoketal adduction profoundly altered protein function, inhibiting potassium current in a dose-dependent manner. These findings indicate that phospholipid-esterified isoketals rapidly adduct membrane proteins and that such modification can alter protein function, suggesting a generalized cellular mechanism for alteration of membrane function as a consequence of oxidative stress.