Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions - Mechanism of action of pyridoxamine
Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions - Mechanism of action of pyridoxamine
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DOI：
10.1074/jbc.m003263200
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发表时间：
2000-07-14
影响因子：
4.8
通讯作者：
Baynes, JW
中科院分区：
文献类型：
--
作者：
Onorato, JM;Jenkins, AJ;Baynes, JW
美拉德反应或布朗宁反应导致蛋白质上形成晚期糖基化终产物（AGEs），并有助于在衰老和糖尿病期间增加蛋白质的化学修饰。AGE抑制剂如氨基胍和吡哆胺（PM）已在动物模型和临床研究中被证明是有效的AGE形成和糖尿病并发症的发展的抑制剂。我们在这里报告，PM也抑制在体外脂质过氧化（脂氧化）反应过程中的蛋白质的化学修饰，我们表明，它的陷阱脂质过氧化过程中形成的反应中间体。在花生四烯酸与模型蛋白质RNase的反应中，PM阻止赖氨酸残基的修饰和高级脂氧化终产物（ALE）N-α-（羧甲基）赖氨酸、N-α-（羧乙基）赖氨酸、丙二酰二亚胺-赖氨酸和4-羟基壬烯醛-赖氨酸的形成。PM还抑制铜催化氧化低密度脂蛋白过程中赖氨酸修饰和ALE的形成。PM的己酸酰胺和壬二酸单酰胺衍生物被确定为在PM存在下亚油酸氧化过程中形成的主要产物。我们提出了一种机制，从9-和13-氧代癸二烯酸中间体形成的亚油酸过氧化过程中形成的这些产品。PM作为AGE和ALE形成的有效抑制剂，可能被证明可用于限制衰老和慢性疾病（包括糖尿病和动脉粥样硬化）中组织蛋白的化学修饰增加和相关病理学。
Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modification of proteins during aging and in diabetes. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) have proven effective in animal model and clinical studies as inhibitors of AGE formation and development of diabetic complications. We report here that PM also inhibits the chemical modification of proteins during lipid peroxidation (lipoxidation) reactions in vitro, and we show that it traps reactive intermediates formed during lipid peroxidation. In reactions of arachidonate with the model protein RNase, PM prevented modification of lysine residues and formation of the advanced lipoxidation end products (ALEs) N-epsilon-(carboxymethyl)lysine, N-epsilon-(carboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-catalyzed oxidation of low density lipoprotein. Hexanoic acid amide and nonanedioic acid monoamide derivatives of PM were identified as major products formed during oxidation of linoleic acid in the presence of PM. We propose a mechanism for formation of these products from the 9- and 13-oxo-decadienoic acid intermediates formed during peroxidation of linoleic acid. PM, as a potent inhibitor of both AGE and ALE formation, may prove useful for limiting the increased chemical modification of tissue proteins and associated pathology in aging and chronic diseases, including both diabetes and atherosclerosis.