Homocystamides promote free-radical and oxidative damage to proteins
Homocystamides promote free-radical and oxidative damage to proteins
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DOI：
10.1073/pnas.0909737107
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发表时间：
2010-01-12
影响因子：
11.1
通讯作者：
Strongin, Robert M.
中科院分区：
文献类型：
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作者：
Sibrian-Vazquez, Martha;Escobedo, Jorge O.;Strongin, Robert M.
同型半胱氨酸水平升高与几种主要疾病有关。然而，尚不清楚同型半胱氨酸是标记物还是致病因子。人类中存在的大部分（约 80%）同型半胱氨酸是蛋白质结合的。高半胱氨酸及其环状同源物高半胱氨酸硫内酯对蛋白质的翻译后修饰的研究正在成为当前备受关注的领域，以解决正在进行的“介导物/标记物争议”[Jacobsen DW (2009) Clin Chem 55: 1-2]。有趣的是，许多与同型半胱氨酸相关的病理也与氧化应激有关。在当前的研究中，提出了同型半胱氨酸结合蛋白与氧化损伤之间因果关系的化学证据。例如，由于人血清白蛋白与同型半胱氨酸硫内酯反应，蛋白质羰基功能性出现可重复的增加。这种情况在生理温度下暴露于空气时发生，无需添加任何氧化剂或自由基引发剂。 α-氨基酸碳中心自由基是众所周知的蛋白质羰基前体，它是通过涉及硫代内酯衍生的同型半胱酰胺的氢原子转移过程形成的。缓冲液中的模型肽以及人血浆中的天然蛋白质还表现出与同型半胱酰胺促进的氢原子转移和由此产生的碳中心自由基一致的特性。
Elevated levels of homocysteine are associated with several major diseases. However, it is not clear whether homocysteine is a marker or a causative agent. The majority (ca. 80%) of the homocysteine present in humans is protein bound. The study of the posttranslational modification of proteins by homocysteine and its cyclic congener, homocysteine thiolactone, is emerging as an area of great current interest for unraveling the ongoing "mediator/marker controversy" [Jacobsen DW (2009) Clin Chem 55: 1-2]. Interestingly, many of the pathologies associated with homocysteine are also linked to oxidative stress. In the current study, chemical evidence for a causal relationship between homocysteine-bound proteins and oxidative damage is presented. For example, a reproducible increase in protein carbonyl functionality occurs as a consequence of the reaction of human serum albumin with homocysteine thiolactone. This occurs at physiological temperature upon exposure to air without any added oxidants or free-radical initiators. Alpha-amino acid carbon-centered radicals, well-known precursors of protein carbonyls, are shown to form via a hydrogen atom transfer process involving thiolactone-derived homocystamides. Model peptides in buffer as well as native proteins in human blood plasma additionally exhibit properties in keeping with the homocystamide-facilitated hydrogen atom transfer and resultant carbon-centered radicals.