Lysophosphatidylcholine is Generated by Spontaneous Deacylation of Oxidized Phospholipids
Lysophosphatidylcholine is Generated by Spontaneous Deacylation of Oxidized Phospholipids
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DOI：
10.1021/tx100305b
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发表时间：
2011-01-01
影响因子：
4.1
通讯作者：
Salomon, Robert G.
中科院分区：
文献类型：
--
作者：
Choi, Jaewoo;Zhang, Wujuan;Salomon, Robert G.
存在于氧化损伤的低密度脂蛋白（oxLDL）中的溶血磷脂酰胆碱（lysoPC）水平升高与心血管并发症有关。LysoPC是由自由基催化的多不饱和pc氧化生成氧化截断的磷脂酰胆碱（oxPCs）。众所周知，oxPCs特别容易被血小板活化因子乙酰水解酶水解，这是一种存在于血浆中的磷脂酶（PL） a(2)，主要与LDL相关。旨在通过抑制PLA(2)催化水解来阻止lysoPC生成的药物正处于后期临床试验中。我们现在报道，在温度和pH （t(1/2) = 30 min, 37℃，pH 7.4）的生理条件下，自发去酰化oxPCs，如1-棕榈基-2-（4-羟基-7-氧-5-庚烯基）-sn-甘油-3-磷酸胆碱，很容易发生。我们还表明，该反应是通过分子内酯交换机制进行的。由于抗磷脂酶药物不能阻断这种非酶途径，因此可能需要额外的治疗措施来避免新发现的oxpc生物分子化学的病理后果。
Elevated levels of lysophosphatidylcholine (lysoPC), present in oxidatively damaged low-density lipoprotein (oxLDL), are implicated in cardiovascular complications. LysoPC is generated by Free radical-catalyzed oxidation of polyunsaturated PCs to oxidatively truncated phosphophatidylcholines (oxPCs). It is known that oxPCs are especially susceptible to hydrolysis by platelet-activating factor acetylhydrolase, a phospholipase (PL) A(2) that exists in plasma largely in association with LDL. Drugs that aim to prevent the generation of lysoPC by inhibiting this PLA(2)-catalyzed hydrolysis are in advanced clinical trials. We now report that spontaneous deacylation oxPCs, such as 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphocholine, occurs readily under physiological conditions of temperature and pH (t(1/2) = 30 min at 37 degrees C and pH 7.4). We also show that this reaction proceeds through an intramolecular transesterification mechanism. Because antiphospholipase drugs cannot block this nonenzymatic pathway to lysoPC, additional therapeutic measures may be needed to avoid the pathological consequences of the newly discovered biomolecular chemistry of oxPCs.