Jakubowski H
Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101, USA.
J Physiol Pharmacol. 2008 Dec;59 Suppl 9:155-67.
Accumulating evidence suggests that homocysteine (Hcy) metabolite, the thioester Hcy-thiolactone, plays an important role in atherothrombosis. Hcy-thiolactone is a product of an error-editing reaction in protein biosynthesis which forms when Hcy is mistakenly selected by methionyl-tRNA synthetase. The thioester chemistry of Hcy-thiolactone underlies its ability to from isopeptide bonds with protein lysine residues, which impairs or alters protein's function. Protein targets for the modification by Hcy-thiolactone include fibrinogen, low-density lipoprotein, high-density lipoprotein, albumin, hemoglobin, and ferritin. Pathophysiological consequences of protein N-homocysteinylation include protein and cell damage, activation of an adaptive immune response and synthesis of auto-antibodies against N-Hcy-proteins, and enhanced thrombosis caused by N-Hcy-fibrinogen. Recent development of highly sensitive chemical and immunohistochemical assays has allowed verification of the hypothesis that the Hcy-thiolactone pathway contributes to pathophysiology of the vascular system, in particular of the prediction that conditions predisposing to atherosclerosis, such as genetic or dietary hyperhomocysteinemia, lead to elevation of Hcy-thiolactone and N-Hcy-protein. This prediction has been confirmed in vivo both in humans and in mice. For example, plasma Hcy-thiolactone was found to be elevated 59-72-fold in human patients with hyperhomocysteinemia secondary to mutations in methylenetetrahydrofolate reductase (MTHFR) or cystathionine beta-synthase (CBS) genes. Plasma N-Hcy-protein levels are elevated 24-30-fold in MTHFR- or CBS-deficiency, both in human patients and in mice. Plasma and urinary Hcy-thiolactone and plasma N-Hcy-protein levels are also elevated up to 30-fold in mice fed a hyperhomocysteinemic (1.5% methionine) diet. Furthermore, plasma levels of prothromobogenic N-Hcy-fibrinogen were elevated in human CBS deficiency, which explains increased atherothrombosis observed in CBS-deficient patients. We also observed increased immunohistochemical staining for N-Hcy-protein in aortic lesions from ApoE-deficient mice with hyperhomocysteinemia induced by a high methionine diet, relative to the mice fed a normal chow diet. We conclude that genetic or dietary hyperhomocysteinemia significantly elevates proatherothrombotic metabolites Hcy-thiolactone and N-Hcy-proteins in humans and mice.
越来越多的证据表明，同型半胱氨酸（Hcy）的代谢产物硫酯型同型半胱氨酸硫内酯（Hcy-硫内酯）在动脉粥样硬化血栓形成中起重要作用。Hcy-硫内酯是蛋白质生物合成中错误编辑反应的产物，当甲硫氨酰-tRNA合成酶错误地选择Hcy时就会形成。Hcy-硫内酯的硫酯化学性质是其与蛋白质赖氨酸残基形成异肽键的能力的基础，这会损害或改变蛋白质的功能。Hcy-硫内酯修饰的蛋白质靶点包括纤维蛋白原、低密度脂蛋白、高密度脂蛋白、白蛋白、血红蛋白和铁蛋白。蛋白质N-同型半胱氨酸化的病理生理后果包括蛋白质和细胞损伤、适应性免疫反应的激活以及针对N-同型半胱氨酸化蛋白质的自身抗体的合成，以及由N-同型半胱氨酸化纤维蛋白原引起的血栓形成增强。高灵敏度化学和免疫组织化学检测方法的最新进展使得能够验证Hcy-硫内酯途径参与血管系统病理生理过程的假说，特别是验证了易患动脉粥样硬化的情况，如遗传性或饮食性高同型半胱氨酸血症，会导致Hcy-硫内酯和N-同型半胱氨酸化蛋白质升高的预测。这一预测在人类和小鼠体内均得到了证实。例如，在因亚甲基四氢叶酸还原酶（MTHFR）或胱硫醚β-合酶（CBS）基因突变导致高同型半胱氨酸血症的人类患者中，血浆Hcy-硫内酯升高了59 - 72倍。在人类患者和小鼠中，MTHFR或CBS缺乏时血浆N-同型半胱氨酸化蛋白质水平升高了24 - 30倍。在喂食高同型半胱氨酸血症（1.5%甲硫氨酸）饮食的小鼠中，血浆和尿液中的Hcy-硫内酯以及血浆N-同型半胱氨酸化蛋白质水平也升高了30倍。此外，在人类CBS缺乏症患者中，促血栓形成的N-同型半胱氨酸化纤维蛋白原的血浆水平升高，这解释了CBS缺乏症患者中观察到的动脉粥样硬化血栓形成增加的现象。我们还观察到，与喂食正常饲料的小鼠相比，喂食高甲硫氨酸饮食诱导高同型半胱氨酸血症的ApoE缺乏小鼠主动脉病变中N-同型半胱氨酸化蛋白质的免疫组织化学染色增加。我们得出结论，遗传性或饮食性高同型半胱氨酸血症会显著升高人类和小鼠中促动脉粥样硬化血栓形成的代谢产物Hcy-硫内酯和N-同型半胱氨酸化蛋白质。
