Generation of intramolecular and intermolecular sulfenamides, sulfinamides, and Sulfonamides by hypochlorous acid: A potential pathway for oxidative cross-linking of low-density lipoprotein by myeloperoxidase
Generation of intramolecular and intermolecular sulfenamides, sulfinamides, and Sulfonamides by hypochlorous acid: A potential pathway for oxidative cross-linking of low-density lipoprotein by myeloperoxidase
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DOI：
10.1021/bi015777z
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发表时间：
2002-01-29
期刊：
影响因子：
2.9
通讯作者：
Heinecke, JW
中科院分区：
文献类型：
--
作者：
Fu, XY;Mueller, DM;Heinecke, JW
氧化低密度脂蛋白（LDL）与动脉粥样硬化形成有关，人类动脉粥样硬化病变中含有被髓过氧化物酶（一种由活化吞噬细胞分泌的血红素蛋白）氧化的LDL。使用过氧化氢（H2 O2），髓过氧化物酶产生次氯酸（HOCl），一种强氧化剂。我们现在证明，HOCl产生亚磺酰胺，亚磺酰胺和磺胺类模型肽，这表明一个潜在的机制LDL氧化和交联。当我们将CG下的合成肽PF（K）暴露于HOCl时，该肽的巯基残基迅速反应，产生接近定量的产物产率。串联质谱分析鉴定了产物为次磺酰胺、亚磺酰胺和磺酰胺，它们都是通过肽的巯基和赖氨酸残基的分子内交联形成的。在CG条下的肽PF（R）暴露于HOCl后也观察到分子内亚磺酰胺，表明精氨酸的胍基也可以形成硫-氮交联。CG下的合成肽PF（V）含有游离巯基残基但缺乏亲核氨基酸侧链，当暴露于HOCl时形成分子间磺酰胺。二聚体的串联质谱分析表明，一个PF（V）的N-末端氨基在bar CG分子下与另一个的巯基残基交联。该肽在暴露于HOCl后也与N-α-乙酰基赖氨酸形成分子间磺酰胺交联，表明赖氨酸残基的ε-氨基可以经历类似的反应。此外，人中性粒细胞使用髓过氧化物酶-H2 O2系统在含有赖氨酸或精氨酸残基的模型肽中产生亚磺酰胺。总的来说，我们的观察提高了髓过氧化物酶产生的HOCl有助于动脉壁中分子内和分子间蛋白质交联的可能性。髓过氧化物酶也可能利用这种机制在其他炎症条件下形成硫-氮交联。
Oxidized low-density lipoprotein (LDL) is implicated in atherogenesis, and human atherosclerotic lesions contain LDL oxidized by myeloperoxidase, a heme protein secreted by activated phagocytes. Using hydrogen peroxide (H2O2), myeloperoxidase generates hypochlorous acid (HOCl), a powerful oxidant. We now demonstrate that HOCl produces sulfenamides, sulfinamides, and sulfonamides in model peptides, which suggests a potential mechanism for LDL oxidation and cross-linking. When we exposed the synthetic peptide PF (K) under bar CG to HOCl, the peptide's thiol residue reacted rapidly, generating a near-quantitative yield of products. Tandem mass spectrometric analysis identified the products as the sulfenamide, sulfinamide, and sulfonamide, all formed by intramolecular cross-linking of the peptide's thiol and lysine residues. An intramolecular sulfinamide was also observed after the peptide PF (R) under bar CG was exposed to HOCl, indicating that the guanidine group of arginine can also form a sulfur-nitrogen crosslink. The synthetic peptide PF (V) under bar CG, which contains a free thiol residue but lacks nucleophilic amino acid side chains, formed an intermolecular sulfonamide when exposed to HOCl. Tandem mass spectrometric analysis of the dimer revealed that the free N-terminal amino group of one PF (V) under bar CG molecule cross-linked with the thiol residue of another. This peptide also formed intermolecular sulfonamide cross-links with N-alpha-acetyllysine after exposure to HOCl, demonstrating that the epsilon-amino group of a lysine residue can undergo a similar reaction. Moreover, human neutrophils used the myeloperoxidase-H2O2 system to generate sulfinamides in model peptides containing lysine or arginine residues. Collectively, our observations raise the possibility that HOCl generated by myeloperoxidase contributes to intramolecular and intermolecular protein cross-linking in the artery wall. Myeloperoxidase might also use this mechanism to form sulfur-nitrogen cross-links in other inflammatory conditions.