期刊
BIOCHEMISTRY
卷 41, 期 4, 页码 1293-1301出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi015777z
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资金
- NCRR NIH HHS [RR00954] Funding Source: Medline
- NHLBI NIH HHS [HL64344] Funding Source: Medline
- NIA NIH HHS [AG19309] Funding Source: Medline
- NIDDK NIH HHS [DK02456, DK56341] Funding Source: Medline
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.
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