Anderson M M, Hazen S L, Hsu F F, Heinecke J W
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 1997 Feb 1;99(3):424-32. doi: 10.1172/JCI119176.
Reactive aldehydes derived from reducing sugars and lipid peroxidation play a critical role in the formation of advanced glycation end (AGE) products and oxidative tissue damage. We have recently proposed another mechanism for aldehyde generation at sites of inflammation that involves myeloperoxidase, a heme enzyme secreted by activated phagocytes. We now demonstrate that human neutrophils employ the myeloperoxidase-H202-chloride system to produce alpha-hydroxy and alpha,beta-unsaturated aldehydes from hydroxy-amino acids in high yield. Identities of the aldehydes were established using mass spectrometry and high performance liquid chromatography. Activated neutrophils converted L-serine to glycolaldehyde, an alpha-hydroxyaldehyde which mediates protein cross-linking and formation of Nepsilon-(carboxymethyl)lysine, an AGE product. L-Threonine was similarly oxidized to 2-hydroxypropanal and its dehydration product, acrolein, an extremely reactive alpha,beta-unsaturated aldehyde which alkylates proteins and nucleic acids. Aldehyde generation required neutrophil activation and a free hydroxy-amino acid; it was inhibited by catalase and heme poisons, implicating H202 and myeloperoxidase in the cellular reaction. Aldehyde production by purified myeloperoxidase required H202 and chloride, and was mimicked by reagent hypochlorous acid (HOCl) in the absence of enzyme, suggesting that the reaction pathway involves a chlorinated intermediate. Collectively, these results indicate that the myeloperoxidase-H202-chloride system of phagocytes converts free hydroxy-amino acids into highly reactive alpha-hydroxy and alpha,beta-unsaturated aldehydes. The generation of glycolaldehyde, 2-hydroxypropanal, and acrolein by activated phagocytes may thus play a role in AGE product formation and tissue damage at sites of inflammation.
由还原糖和脂质过氧化产生的反应性醛类在晚期糖基化终末（AGE）产物的形成以及氧化组织损伤中起着关键作用。我们最近提出了另一种在炎症部位产生醛类的机制，该机制涉及髓过氧化物酶，一种由活化吞噬细胞分泌的血红素酶。我们现在证明，人类中性粒细胞利用髓过氧化物酶-H2O2-氯化物系统从羟基氨基酸中高产率地产生α-羟基醛和α,β-不饱和醛。通过质谱和高效液相色谱确定了醛类的身份。活化的中性粒细胞将L-丝氨酸转化为乙醇醛，一种介导蛋白质交联和AGE产物Nε-（羧甲基）赖氨酸形成的α-羟基醛。L-苏氨酸同样被氧化为2-羟基丙醛及其脱水产物丙烯醛，一种极具反应性的α,β-不饱和醛，可使蛋白质和核酸烷基化。醛类的产生需要中性粒细胞活化和游离的羟基氨基酸；它受到过氧化氢酶和血红素毒物的抑制，这表明H2O2和髓过氧化物酶参与了细胞反应。纯化的髓过氧化物酶产生醛类需要H2O2和氯化物，并且在没有酶的情况下被试剂次氯酸（HOCl）模拟，这表明反应途径涉及一种氯化中间体。总体而言，这些结果表明吞噬细胞的髓过氧化物酶-H2O2-氯化物系统将游离的羟基氨基酸转化为高反应性的α-羟基醛和α,β-不饱和醛。因此，活化吞噬细胞产生乙醇醛、2-羟基丙醛和丙烯醛可能在炎症部位的AGE产物形成和组织损伤中起作用。
