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首页> 美国卫生研究院文献>Environmental Health Perspectives >Formation of reactive nitrogen species at biologic heme centers: a potential mechanism of nitric oxide-dependent toxicity.
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Formation of reactive nitrogen species at biologic heme centers: a potential mechanism of nitric oxide-dependent toxicity.

机译：在生物血红素中心形成反应性氮物种：一氧化氮依赖性毒性的潜在机制。

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The peroxidase-catalyzed nitration of tyrosine derivatives by nitrite and hydrogen peroxide has been studied in detail using the enzymes lactoperoxidase (LPO) from bovine milk and horseradish peroxidase (HRP). The results indicate the existence of two competing pathways, in which the nitrating species is either nitrogen dioxide or peroxynitrite. The first pathway involves one-electron oxidation of nitrite by the classical peroxidase intermediates compound I and compound II, whereas in the second pathway peroxynitrite is generated by reaction between enzyme-bound nitrite and hydrogen peroxide. The two mechanisms can be simultaneously operative, and their relative importance depends on the reagent concentrations. With HRP the peroxynitrite pathway contributes significantly only at relatively high nitrite concentrations, but for LPO this represents the main pathway even at relatively low (pathophysiological) nitrite concentrations and explains the high efficiency of the enzyme in the nitration. Myoglobin and hemoglobin are also active in the nitration of phenolic compounds, albeit with lower efficiency compared with peroxidases. In the case of myoglobin, endogenous nitration of the protein has been shown to occur in the absence of substrate. The main nitration site is the heme, but a small fraction of nitrated Tyr146 residue has been identified upon proteolytic digestion and high-performance liquid chromatography/mass spectrometry analysis of the peptide fragments. Preliminary investigation of the nitration of tryptophan derivatives by the peroxidaseitrite/hydrogen peroxide systems shows that a complex pattern of isomeric nitration products is produced, and this pattern varies with nitrite concentration. Comparative experiments using chemical nitrating agents indicate that at low nitrite concentrations, the enzymatic nitration produces a regioisomeric mixture of nitrotryptophanyl derivatives resembling that obtained using nitrogen dioxide, whereas at high nitrite concentrations the product pattern resembles that obtained using peroxynitrite.
机译：使用来自牛乳和辣根过氧化物酶（HRP）的乳过氧化物酶（LPO），详细研究了亚硝酸盐和过氧化氢对酪氨酸衍生物的过氧化物酶催化硝化作用。结果表明存在两个竞争途径，其中硝化物种是二氧化氮或过亚硝酸盐。第一种途径涉及经典的过氧化物酶中间体化合物I和化合物II对亚硝酸盐的单电子氧化，而在第二种途径中，过氧亚硝酸盐是通过酶结合的亚硝酸盐与过氧化氢之间的反应生成的。这两种机制可以同时起作用，它们的相对重要性取决于试剂浓度。对于HRP，过亚硝酸盐途径仅在相对较高的亚硝酸盐浓度下才有显着贡献，但对于LPO，即使在相对较低的（病理生理学）亚硝酸盐浓度下，它仍是主要途径，并解释了酶在硝化中的高效率。肌红蛋白和血红蛋白在酚类化合物的硝化中也有活性，尽管与过氧化物酶相比效率较低。对于肌红蛋白，已经证明蛋白质的内源硝化作用在没有底物的情况下发生。主要的硝化位点是血红素，但是通过蛋白水解和肽片段的高效液相色谱/质谱分析已鉴定出一小部分硝化的Tyr146残留物。通过过氧化物酶/亚硝酸盐/过氧化氢系统对色氨酸衍生物的硝化作用的初步研究表明，会生成复杂的异构化硝化产物模式，并且该模式随亚硝酸盐浓度而变化。使用化学硝化剂的对比实验表明，在低亚硝酸盐浓度下，酶促硝化产生的硝基色氨酸衍生物的区域异构体混合物类似于使用二氧化氮获得的硝基色氨酸衍生物，而在高亚硝酸盐浓度下，产品模式类似于使用过亚硝酸盐获得的产物。

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