Inhibition effect of pyridoxamine on lipid hydroperoxide-derived modifications to human serum albumin.
Inhibition effect of pyridoxamine on lipid hydroperoxide-derived modifications to human serum albumin.
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DOI：
10.1371/journal.pone.0196050
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Oe T
中科院分区：
文献类型：
--
作者：
Lee SH;Matsunaga A;Oe T
吡哆胺（PM）是治疗各种慢性病/疾病的有前途的候选药物，其中氧化应激和羰基化合物是影响致病性的重要因素。 PM 的这些能力主要归因于它通过清除反应性羰基物质来抑制高级糖化和脂氧化终产物的形成。因此，PM 可能通过捕获脂质氢过氧化物衍生的醛（例如 4-oxo-2(E)-nonenal (ONE) 和 4-羟基-2(E)-nonenal (HNE)）来防止蛋白质损伤。此前有报道称PM与ONE反应通过形成吡啶并-1,3-恶嗪(PO1/PO2)生成吡咯-1,3-恶嗪(PO8)。在这项研究中，我们发现 ONE 和 HNE 在与 PM 反应时产生相同的含有吡咯环（PO7、PH2）的产物。 PO7/PH2的结构经LC-MS和NMR分析显示为1-(2-羟基-6-羟甲基-3-甲基吡啶-4-基甲基)-2-戊基吡咯。 PO1、PO7/PH2 和 PO8 是主要的稳定 PM-ONE/HNE 加合物。在人血清白蛋白（HSA）与ONE或HNE的孵育中，Lys残基为两种醛提供了最有利的修饰位点，并且HNE修饰位点的数量高于ONE修饰位点的数量。当 HSA 在抗坏血酸存在下与亚油酸氢过氧化物反应时，ONE 修饰的残基（10 个赖氨酸、3 个组氨酸、2 个精氨酸）比 HNE（8 个组氨酸、2 个赖氨酸）更多，表明醛对氨基酸残基的相对反应性。在用浓度增加的 PM 处理后，ONE 修饰的 HSA 肽的浓度显着降低，但 HNE 修饰的肽的浓度没有降低，并且呈剂量依赖性。与此同时，PM-ONE 加合物的形成以剂量依赖性方式增加。 PM的抑制作用也在遭受氧化应激的细胞系统中得到证实。我们的结果表明，PM 可以通过优先捕获 ONE 来抑制脂质过氧化氢衍生的蛋白质损伤，所得的 PM-ONE 加合物可用作 ONE 生产的剂量计，以确定脂质过氧化水平。
Pyridoxamine (PM) is a promising drug candidate for treating various chronic conditions/diseases in which oxidative stress and carbonyl compounds are important factors affecting pathogenicity. These abilities of PM are mainly attributed to its inhibition of advanced glycation and lipoxidation end product formation, by scavenging reactive carbonyl species. PM might therefore prevent protein damage from lipid hydroperoxide-derived aldehydes such as 4-oxo-2(E)-nonenal (ONE) and 4-hydroxy-2(E)-nonenal (HNE) by trapping them. It was previously reported that PM reacts with ONE to produce pyrrolo-1,3-oxazine (PO8) through the formation of pyrido-1,3-oxazine (PO1/PO2). In this study, we found that ONE and HNE yield an identical product containing a pyrrole ring (PO7, PH2) upon reaction with PM. The structure of PO7/PH2 was shown by LC-MS and NMR analyses to be 1-(2-hydroxy-6-hydroxymethyl-3-methylpyridin-4-ylmethyl)-2-pentylpyrrole. PO1, PO7/PH2, and PO8 were the main stable PM-ONE/HNE adducts. In the incubation of human serum albumin (HSA) with ONE or HNE, Lys residues provided the most favorable modification sites for both aldehydes, and the number of HNE-modified sites was higher than that of ONE-modified sites. When HSA was allowed to react with a linoleic acid hydroperoxide in the presence of ascorbic acid, ONE modified more residues (10 Lys, 3 His, 2 Arg) than did HNE (8 His, 2 Lys), indicating the relative reactivity of aldehydes towards amino acid residues. Upon treatment with increasing concentrations of PM, the concentrations of ONE-modified HSA peptides, but not of HNE-modified peptides, were reduced significantly and dose-dependently. Concomitantly, the formation of PM-ONE adducts increased in a dose-dependent manner. The inhibition effect of PM was also confirmed in the cell system subjected to oxidative stress. Our results demonstrate that PM can inhibit lipid hydroperoxide-derived damage to proteins by trapping ONE preferentially, and the resulting PM-ONE adducts can be used as a dosimeter for ONE production to determine the levels of lipid peroxidation.
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影响因子：
4.8
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