Human serum albumin (HSA) is the most abundant serum protein, contributing to the maintenance of redox balance in the extracellular fluids. One single free cysteine residue at position 34 is believed to be a target of oxidation. However, the molecular details and functions of oxidized HSAs remain obscure. Here we analyzed serum samples from normal subjects and hyperlipidemia patients and observed an enhanced S-thiolation of HSA in the hyperlipidemia patients as compared to the control individuals. Both cysteine and homocysteine were identified as the low molecular weight thiols bound to the HSAs. Intriguingly, S-thiolations were observed not only at Cys34, but also at multiple cysteine residues in the disulfide bonds of HSA. When the serum albumins from genetically modified mice that exhibit high levels of total homocysteine in serum were analyzed, we observed an enhanced S-homocysteinylation at multiple cysteine residues. In addition, the cysteine residues in the disulfide bonds were also thiolated in recombinant HSA that had been treated with the disulfide molecules. These findings and the result that S-homocysteinylation mediated increased surface hydrophobicity and ligand binding activity of HSA offer new insights into structural and functional alternation of serum albumins via S-thiolation.

中文翻译：

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对人血清白蛋白 S-硫醇化的结构和功能见解。

人血清白蛋白 (HSA) 是最丰富的血清蛋白，有助于维持细胞外液中的氧化还原平衡。34位上的一个游离半胱氨酸残基被认为是氧化的目标。然而，氧化 HSA 的分子细节和功能仍然不清楚。在这里，我们分析了来自正常受试者和高脂血症患者的血清样本，并观察到与对照个体相比，高脂血症患者中 HSA 的 S-硫醇化增强。半胱氨酸和同型半胱氨酸都被鉴定为与HSA结合的低分子量硫醇。有趣的是，不仅在 Cys34 上观察到 S-硫醇化，而且在 HSA 二硫键中的多个半胱氨酸残基上也观察到。当分析来自血清中总同型半胱氨酸水平高的转基因小鼠的血清白蛋白时，我们观察到多个半胱氨酸残基处的 S-同型半胱氨酸化增强。此外，二硫键中的半胱氨酸残基也在用二硫键处理过的重组HSA中被硫醇化。这些发现和 S-同型半胱氨酸化介导 HSA 表面疏水性和配体结合活性增加的结果为通过 S-硫醇化改变血清白蛋白的结构和功能提供了新的见解。