Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan.
PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, 332-0012, Japan.
Sci Rep. 2018 Jan 17;8(1):932. doi: 10.1038/s41598-018-19610-9.
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.
人血清白蛋白（HSA）是血清中含量最丰富的蛋白质，有助于维持细胞外液的氧化还原平衡。位置 34 处的一个游离半胱氨酸残基被认为是氧化的靶标。然而，氧化 HSA 的分子细节和功能仍不清楚。在这里，我们分析了正常受试者和高脂血症患者的血清样本，观察到与对照组相比，高脂血症患者的 HSA 巯基化增强。半胱氨酸和同型半胱氨酸都被鉴定为与 HSA 结合的低分子量巯基。有趣的是，巯基化不仅发生在 Cys34，而且发生在 HSA 的二硫键中的多个半胱氨酸残基上。当分析血清白蛋白时，我们观察到来自遗传修饰小鼠的血清总同型半胱氨酸水平升高的血清白蛋白在多个半胱氨酸残基上的 S-同型半胱氨酸化增强。此外，用二硫键分子处理重组 HSA 后，二硫键中的半胱氨酸残基也被巯基化。这些发现以及 S-同型半胱氨酸化介导的 HSA 表面疏水性和配体结合活性增加的结果，为通过 S-巯基化对血清白蛋白的结构和功能改变提供了新的见解。
