S-(2-chloroacetyl)glutathione, a reactive glutathione thiol ester and a putative metabolite of 1,1-dichloroethylene.
S-(2-chloroacetyl)glutathione, a reactive glutathione thiol ester and a putative metabolite of 1,1-dichloroethylene.
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DOI：
10.1021/bi00410a020
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发表时间：
1988-05
期刊：
影响因子：
2.9
通讯作者：
Daniel C. Liebler;D. G. Latwesen;Thaddeus C. Reeder
中科院分区：
文献类型：
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作者：
Daniel C. Liebler;D. G. Latwesen;Thaddeus C. Reeder
有毒的卤乙烯 1,1-二氯乙烯 (DCE) 转化为 S-(2-S-谷胱甘肽-乙酰基)谷胱甘肽 (GSCH2COSG) 涉及两个谷胱甘肽 (GSH) 分子被微粒体 DCE 代谢物 ClCH2COCl 连续酰化和烷基化。为了研究其在 DCE 生物转化中的可能作用，我们合成了假定的中间体 S-(2-氯乙酰基)谷胱甘肽 (ClCH2COSG)。在水性缓冲液中，ClCH2COSG 不会水解释放 GSH，而是经历两步重排产生环状产物。通过液体二次离子质谱和 1H-13C 异核相关核磁共振光谱进行的产物分析表明，重排涉及氯乙酰基部分从半胱氨酰硫醇到γ-谷氨酰α-胺的初始转移。然后半胱氨酰硫醇置换2-氯乙酰基亚甲基碳上的氯，得到环状产物。 2 mM ClCH2COSG 与 20 mM GSH 一起孵育产生的环状产物比 GSCH2COSG 多约 4.5 倍。 ClCH2COSG 烷基化催产辛二硫醇和 N-乙酰基-L-半胱氨酸产生类似于 GSCH2COSG 的 S-[2-(烷硫基)乙酰基]谷胱甘肽加合物。不存在S-2-氯乙酰化产物。在通过烷基化与硫醇反应以及通过重排分解时，ClCH2COSG表现出与ClCH2COCl显着不同的性质。尽管其反应性比其酰卤前体低得多，但 ClCH2COSG 在 DCE 中毒中的细胞靶标的共价修饰中可能表现出更大的选择性。
Conversion of the toxic vinyl halide 1,1-dichloroethylene (DCE) to S-(2-S-glutathionyl-acetyl)glutathione (GSCH2COSG) involves sequential acylation and alkylation of two glutathione (GSH) molecules by the microsomal DCE metabolite ClCH2COCl. To examine its possible role in DCE biotransformation, we synthesized the putative intermediate S-(2-chloroacetyl)glutathione (ClCH2COSG). In aqueous buffer, ClCH2COSG did not hydrolyze to release GSH, but instead underwent a two-step rearrangement to yield a cyclic product. Product analyses by liquid secondary ion mass spectrometry and 1H-13C heteronuclear correlation nuclear magnetic resonance spectroscopy indicated that rearrangement involved initial transfer of the chloroacetyl moiety from the cysteinyl thiol to the gamma-glutamyl alpha-amine. The cysteinyl thiol then displaced chloride from the 2-chloroacetyl methylene carbon to yield the cyclic product. Incubation of 2 mM ClCH2COSG with 20 mM GSH yielded approximately 4.5-fold more cyclic product than GSCH2COSG. ClCH2COSG alkylated oxytocindithiol and N-acetyl-L-cysteine to yield S-[2-(alkylthio)acetyl]glutathione adducts analogous to GSCH2COSG. S-2-Chloroacetylation products were absent. In reacting with thiols by alkylation and in decomposing by rearrangement, ClCH2COSG displayed properties strikingly different from those of ClCH2COCl. Although much less reactive than its acyl halide precursor, ClCH2COSG may display greater selectivity in covalent modification of cellular targets in DCE intoxication.