Thiol-disulfide exchanges modulate aldo-keto reductase family 1 member B10 activity and sensitivity to inhibitors
Thiol-disulfide exchanges modulate aldo-keto reductase family 1 member B10 activity and sensitivity to inhibitors
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DOI：
10.1016/j.biochi.2010.02.001
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发表时间：
2010-05-01
期刊：
影响因子：
3.9
通讯作者：
Cao, Deliang
中科院分区：
文献类型：
--
作者：
Shen, Yi;Zhong, Linlin;Cao, Deliang
可逆的巯基/二硫键交换是蛋白酶活性的重要调节机制。许多蛋白酶对活性氧（ROS）诱导的S-巯基化敏感;谷胱甘肽（GSH）和游离氨基酸半胱氨酸（Cys）是关键的细胞巯基抗氧化剂，保护蛋白质免受不可逆的氧化损伤。在这项研究中，我们发现醛酮还原酶家族1成员B10（AKR 1B 10）含有4个Cys残基，即，Cys 45、Cys 187、Cys 200和Cys 299。将AKR 1B 10暴露于ROS混合物导致其游离巯基显著减少，在0.5或1.0 mM生理巯基半胱氨酸存在下减少高达40-50%;因此，AKR 1B 10酶活性可逆地降低，与巯基的氧化平行。ROS诱导的巯基化也影响AKR 1B 10对抑制剂EBPC、依帕司他和他汀的敏感性。我们的研究结果首次表明，AKR 1B 10的酶活性和抑制剂敏感性是由巯基/二硫键交换调节的。(C)2010年由Elsevier Masson SAS出版。
The reversible thiol/disulfide exchange is an important regulatory mechanism of protein enzymatic activity. Many protein enzymes are susceptible to S-thiolation induced by reactive oxygen species (ROS); and the glutathione (GSH) and free amino acid cysteine (Cys) are critical cellular thiol anti-oxidants, protecting proteins from irreversible oxidative damage. In this study, we found that aldo keto reductase family 1 member B10 (AKR1B10) contains 4 Cys residues, i.e., Cys45, Cys187, Cys200, and Cys299. Exposing AKR1B10 to ROS mixtures resulted in significant decrease of its free sulfhydryl groups, up to 40-50% in the presence of physiological thiol cysteine at 0.5 or 1.0 mM; and accordingly, AKR1B10 enzymatic activity was reversibly decreased, in parallel with the oxidation of the sulfhydryl groups. ROS-induced thiolation also affected the sensitivity of AKR1B10 to inhibitors EBPC, epalrestat, and statil. Together our results showed for the first time that AKR1B10's enzymatic activity and inhibitor sensitivity are modulated by thiol/disulfide exchanges. (C) 2010 Published by Elsevier Masson SAS.