Evaluation of a dithiocarbamate derivative as an inhibitor of human glutaredoxin-1.
Evaluation of a dithiocarbamate derivative as an inhibitor of human glutaredoxin-1.
复制标题
评估二硫代氨酸衍生物作为人戊二蛋白1的抑制剂。
DOI：
10.3109/14756366.2011.649267
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发表时间：
2013-06
影响因子：
5.6
通讯作者：
Seefeldt T
中科院分区：
文献类型：
--
作者：
Sadhu SS;Callegari E;Zhao Y;Guan X;Seefeldt T
谷氧还蛋白（GRX）参与巯基氧化还原状态的调节。GRX-1是一种细胞溶质酶，负责催化蛋白质的脱谷胱甘肽化。迄今为止，很少有GRX-1抑制剂的报道。本文的目的是报告2-乙酰氨基-3-[4-（2-乙酰氨基-2-羧乙基-硫烷基硫羰基氨基）苯基硫代氨基甲酰基硫烷基]丙酸（2-AAPA）作为人GRX-1的抑制剂。采用透析法、底物保护法和质谱法研究了GRX-1的抑制机制。2-AAPA以时间和浓度依赖性方式抑制GRX-1。透析后活性没有恢复，表明抑制是不可逆的。底物保护和质谱分析的结果表明，抑制作用发生在活性位点。该化合物还在人卵巢癌细胞中产生GRX抑制。2-AAPA是一种不可逆的GRX-1抑制剂，与以前报道的抑制剂相比具有相似或更高的效力。2-AAPA对GRX-1的抑制作用可作为研究巯基氧化还原状态的工具。
Glutaredoxins (GRX) are involved in the regulation of thiol redox state. GRX-1 is a cytosolic enzyme responsible for the catalysis of deglutathionylation of proteins. To date, very few inhibitors of GRX-1 have been reported. The objective of this paper is to report 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethyl-sulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) as an inhibitor of human GRX-1. The mechanism of inhibition of GRX-1 was investigated using dialysis, substrate protection, and mass spectrometry. 2-AAPA inhibits GRX-1 in a time and concentration dependent manner. The activity did not return following dialysis indicating that inhibition is irreversible. Results of substrate protection and mass spectrometry indicate that the inhibition is occurring at the active site. The compound also produced GRX inhibition in human ovarian cancer cells. 2-AAPA is an irreversible GRX-1 inhibitor with similar or greater potency compared to previously reported inhibitors. The inhibition of GRX-1 by 2-AAPA could be used as a tool to study thiol redox state.
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