评价一种二硫代氨基甲酸盐衍生物作为人谷胱甘肽还原酶-1 的抑制剂。
Evaluation of a dithiocarbamate derivative as an inhibitor of human glutaredoxin-1.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD, USA.
出版信息
J Enzyme Inhib Med Chem. 2013 Jun;28(3):456-62. doi: 10.3109/14756366.2011.649267. Epub 2012 Feb 3.
Abstract
CONTEXT
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.
OBJECTIVE
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.
MATERIALS AND METHODS
The mechanism of inhibition of GRX-1 was investigated using dialysis, substrate protection, and mass spectrometry.
RESULTS
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.
DISCUSSION
2-AAPA is an irreversible GRX-1 inhibitor with similar or greater potency compared to previously reported inhibitors.
CONCLUSION
The inhibition of GRX-1 by 2-AAPA could be used as a tool to study thiol redox state.
摘要
背景
谷氧还蛋白（GRX）参与巯基氧化还原状态的调节。GRX-1 是一种细胞质酶，负责催化蛋白质的去谷胱甘肽化。迄今为止，报道的 GRX-1 抑制剂很少。
目的
本文旨在报道 2-乙酰氨基-3-[4-(2-乙酰氨基-2-羧乙基-硫代羰基氨基)苯硫基]硫代羰氨基磺酰基丙酸（2-AAPA）作为人 GRX-1 的抑制剂。
材料和方法
使用透析、底物保护和质谱法研究了 GRX-1 的抑制机制。
结果
2-AAPA 以时间和浓度依赖的方式抑制 GRX-1。透析后活性未恢复，表明抑制是不可逆的。底物保护和质谱结果表明，抑制发生在活性部位。该化合物还在人卵巢癌细胞中产生 GRX 抑制作用。
讨论
2-AAPA 是一种不可逆的 GRX-1 抑制剂，其活性与先前报道的抑制剂相似或更强。
结论
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。
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