Dec 4, 2008

Characterization of a novel dithiocarbamate glutathione reductase inhibitor and its use as a tool to modulate intracellular glutathione

The Journal of Biological Chemistry
Teresa SeefeldtXiangming Guan


Thiol redox state (TRS) is an important parameter to reflect intracellular oxidative stress and is associated with various normal and abnormal biochemical processes. Agents that can be used to increase intracellular TRS will be valuable tools in TRS-related research. Glutathione reductase (GR) is a critical enzyme in the homeostasis of TRS. The enzyme catalyzes the reduction of GSSG to GSH to maintain a high GSH:GSSG ratio. Inhibition of the enzyme can be used to increase TRS. Despite the reports of various GR inhibitors, N,N-bis(2-chloroethyl)-N-nitrosourea, an anticancer drug with IC(50) = 647 microm against yeast GR, remains the most commonly used GR inhibitor in the literature. However, the toxicity caused by nonspecific interactions, as well as inhibition of DNA synthesis, complicates the use of N,N-bis(2-chloroethyl)-N-nitrosourea as a GR inhibitor. We report 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2-AAPA) as a novel irreversible GR inhibitor. 2-AAPA was prepared by one-step synthesis from commercially available reagents. The K(i) and k(inact) of 2-AAPA against yeast GR were determined to be 56 microm and 0.1 min(-1), respectively. At the concen...Continue Reading

Mentioned in this Paper

Propionic acid
Antibiotic CV-1
Glutathione Disulfide
Glutamate-Cysteine Ligase
One-Step Dentin Bonding System
Oxidative Stress
Oxidative Stress Analysis
Sulfhydryl Compounds

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