Glutathione: an endogenous substrate for thiopurine methyltransferase?

An investigation was initiated to determine if glutathione is an endogenous substrate for thiopurine methyltransferase. Glutathione, as well as S-methylglutathione, were each capable of inhibiting the enzyme in a concentration-dependent manner, which suggested competitive and product inhibition, respectively. However, radiochromatography revealed that S-methylation of glutathione is not a catalytic activity of this sulfhydryl transmethylase. Subsequent experiments indicated that the inhibitory effects of both glutathione and S-methylglutathione on thiopurine methyltransferase may be due to their acidic natures, changing the reaction mixture pH away from the optimal range for the enzyme.