Glutathione transferase activity with a novel substrate mimics the activation of the prodrug azathioprine

Analytical Biochemistry
Sanela KurtovicBengt Mannervik

Abstract

Azathioprine is a prodrug that is widely used clinically as an immunosuppressive agent. The pharmacological action of azathioprine is associated with the release of 6-mercaptopurine by a reaction involving glutathione. This biotransformation of azathioprine is catalyzed by glutathione transferases (GSTs). The nonenzymatic reaction with glutathione is minimal in comparison with the GST-catalyzed process, but azathioprine is still a slow substrate in comparison with the most effective GST substrates. Novel GSTs with higher catalytic efficiency toward azathioprine could be useful in novel therapeutic applications; therefore, directed evolution of GSTs for enhanced activities is desirable. However, screening for variants having higher catalytic activity with azathioprine is a time-consuming process due to the low activity with this substrate. A new chromogenic and faster substrate, 1-methyl-4-nitro-5-(4-nitrophenylthio)-1H-imidazole (NPTI), has been synthesized and characterized by assays with several GSTs. The novel substrate mimicked azathioprine in the reaction with glutathione catalyzed by alpha class GSTs and, therefore, is a valuable surrogate in the screening of large mutant libraries. NPTI may also find use in the elucidati...Continue Reading

References

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May 24, 2006·Molecular Pharmacology·Birgitta I EklundBengt Mannervik

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Citations

Nov 30, 2018·International Journal of Molecular Sciences·Marija Pljesa-ErcegovacTatjana Simic
Sep 1, 2012·Personalized Medicine·Paul Andrew BlakerJeremy David Sanderson

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