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Structure-Based Redesign of GST A2-2 for Enhanced Catalytic Efficiency with Azathioprine
Stockholm University, Faculty of Science, Department of Neurochemistry. Uppsala University, Sweden.
Number of Authors: 42012 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 19, no 3, p. 414-421Article in journal (Refereed) Published
Abstract [en]

Glutathione transferase (GST) A2-2 is the most efficient human enzyme in the biotransformation of the prodrug azathioprine (Aza). The activation of Aza has therapeutic potential for possible use of GSTs in targeted enzyme-prodrug treatment of diseases. Based on the assumed catalytic mechanism and computational docking of Aza to the active site of the enzyme, active-site residues were selected for construction of focused mutant libraries, which were thereafter screened for Aza activity. Mutants with elevated Aza activity were identified, DNA sequenced, and the proteins purified. The two most active mutants showed up to 70-fold higher catalytic efficiency than the parental GST A2-2. The structure of the most active triple mutant (L107G/L108D/F222H) enzyme was determined by X-ray crystallography demonstrating significant changes in the topography of the active site facilitating productive binding of Aza as a substrate.

Place, publisher, year, edition, pages
2012. Vol. 19, no 3, p. 414-421
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Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-162411DOI: 10.1016/j.chembiol.2012.01.021ISI: 000302588900014PubMedID: 22444596OAI: oai:DiVA.org:su-162411DiVA, id: diva2:1287610
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved

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Tars, KasparsMannervik, Bengt
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