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Structure-Based Redesign of GST A2-2 for Enhanced Catalytic Efficiency with Azathioprine
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. Uppsala University, Sweden.ORCID-id: 0000-0002-6416-064X
Rekke forfattare: 42012 (engelsk)Inngår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 19, nr 3, s. 414-421Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2012. Vol. 19, nr 3, s. 414-421
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URN: urn:nbn:se:su:diva-162411DOI: 10.1016/j.chembiol.2012.01.021ISI: 000302588900014PubMedID: 22444596OAI: oai:DiVA.org:su-162411DiVA, id: diva2:1287610
Tilgjengelig fra: 2019-02-11 Laget: 2019-02-11 Sist oppdatert: 2019-12-12bibliografisk kontrollert

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