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Glutathione Transferases in the Bioactivation of Azathioprine
Stockholm University, Faculty of Science, Department of Neurochemistry. Uppsala University, Sweden.ORCID iD: 0000-0002-6416-064X
Number of Authors: 2
2014 (English)In: Redox and Cancer Part A, San Diego: Elsevier, 2014, 199-244 p.Chapter in book (Refereed)
Abstract [en]

The prodrug azathioprine is primarily used for maintaining remission in inflammatory bowel disease, but approximately 30% of the patients suffer adverse side effects. The prodrug is activated by glutathione conjugation and release of 6-mercaptopurine, a reaction most efficiently catalyzed by glutathione transferase (GST) A2-2. Among five genotypes of GST A2-2, the variant A2*E has threefold fourfold higher catalytic efficiency with azathioprine, suggesting that the expression of A2*E could boost 6-mercaptopurine release and adverse side effects in treated patients. Structure-activity studies of the GST A2-2 variants and homologous alpha class GSTs were made to delineate the determinants of high catalytic efficiency compared to other alpha class GSTs. Engineered chimeras identified GST peptide segments of importance, and replacing the corresponding regions in low-activity GSTs by these short segments produced chimeras with higher azathioprine activity. By contrast, H-site mutagenesis led to decreased azathioprine activity when active-site positions 208 and 213 in these favored segments were mutagenized. Alternative substitutions indicated that hydrophobic residues were favored. A pertinent question is whether variant A2*E represents the highest azathioprine activity achievable within the GST structural framework. This issue was addressed by mutagenesis of H-site residues assumed to interact with the substrate based on molecular modeling. The mutants with notably enhanced activities had small or polar residues in the mutated positions. The most active mutant L107G/L108D/F222H displayed a 70-fold enhanced catalytic efficiency with azathioprine. The determination of its structure by X-ray crystallography showed an expanded H-site, suggesting improved accommodation of the transition state for catalysis.

Place, publisher, year, edition, pages
San Diego: Elsevier, 2014. 199-244 p.
Series
Advances in Cancer Research, ISSN 0065-230X ; 122
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:su:diva-106773DOI: 10.1016/B978-0-12-420117-0.00006-2ISI: 000341414500007ISBN: 978-0-12-420117-0 (print)OAI: oai:DiVA.org:su-106773DiVA: diva2:738755
Note

AuthorCount:2;

Available from: 2014-08-19 Created: 2014-08-19 Last updated: 2015-03-16Bibliographically approved

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