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Regio- and enantioselectivities in epoxide conjugations are modulated by residue 210 in Mu class glutathione transferases.
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry. Department of Biochemistry and Organic Chemistry, Biochemistry.
2005 (English)In: Protein Eng Des Sel, ISSN 1741-0126, Vol. 18, no 12, 607-16 p.Article in journal (Refereed) Published
Abstract [en]

The homologous human glutathione transferases (GSTs) M1-1 and M2-2 have similar catalytic activities with many electrophilic substrates, but differ strikingly in their conjugation of epoxides with glutathione. Residue 210, Thr in GST M2-2 and Ser in GST M1-1, is a key active-site component in determining the activity profile with epoxide substrates. This residue is hypervariable in Mu class GSTs, suggesting that it has special significance in the evolution of new functions. The present study shows that minor modifications of this residue can have major consequences for the enzyme-catalyzed epoxide conjugations. In general, a Ser at position 210 gives the highest catalytic efficiency, but the relatively high activity with an Ala placed on this position demonstrates that a hydroxyl group is not required. In contrast, a Thr residue suppresses the activity with epoxides by several orders of magnitude without major effects on the activity with alternative GST substrates. Residue 210 influences both the regio- and enantioselectivity with chiral and prochiral epoxides of stilbene and styrene and influences the distribution of isomeric glutathione conjugates. Thus, residue 210 contributes to both stereoselective recognition of the substrates and to partitioning of the isomeric reactants to the alternative transition states leading to separate chiral products.

Place, publisher, year, edition, pages
2005. Vol. 18, no 12, 607-16 p.
Keyword [en]
Amino Acid Substitution, Catalysis, Epoxy Compounds/*chemistry, Glutathione/chemistry, Glutathione Transferase/*chemistry/genetics, Humans, Kinetics, Models; Molecular, Mutation, Research Support; Non-U.S. Gov't, Serine/chemistry, Stereoisomerism, Substrate Specificity, Threonine/chemistry
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-76695PubMedID: 16251220OAI: oai:DiVA.org:uu-76695DiVA: diva2:104607
Available from: 2006-03-06 Created: 2006-03-06 Last updated: 2011-01-11

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Ivarsson, YlvaMannervik, Bengt

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