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Glutathione transferase: new model for glutathione activation
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Biokemi I)
2008 (English)In: Chemistry - A European Journal, ISSN 0947-6539, Vol. 14, no 31, 9591-8 p.Article in journal (Refereed) Published
Abstract [en]

Glutathione transferases are enzymes of the cellular detoxification system that metabolize a vast spectrum of xenobiotic and endobiotic toxic compounds. They are homodimers or heterodimers and each monomer has an active center composed of a G-site in which glutathione (GSH) binds and an H-site for the electrophilic substrate. When GSH binds to the G-site, the pKa value of its thiol group drops by 2.5 units; this promotes its deprotonation and, therefore, produces a strong nucleophilic thiolate that is able to react with the electrophilic substrate. The mechanism behind the deprotonation of the thiol group is still unknown. Some studies point to the fact that the GSH glutamyl alpha-carboxylate group is essential for GSH activation, whereas others indicate the importance of the active-center water molecules. On the basis of QM/MM calculations, we propose a mechanism of GSH activation in which a water molecule, acting as a bridge, is able to assist in the transfer of the proton from the GSH thiol group to the GSH glutamyl alpha-carboxylate group, after an initial GSH conformational rearrangement. We calculated the potential of mean force of this GSH structural rearrangement that would be necessary for the approach of both groups and we then performed a QM/MM ONIOM scan of water-assisted proton transfer. The overall free-energy barrier for the process is consistent with experimental studies of the enzyme kinetics.

Place, publisher, year, edition, pages
2008. Vol. 14, no 31, 9591-8 p.
Keyword [en]
enzyme catalysis, glutathione, proton transfer, reaction mechanisms, transferases
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-106018DOI: 10.1002/chem.200800946ISI: 000260896200019PubMedID: 18792041OAI: oai:DiVA.org:uu-106018DiVA: diva2:223303
Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2009-07-13Bibliographically approved

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