title: Glutathione Adduct Patterns of Michael-Acceptor Carbonyls.
abstract: Glutathione (GSH) has so far been considered to facilitate detoxification of soft organic electrophiles through covalent binding at its cysteine (Cys) thiol group, followed by stepwise catalyzed degradation and eventual elimination along the mercapturic acid pathway. Here we show that in contrast to expectation from HSAB theory, Michael-acceptor ketones, aldehydes and esters may form also single, double and triple adducts with GSH involving β-carbon attack at the much harder N-terminus of the γ-glutamyl (Glu) unit of GSH. In particular, formation of the GSH-N single adduct contradicts the traditional view that S alkylation always forms the initial reaction of GSH with Michael-acceptor carbonyls. To this end, chemoassay analyses of the adduct formation of GSH with nine α,β-unsaturated carbonyls employing high performance liquid chromatography and tandem mass spectrometry have been performed. Besides enriching the GSH adductome and potential biomarker applications, electrophilic N-terminus functionalization is likely to impair GSH homeostasis substantially through blocking the γ-glutamyl transferase catalysis of the first breakdown step of modified GSH, and thus its timely reconstitution. The discussion includes a comparison with cyclic adducts of GSH and furan metabolites as reported in literature, and quantum chemically calculated thermodynamics of hard-hard, hard-soft, and soft-soft adducts.
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstraße 15, 04318 Leipzig, Germany.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg , Leipziger Straße 29, 09596 Freiberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Slawik
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Rickmeyer
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Brehm
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Böhme
authors.affiliation: UFZ Department of Ecological Chemistry, Helmholtz Centre for Environmental Research , Permoserstraße 15, 04318 Leipzig, Germany.|Institute for Organic Chemistry, Technical University Bergakademie Freiberg , Leipziger Straße 29, 09596 Freiberg, Germany.
authors.forename: Gerrit
authors.identifier: 0000-0002-3789-1703
authors.initials: G
authors.lastname: Schüürmann
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000737:chemistry*; D005982:Glutathione Transferase; D007659:Ketones / Q000737:chemistry; D053719:Tandem Mass Spectrometry
chemical_list: D000447:Aldehydes; D007659:Ketones; D005982:Glutathione Transferase; D005978:Glutathione