title: Glutathione-conjugated sulfanylalkanols are substrates for ABCC11 and γ-glutamyl transferase 1: a potential new pathway for the formation of odorant precursors in the apocrine sweat gland.
abstract: We have previously shown that precursors of odorous components characteristic of axillary sweat are hardly detectable or undetectable in individuals carrying the 538G > A SNP in the ABCC11 transporter gene. However, it is unclear, whether ABCC11 is directly involved in the transport of these compounds. To approach this question, transport of peptide-conjugated potential precursors of 3-methyl-3-sulfanylhexanol (3M3SH), a key determinant of axillary malodour, was measured using membrane vesicles of Sf9 insect cells overexpressing human ABCC11. Whilst no ABCC11-mediated transport was detected for the dipeptide precursor Cys-Gly-3M3SH, the glutathione conjugate of 3M3SH (SG-3M3SH) was robustly taken up by ABCC11 at a transport rate of 0.47 pmol/mg/min. Collectively, these results illuminate SG-3M3SH as a putative precursor of 3M3SH, which then may undergo intra-vesicular maturation to generate Cys-Gly-3M3SH. Critically, the apocrine sweat gland was demonstrated to express γ-glutamyl transferase 1 (GGT1) protein, which is known to catalyse the deglutamylation of glutathionyl conjugates. Additionally, we provide evidence that recombinant and isolated hepatic human GGT1 is capable of transforming SG-3M3SH to Cys-Gly-3M3SH in vitro. To sum up, we demonstrate that the functionality of ABCC11 is likely to play an important role in the generation of axillary malodour. Furthermore, we identify GGT1 as a key enzyme involved in the biosynthesis of Cys-Gly-3M3SH.
authors.affiliation: Research Center, Beiersdorf AG, Hamburg, Germany; Department of Pharmacology, Center of Drug Absorption and Transport, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Baumann
authors.forename: Sophia
authors.initials: S
authors.lastname: Bergmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt-Rose
authors.forename: Heiner
authors.initials: H
authors.lastname: Max
authors.forename: Annette
authors.initials: A
authors.lastname: Martin
authors.forename: Bernd
authors.initials: B
authors.lastname: Enthaler
authors.forename: Lara
authors.initials: L
authors.lastname: Terstegen
authors.forename: Dorothea
authors.initials: D
authors.lastname: Schweiger
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: Horst
authors.initials: H
authors.lastname: Wenck
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Zorica
authors.initials: Z
authors.lastname: Jovanovic
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001050:Apocrine Glands / Q000378:metabolism*; D002460:Cell Line; D000441:Hexanols / Q000378:metabolism*; D006801:Humans; D009812:Odorants; D013425:Sulfanilic Acids / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: C516951:3-methyl-3-sulfonylhexan-1-ol; C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000441:Hexanols; D013425:Sulfanilic Acids; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human
keywords: ABCC11; apocrine sweat; odour precursors