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.

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.

The specific biochemistry of human axilla odour formation viewed in an evolutionary context.

Human body odour is dominated by the scent of specific odourants emanating from specialized glands in the axillary region. These specific odourants are produced by an intricate interplay between biochemical pathways in the host and odour-releasing enzymes present in commensal microorganisms of the axillary microbiome. Key biochemical steps for the release of highly odouriferous carboxylic acids and sulfur compounds have been elucidated over the past 15 years. Based on the profound molecular understanding and specific analytical methods developed, evolutionary questions could be asked for the first time with small population studies: (i) a genetic basis for body odour could be shown with a twin study, (ii) no effect of genes in the human leukocyte antigen complex on the pattern of odourant carboxylic acid was found, and (iii) loss of odour precursor secretion by a mutation in the ABCC11 gene could explain why a large fraction of the population in the Far East lack body odour formation. This review summarizes what is currently known at the molecular level on the biochemistry of the formation of key odourants in the human axilla. At the same time, we present for the first time the crystal structure of the Nα-acyl-aminoacylase, a key human odour-releasing enzyme, thus describing at the molecular level how bacteria on the skin surface have adapted their enzyme to the specific substrates secreted by the human host. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.