title: Pityriazepin and other potent AhR ligands isolated from Malassezia furfur yeast.
abstract: Malassezia furfur yeast strains isolated from diseased human skin preferentially biosynthesize indole alkaloids which can be detected in the human skin and are highly potent activators of the aryl hydrocarbon receptor (AhR) and AhR-dependent gene expression. Chemical analysis of an EtOAc extract of a M. furfur strain obtained from diseased human skin and grown on l-tryptophan agar revealed several known AhR active tryptophan metabolites along with a previously unidentified compound, pityriazepin. While its structure resembled that of the known alkaloid pityriacitrin, the comprised pyridine ring had been transformed into an azepinone. The indoloazepinone scaffold of pityriazepin is extremely rare in nature and has only been reported once previously. Pityriazepin, like the other isolated compounds, was found to be a potent activator of the AhR-dependent reporter gene assay in recombinant cell lines derived from four different species, although significant species differences in relative potency were observed. The ability of pityriazepin to competitively bind to the AhR and directly stimulate AhR DNA binding classified it as a new naturally-occurring potent AhR agonist. M. furfur produces an expanded collection of extremely potent naturally occurring AhR agonists, which produce their biological effects in a species-specific manner.
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Athens 15771, Greece.
authors.forename: Nikitia
authors.initials: N
authors.lastname: Mexia
authors.affiliation: Department of Skin and Venereal Diseases, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Gaitanis
authors.affiliation: Mycology Laboratory, Department of Microbiology, Medical School, University of Athens, Greece.
authors.forename: Aristea
authors.initials: A
authors.lastname: Velegraki
authors.affiliation: Department of Environmental Toxicology, University of California, Davis 95616, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Soshilov
authors.affiliation: Department of Environmental Toxicology, University of California, Davis 95616, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Athens 15771, Greece; Department of Environmental Toxicology, University of California, Davis 95616, USA. Electronic address: magiatis@pharm.uoa.gr.
authors.forename: Prokopios
authors.initials: P
authors.lastname: Magiatis
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008024:Ligands; D008290:Malassezia / Q000737:chemistry*; D051379:Mice; D011817:Rabbits; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity
chemical_list: D001381:Azepines; D026121:Indole Alkaloids; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; C000598352:pityriazepin
keywords: Aryl-hydrocarbon receptor; Indole metabolites; Malassezia furfur; Pityriacitrin; Pityriazepin