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DOI: 10.1055/s-0028-1084510
Identification of Indirubin as a metabolite of Malassezia furfur strains isolated from diseased skin
Seborrheic dermatitis (SD), pityriasis versicolor (PV) and dandruff (DF) are common skin diseases that are unequivocally associated with Malassezia yeasts. In a previous work [1] we compared M. furfur isolates from healthy and SD skin for the production of indole derivatives, using HPLC-UV and identified the preferential biosynthesis of several known indole derivatives [2,3] such as malassezin, pityriacitrin, malassezindol A, indol-3-carboxaldehyde, indolo[3,2-b]carbazol (ICZ) by M. furfur strains isolated from diseased skin. Further investigation of ethyl acetate extracts of M. furfur strains grown on L-tryptophan agar originating from SD, PV and DF, using preparative HPLC, led to -in addition to the aforementioned indoles- the isolation and structure elucidation by NMR and MS of indirubin. Indirubin which is a known highly potent ligand of the Aryl hydrocarbon receptor (AhR) and a strong inhibitor of several protein kinases is described for the first time as a metabolite of M.furfur. Isolated indirubin was used as standard for the development of an analytic methodology using HPLC-DAD. HPLC analysis of the extracts coming from 15 reference and clinical strains (7 healthy, 8 disease) revealed the preferential in vitro production of indirubin only by M. furfur strains isolated from skin lesions and not healthy skin controls. The selective production of compounds like ICZ and indirubin which are active AhR ligands offers indirect, statistical significant evidence in favor of the variable pathogenic potential within M. furfur strains as well as the possible implication of AhR activation in the pathogenesis of PV, SD and DF. In addition, the common facial distribution of SD and basal cell carcinoma, coupled by the inhibitory effect of indirubin on the GSK-3 enzyme – a Hedgehog pathway implicated enzyme – are suggestive of the potential implication of Malassezia metabolites in the development of non-melanoma skin cancer.
References: 1. Gaitanis, G. et al. (2008)J Invest Dermatol 128: 1620–1625 2. Wille, G. et al. (2002) Bioorg. Med. Chem 9: 955–960 3. Krämer, H.J. et al. (2005) ChemBioChem 6: 860–865.