The cyclochlorotine mycotoxin is produced by the nonribosomal peptide synthetase CctN in Talaromyces islandicus (“Penicillium islandicum”)

Thomas Schafhauser, Norbert Kirchner, Andreas Kulik, Mieke M.E. Huijbers, Liane Flor, Thibault Caradec, David P. Fewer, Harald Gross, Philippe Jacques, Linda Jahn, Jouni Jokela, Valérie Leclère, Jutta Ludwig-Müller, Kaarina Sivonen, Willem J.H. van Berkel, Tilmann Weber, Wolfgang Wohlleben, Karl-Heinz van Pée

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Abstract

Talaromyces islandicus (“Penicillium islandicum”) is a widespread foodborne mold that produces numerous secondary metabolites, among them potent mycotoxins belonging to different chemical classes. A notable metabolite is the hepatotoxic and carcinogenic pentapeptide cyclochlorotine that contains the unusual amino acids β-phenylalanine, 2-aminobutyric acid and 3,4-dichloroproline. Although the chemical structure has been known for over five decades, nothing is known about the biosynthetic pathway of cyclochlorotine. Bioinformatic analysis of the recently sequenced genome of T. islandicus identified a wealth of gene clusters potentially coding for the synthesis of secondary metabolites. Here we show by RNA interference-mediated gene silencing that a nonribosomal peptide synthetase, CctN, is responsible for the synthesis of cyclochlorotine. Moreover, we identified novel cyclochlorotine chemical variants, whose production also depended on cctN expression. Surprisingly, the halogenase required for cyclochlorotine biosynthesis is not encoded in the cct cluster. Nonetheless, our findings enabled us to propose a detailed model for cyclochlorotine biosynthesis. In addition, comparative genomics revealed cct-like clusters are present in all of the sequenced Talaromyces strains indicating a high prevalence of cyclochlorotine production ability.
Original languageEnglish
JournalEnvironmental Microbiology
Volume18
Issue number11
Pages (from-to)3728–3741
ISSN1462-2912
DOIs
Publication statusPublished - 2016

Cite this

Schafhauser, T., Kirchner, N., Kulik, A., Huijbers, M. M. E., Flor, L., Caradec, T., Fewer, D. P., Gross, H., Jacques, P., Jahn, L., Jokela, J., Leclère, V., Ludwig-Müller, J., Sivonen, K., van Berkel, W. J. H., Weber, T., Wohlleben, W., & van Pée, K-H. (2016). The cyclochlorotine mycotoxin is produced by the nonribosomal peptide synthetase CctN in Talaromyces islandicus (“Penicillium islandicum”). Environmental Microbiology, 18(11), 3728–3741. https://doi.org/10.1111/1462-2920.13294