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

Research output: Contribution to journalResearch articleContributedpeer-review


  • Thomas Schafhauser - , University of Tübingen (Author)
  • Norbert Kirchner - , University of Tübingen (Author)
  • Andreas Kulik - , University of Tübingen (Author)
  • Mieke M E Huijbers - , Wageningen University & Research (WUR) (Author)
  • Liane Flor - , Chair of Biochemistry (Author)
  • Thibault Caradec - , Université de Lille (Author)
  • David P Fewer - , University of Helsinki (Author)
  • Harald Gross - , University of Tübingen (Author)
  • Philippe Jacques - , Université de Lille (Author)
  • Linda Jahn - , Chair of Plant Physiology (Author)
  • Jouni Jokela - , University of Helsinki (Author)
  • Valérie Leclère - , Université de Lille (Author)
  • Jutta Ludwig-Müller - , Chair of Plant Physiology (Author)
  • Kaarina Sivonen - , University of Helsinki (Author)
  • Willem J H van Berkel - , Wageningen University & Research (WUR) (Author)
  • Tilmann Weber - , University of Tübingen (Author)
  • Wolfgang Wohlleben - , University of Tübingen (Author)
  • Karl-Heinz van Pée - , Chair of Biochemistry (Author)


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-aminobutyrate 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 that cct-like clusters are present in all of the sequenced Talaromyces strains indicating a high prevalence of cyclochlorotine production ability.


Original languageEnglish
Pages (from-to)3728-3741
Number of pages14
JournalEnvironmental Microbiology
Issue number11
Publication statusPublished - Nov 2016

External IDs

Scopus 84976905121
ORCID /0000-0001-9147-4188/work/142257660



  • Fungal Proteins/genetics, Mycotoxins/biosynthesis, Penicillium/metabolism, Peptide Synthases/genetics, Peptides, Cyclic/biosynthesis, Phenylalanine/metabolism, Talaromyces/enzymology