Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

Publication: Research - peer-reviewJournal article – Annual report year: 2012

  • Author: O'Hanlon, Karen A.

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

  • Author: Gallagher, Lorna

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

  • Author: Schrettl, Markus

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

  • Author: Jöchl, Christoph

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

  • Author: Kavanagh, Kevin

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

  • Author: Larsen, Thomas Ostenfeld

    Center for Microbial Biotechnology, Department of Systems Biology, Technical University of Denmark, Søltofts Plads, 2800, Kgs. Lyngby, Denmark

  • Author: Doyle, Sean

    Department of Biology and National Institute for Cellular Biotechnology, National University of Ireland Maynooth, Ireland

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The identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen, Aspergillus fumigatus, remains outstanding. We found that the nonribosomal peptide (NRP) synthetases PesL and Pes1 were essential for fumigaclavine C biosynthesis, the end product of the complex ergot alkaloid (EA) pathway in A. fumigatus. Deletion of either pesL (ΔpesL) or pes1 (Δpes1) resulted in complete loss of fumigaclavine C biosynthesis, relatively increased production of fumitremorgins such as TR-2, fumitremorgin C and verruculogen, increased sensitivity to H2O2, and increased sensitivity to the antifungals, voriconazole, and amphotericin B. Deletion of pesL resulted in severely reduced virulence in an invertebrate infection model (P <0.001). These findings indicate that NRP synthesis plays an essential role in mediating the final prenylation step of the EA pathway, despite the apparent absence of NRP synthetases in the proposed EA biosynthetic cluster for A. fumigatus. Liquid chromatography/diode array detection/mass spectrometry analysis also revealed the presence of fumiquinazolines A to F in both A. fumigatus wild-type and ΔpesL strains. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, since PesL has been shown to mediate fumiquinazoline biosynthesis in vitro. Furthermore, we provide here the first direct link between EA biosynthesis and virulence, in agreement with the observed toxicity associated with EA exposure. Finally, we demonstrate a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.
Original languageEnglish
JournalApplied and Environmental Microbiology
Publication date2012
Volume78
Issue9
Pages3166-3176
ISSN0099-2240
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 5
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