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Non-Ribosomal Peptide Synthetases pesL and pes1 are essential for Fumigaclavine C production in Aspergillus fumigatus

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  • Karen O'Hanlon
  • ,
  • Lorna Gallagher
  • ,
  • Markus Schrettl
  • ,
  • Christoph Jöchl
  • ,
  • Kevin Kavanagh
  • ,
  • Thomas O Larsen
  • ,
  • Sean Doyle
  • Afgrødeøkologi og Produktkvalitet

The identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen, Aspergillus fumigatus, remains outstanding. We found that the 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 nonribosomal peptide synthesis (NRPS) 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. LC-DAD-MS analysis also revealed the presence of fumiquinazolines A-F in both A. fumigatus wild-type and ΔpesL. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, as PesL has been shown to mediate fumiquinazoline biosynthesis, in vitro. Furthermore, this work provides the first direct link between EA biosynthesis and virulence, in agreement with observed toxicity associated with EA exposure. Finally, this study has uncovered a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.

TidsskriftApplied and Environmental Microbiology
Sider (fra-til)3166-3176
StatusUdgivet - 2012

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