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

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Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus. / O'Hanlon, Karen A.; Gallagher, Lorna; Schrettl, Markus; Jöchl, Christoph; Kavanagh, Kevin; Larsen, Thomas Ostenfeld; Doyle, Sean.

In: Applied and Environmental Microbiology, Vol. 78, No. 9, 2012, p. 3166-3176.

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

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O'Hanlon, Karen A.; Gallagher, Lorna; Schrettl, Markus; Jöchl, Christoph; Kavanagh, Kevin; Larsen, Thomas Ostenfeld; Doyle, Sean / Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus.

In: Applied and Environmental Microbiology, Vol. 78, No. 9, 2012, p. 3166-3176.

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

Bibtex

@article{58cfff3ce4584f7e861c886db5b4fe64,
title = "Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus",
publisher = "American Society for Microbiology",
author = "O'Hanlon, {Karen A.} and Lorna Gallagher and Markus Schrettl and Christoph Jöchl and Kevin Kavanagh and Larsen, {Thomas Ostenfeld} and Sean Doyle",
year = "2012",
doi = "10.1128/AEM.07249-11",
volume = "78",
number = "9",
pages = "3166--3176",
journal = "Applied and Environmental Microbiology",
issn = "0099-2240",

}

RIS

TY - JOUR

T1 - Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

A1 - O'Hanlon,Karen A.

A1 - Gallagher,Lorna

A1 - Schrettl,Markus

A1 - Jöchl,Christoph

A1 - Kavanagh,Kevin

A1 - Larsen,Thomas Ostenfeld

A1 - Doyle,Sean

AU - O'Hanlon,Karen A.

AU - Gallagher,Lorna

AU - Schrettl,Markus

AU - Jöchl,Christoph

AU - Kavanagh,Kevin

AU - Larsen,Thomas Ostenfeld

AU - Doyle,Sean

PB - American Society for Microbiology

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.1128/AEM.07249-11

DO - 10.1128/AEM.07249-11

JO - Applied and Environmental Microbiology

JF - Applied and Environmental Microbiology

SN - 0099-2240

IS - 9

VL - 78

SP - 3166

EP - 3176

ER -