The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • Kate M.J. De Mattos-Shipley
  • Claudio Greco
  • David M. Heard
  • Gemma Hough
  • Nicholas P. Mulholland
  • Jason L. Vincent
  • Jason Micklefield
  • Thomas J. Simpson
  • Christine L. Willis
  • Russell J. Cox
  • Andrew M. Bailey

Externe Organisationen

  • University of Bristol
  • Syngenta
  • University of Manchester
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Details

OriginalspracheEnglisch
Seiten (von - bis)4109-4117
Seitenumfang9
FachzeitschriftChemical science
Jahrgang9
Ausgabenummer17
Frühes Online-Datum10 Apr. 2018
PublikationsstatusVeröffentlicht - 7 Mai 2018

Abstract

The cycloaspeptides are bioactive pentapeptides produced by various filamentous fungi, which have garnered interest from the agricultural industry due to the reported insecticidal activity of the minor metabolite, cycloaspeptide E. Genome sequencing, bioinformatics and heterologous expression confirmed that the cycloaspeptide gene cluster contains a minimal 5-module nonribosomal peptide synthetase (NRPS) and a new type of trans-acting N-methyltransferase (N-MeT). Deletion of the N-MeT encoding gene and subsequent feeding studies determined that two modules of the NRPS preferentially accept and incorporate N-methylated amino acids. This discovery allowed the development of a system with unprecedented control over substrate supply and thus output, both increasing yields of specific metabolites and allowing the production of novel fluorinated analogues. Furthermore, the biosynthetic pathway to ditryptophenaline, another fungal nonribosomal peptide, was shown to be similar, in that methylated phenylalanine is accepted by the ditryptophenaline NRPS. Again, this allowed the directed biosynthesis of a fluorinated analogue, through the feeding of a mutant strain. These discoveries represent a new paradigm for the production of N-methylated cyclic peptides via the selective incorporation of N-methylated free amino acids.

ASJC Scopus Sachgebiete

Zitieren

The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis. / De Mattos-Shipley, Kate M.J.; Greco, Claudio; Heard, David M. et al.
in: Chemical science, Jahrgang 9, Nr. 17, 07.05.2018, S. 4109-4117.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

De Mattos-Shipley, KMJ, Greco, C, Heard, DM, Hough, G, Mulholland, NP, Vincent, JL, Micklefield, J, Simpson, TJ, Willis, CL, Cox, RJ & Bailey, AM 2018, 'The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis', Chemical science, Jg. 9, Nr. 17, S. 4109-4117. https://doi.org/10.1039/c8sc00717a, https://doi.org/10.15488/3457
De Mattos-Shipley, K. M. J., Greco, C., Heard, D. M., Hough, G., Mulholland, N. P., Vincent, J. L., Micklefield, J., Simpson, T. J., Willis, C. L., Cox, R. J., & Bailey, A. M. (2018). The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis. Chemical science, 9(17), 4109-4117. https://doi.org/10.1039/c8sc00717a, https://doi.org/10.15488/3457
De Mattos-Shipley KMJ, Greco C, Heard DM, Hough G, Mulholland NP, Vincent JL et al. The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis. Chemical science. 2018 Mai 7;9(17):4109-4117. Epub 2018 Apr 10. doi: 10.1039/c8sc00717a, 10.15488/3457
De Mattos-Shipley, Kate M.J. ; Greco, Claudio ; Heard, David M. et al. / The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis. in: Chemical science. 2018 ; Jahrgang 9, Nr. 17. S. 4109-4117.
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title = "The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis",
abstract = "The cycloaspeptides are bioactive pentapeptides produced by various filamentous fungi, which have garnered interest from the agricultural industry due to the reported insecticidal activity of the minor metabolite, cycloaspeptide E. Genome sequencing, bioinformatics and heterologous expression confirmed that the cycloaspeptide gene cluster contains a minimal 5-module nonribosomal peptide synthetase (NRPS) and a new type of trans-acting N-methyltransferase (N-MeT). Deletion of the N-MeT encoding gene and subsequent feeding studies determined that two modules of the NRPS preferentially accept and incorporate N-methylated amino acids. This discovery allowed the development of a system with unprecedented control over substrate supply and thus output, both increasing yields of specific metabolites and allowing the production of novel fluorinated analogues. Furthermore, the biosynthetic pathway to ditryptophenaline, another fungal nonribosomal peptide, was shown to be similar, in that methylated phenylalanine is accepted by the ditryptophenaline NRPS. Again, this allowed the directed biosynthesis of a fluorinated analogue, through the feeding of a mutant strain. These discoveries represent a new paradigm for the production of N-methylated cyclic peptides via the selective incorporation of N-methylated free amino acids.",
author = "{De Mattos-Shipley}, {Kate M.J.} and Claudio Greco and Heard, {David M.} and Gemma Hough and Mulholland, {Nicholas P.} and Vincent, {Jason L.} and Jason Micklefield and Simpson, {Thomas J.} and Willis, {Christine L.} and Cox, {Russell J.} and Bailey, {Andrew M.}",
note = "Acknowledgements: This research was supported by funding from BBSRC and Syngenta (BB/K002341/1), BBSRC and EPSRC through BrisSynBio, the Bristol Centre for Synthetic Biology (BB/L01386X/1) and the Bristol Chemical Synthesis Centre for Doctoral Training which provided a PhD studentship for DMH (EP/L015366/1). Genome sequencing and the production of assembled draft genomes was carried out at the DNA sequencing facility in the Biochemistry Department of Cambridge University. Bioactivity screening was conducted at Syngenta with the assistance of Emily Aldridge. Thanks go to all members of the natural product sLola consortium for discussions and input to experimental design.",
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AU - De Mattos-Shipley, Kate M.J.

AU - Greco, Claudio

AU - Heard, David M.

AU - Hough, Gemma

AU - Mulholland, Nicholas P.

AU - Vincent, Jason L.

AU - Micklefield, Jason

AU - Simpson, Thomas J.

AU - Willis, Christine L.

AU - Cox, Russell J.

AU - Bailey, Andrew M.

N1 - Acknowledgements: This research was supported by funding from BBSRC and Syngenta (BB/K002341/1), BBSRC and EPSRC through BrisSynBio, the Bristol Centre for Synthetic Biology (BB/L01386X/1) and the Bristol Chemical Synthesis Centre for Doctoral Training which provided a PhD studentship for DMH (EP/L015366/1). Genome sequencing and the production of assembled draft genomes was carried out at the DNA sequencing facility in the Biochemistry Department of Cambridge University. Bioactivity screening was conducted at Syngenta with the assistance of Emily Aldridge. Thanks go to all members of the natural product sLola consortium for discussions and input to experimental design.

PY - 2018/5/7

Y1 - 2018/5/7

N2 - The cycloaspeptides are bioactive pentapeptides produced by various filamentous fungi, which have garnered interest from the agricultural industry due to the reported insecticidal activity of the minor metabolite, cycloaspeptide E. Genome sequencing, bioinformatics and heterologous expression confirmed that the cycloaspeptide gene cluster contains a minimal 5-module nonribosomal peptide synthetase (NRPS) and a new type of trans-acting N-methyltransferase (N-MeT). Deletion of the N-MeT encoding gene and subsequent feeding studies determined that two modules of the NRPS preferentially accept and incorporate N-methylated amino acids. This discovery allowed the development of a system with unprecedented control over substrate supply and thus output, both increasing yields of specific metabolites and allowing the production of novel fluorinated analogues. Furthermore, the biosynthetic pathway to ditryptophenaline, another fungal nonribosomal peptide, was shown to be similar, in that methylated phenylalanine is accepted by the ditryptophenaline NRPS. Again, this allowed the directed biosynthesis of a fluorinated analogue, through the feeding of a mutant strain. These discoveries represent a new paradigm for the production of N-methylated cyclic peptides via the selective incorporation of N-methylated free amino acids.

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