Details
| Original language | English |
|---|---|
| Pages (from-to) | 4109-4117 |
| Number of pages | 9 |
| Journal | Chemical science |
| Volume | 9 |
| Issue number | 17 |
| Early online date | 10 Apr 2018 |
| Publication status | Published - 7 May 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.
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In: Chemical science, Vol. 9, No. 17, 07.05.2018, p. 4109-4117.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046636434&partnerID=8YFLogxK
U2 - 10.1039/c8sc00717a
DO - 10.1039/c8sc00717a
M3 - Article
C2 - 29780540
AN - SCOPUS:85046636434
VL - 9
SP - 4109
EP - 4117
JO - Chemical science
JF - Chemical science
SN - 2041-6520
IS - 17
ER -