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

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

Chemical Science, Volume: 9, Issue: 17, Pages: 4109 - 4117

Swansea University Author: Claudio Greco Orcid Logo

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DOI (Published version): 10.1039/c8sc00717a

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 confir...

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Published in: Chemical Science
ISSN: 2041-6520 2041-6539
Published: Royal Society of Chemistry (RSC) 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa61526
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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. 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spelling 2022-10-20T12:22:44.2234867 v2 61526 2022-10-10 The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis cacac6459bd7cf4a241f63661006036f 0000-0003-3067-0999 Claudio Greco Claudio Greco true false 2022-10-10 SBI 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. Journal Article Chemical Science 9 17 4109 4117 Royal Society of Chemistry (RSC) 2041-6520 2041-6539 10 4 2018 2018-04-10 10.1039/c8sc00717a COLLEGE NANME Biosciences COLLEGE CODE SBI Swansea University 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). 2022-10-20T12:22:44.2234867 2022-10-10T17:25:58.8599820 Faculty of Science and Engineering School of Biosciences, Geography and Physics - Biosciences Kate M. J. de Mattos-Shipley 1 Claudio Greco 0000-0003-3067-0999 2 David M. Heard 0000-0003-3005-8222 3 Gemma Hough 4 Nicholas P. Mulholland 5 Jason L. Vincent 6 Jason Micklefield 0000-0001-8951-4873 7 Thomas J. Simpson 0000-0003-0777-1935 8 Christine L. Willis 0000-0002-3919-3642 9 Russell J. Cox 0000-0002-1844-0157 10 Andrew M. Bailey 0000-0002-7594-3703 11 61526__25516__bc34a2badef94a77a0f3720e29195a4b.pdf 61526_VoR.pdf 2022-10-20T12:21:14.2418231 Output 1052997 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. true eng http://creativecommons.org/licenses/by/3.0/
title The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
spellingShingle The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
Claudio Greco
title_short The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
title_full The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
title_fullStr The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
title_full_unstemmed The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
title_sort The cycloaspeptides: uncovering a new model for methylated nonribosomal peptide biosynthesis
author_id_str_mv cacac6459bd7cf4a241f63661006036f
author_id_fullname_str_mv cacac6459bd7cf4a241f63661006036f_***_Claudio Greco
author Claudio Greco
author2 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
format Journal article
container_title Chemical Science
container_volume 9
container_issue 17
container_start_page 4109
publishDate 2018
institution Swansea University
issn 2041-6520
2041-6539
doi_str_mv 10.1039/c8sc00717a
publisher Royal Society of Chemistry (RSC)
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Biosciences, Geography and Physics - Biosciences{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Biosciences, Geography and Physics - Biosciences
document_store_str 1
active_str 0
description 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.
published_date 2018-04-10T04:20:24Z
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score 11.0133505

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