Issue 17, 2018

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
12 Feb 2018
Accepted
03 Apr 2018
First published
10 Apr 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 4109-4117

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

Kate M. J. de Mattos-Shipley, C. Greco, D. M. Heard, G. Hough, N. P. Mulholland, J. L. Vincent, J. Micklefield, T. J. Simpson, C. L. Willis, R. J. Cox and A. M. Bailey, Chem. Sci., 2018, 9, 4109 DOI: 10.1039/C8SC00717A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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