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Discovery of a new peptide natural product by Streptomyces coelicolor genome mining

Abstract

Analyses of microbial genome sequences reveal numerous examples of gene clusters encoding proteins typically involved in complex natural product biosynthesis but not associated with the production of known natural products1,2,3. In Streptomyces coelicolor M145 there are several gene clusters encoding new nonribosomal peptide synthetase (NRPS) systems not associated with known metabolites. Application of structure-based models for substrate recognition by NRPS adenylation domains4,5,6 predicts the amino acids incorporated into the putative peptide products of these systems7,3, but the accuracy of these predictions is untested. Here we report the isolation and structure determination of the new tris-hydroxamate tetrapeptide iron chelator coelichelin from S. coelicolor using a genome mining approach guided by substrate predictions for the trimodular NRPS CchH, and we show that this enzyme, which lacks a C-terminal thioesterase domain, together with a homolog of enterobactin esterase (CchJ), are required for coelichelin biosynthesis. These results demonstrate that accurate prediction of adenylation domain substrate selectivity is possible and raise intriguing mechanistic questions regarding the assembly of a tetrapeptide by a trimodular NRPS.

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Figure 1: Organization of coelichelin NRPS and biosynthetic gene cluster.
Figure 2: Structure elucidation of coelichelin.
Figure 3: Model for coelichelin biosynthesis.

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Acknowledgements

P. Grice (Department of Chemistry, University of Cambridge, Cambridge, UK) and A. Clarke (Department of Chemistry, University of Warwick, Coventry, UK) are very gratefully acknowledged for assistance with recording and processing of NMR data. We thank A. Giannakopulos and P.J. Derrick (Department of Chemistry, University of Warwick, Coventry, UK) for assistance with ESI-FT-ICR-MS and A. Lubben (Bruker Daltonics, Coventry, UK) for assistance with ESI-MS-MS and ES-TOF-MS. J.L. Pernodet (University of Paris-Sud 11) is gratefully acknowledged for the gift of the plasmid pSPM83. J. Irwin is gratefully acknowledged for assistance with the GC analysis. F. Barona-Gómez, C. Corre, C. Blindauer and J.P. Rourke (Department of Chemistry, University of Warwick, Coventry, UK) are acknowledged for helpful discussions. This work was supported by grants from the UK Biotechnology and Biological Sciences Research Council and Wellcome Trust. S.L. thanks the EU for a Marie Curie fellowship.

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Correspondence to Gregory L Challis.

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Lautru, S., Deeth, R., Bailey, L. et al. Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat Chem Biol 1, 265–269 (2005). https://doi.org/10.1038/nchembio731

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