Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution

Reprogramming of the NRPS/PKS assembly line is an attractive method for the production of new bioactive molecules. However, it is usually hampered by the loss of intimate domain/module interactions required for the precise control of chain transfer and elongation reactions. In this study, we first e...

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Veröffentlicht in:Nature communications 2018-08, Vol.9 (1), p.3534-10, Article 3534
Hauptverfasser: Awakawa, Takayoshi, Fujioka, Takuma, Zhang, Lihan, Hoshino, Shotaro, Hu, Zhijuan, Hashimoto, Junko, Kozone, Ikuko, Ikeda, Haruo, Shin-Ya, Kazuo, Liu, Wen, Abe, Ikuro
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Sprache:eng
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Zusammenfassung:Reprogramming of the NRPS/PKS assembly line is an attractive method for the production of new bioactive molecules. However, it is usually hampered by the loss of intimate domain/module interactions required for the precise control of chain transfer and elongation reactions. In this study, we first establish heterologous expression systems of the unique antimycin-type cyclic depsipeptides: JBIR-06 (tri-lactone) and neoantimycin (tetra-lactone), and engineer their biosyntheses by taking advantage of bioinformatic analyses and evolutionary insights. As a result, we successfully accomplish three manipulations: (i) ring contraction of neoantimycin (from tetra-lactone to tri-lactone), (ii) ring expansion of JBIR-06 (from tri-lactone to tetra-lactone), and (iii) alkyl chain diversification of JBIR-06 by the incorporation of various alkylmalonyl-CoA extender units, to generate a set of unnatural derivatives in practical yields. This study presents a useful strategy for engineering NRPS-PKS module enzymes, based on nature’s diversification of the domain and module organizations. Modifying the non-ribosomal peptide synthase (NRPS)/polyketide synthase (PKS) pathway to generate novel non-ribosomal peptides often results in a loss of productivity. Here the authors use evolutionary alignments of NRPS/PKS gene clusters to guide rational design of complexes that can produce novel lactones.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-05877-z