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

Takayoshi Awakawa (), Takuma Fujioka, Lihan Zhang, Shotaro Hoshino, Zhijuan Hu, Junko Hashimoto, Ikuko Kozone, Haruo Ikeda, Kazuo Shin-Ya (), Wen Liu and Ikuro Abe ()
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Takayoshi Awakawa: The University of Tokyo
Takuma Fujioka: The University of Tokyo
Lihan Zhang: The University of Tokyo
Shotaro Hoshino: The University of Tokyo
Zhijuan Hu: The University of Tokyo
Junko Hashimoto: Japan Biological Informatics Consortium
Ikuko Kozone: Japan Biological Informatics Consortium
Haruo Ikeda: Kitasato University
Kazuo Shin-Ya: The University of Tokyo
Wen Liu: Chinese Academy of Sciences
Ikuro Abe: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05877-z

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