September 22, 2019  |  

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

Authors: Awakawa, Takayoshi and Fujioka, Takuma and Zhang, Lihan and Hoshino, Shotaro and Hu, Zhijuan and Hashimoto, Junko and Kozone, Ikuko and Ikeda, Haruo and Shin-Ya, Kazuo and Liu, Wen and Abe, Ikuro

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.

Journal: Nature communications
DOI: 10.1038/s41467-018-05877-z
Year: 2018

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