Emulating evolutionary processes to morph aureothin-type modular polyketide synthases and associated oxygenases

Huiyun Peng, Keishi Ishida, Yuki Sugimoto, Holger Jenke-Kodama and Christian Hertweck ()
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Huiyun Peng: Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a
Keishi Ishida: Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a
Yuki Sugimoto: Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a
Holger Jenke-Kodama: The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku
Christian Hertweck: Leibniz Institute for Natural Product Research and Infection Biology (HKI), Beutenbergstrasse 11a

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Polyketides produced by modular type I polyketide synthases (PKSs) play eminent roles in the development of medicines. Yet, the production of structural analogs by genetic engineering poses a major challenge. We report an evolution-guided morphing of modular PKSs inspired by recombination processes that lead to structural diversity in nature. By deletion and insertion of PKS modules we interconvert the assembly lines for related antibiotic and antifungal agents, aureothin (aur) and neoaureothin (nor) (aka spectinabilin), in both directions. Mutational and functional analyses of the polyketide-tailoring cytochrome P450 monooxygenases, and PKS phylogenies give contradictory clues on potential evolutionary scenarios (generalist-to-specialist enzyme evolution vs. most parsimonious ancestor). The KS-AT linker proves to be well suited as fusion site for both excision and insertion of modules, which supports a model for alternative module boundaries in some PKS systems. This study teaches important lessons on the evolution of PKSs, which may guide future engineering approaches.

Date: 2019
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DOI: 10.1038/s41467-019-11896-1

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