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

Author

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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
    Friedrich Schiller University Jena)

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.

Suggested Citation

  • Huiyun Peng & Keishi Ishida & Yuki Sugimoto & Holger Jenke-Kodama & Christian Hertweck, 2019. "Emulating evolutionary processes to morph aureothin-type modular polyketide synthases and associated oxygenases," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11896-1
    DOI: 10.1038/s41467-019-11896-1
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    Cited by:

    1. Guifa Zhai & Yan Zhu & Guo Sun & Fan Zhou & Yangning Sun & Zhou Hong & Chuan Dong & Peter F. Leadlay & Kui Hong & Zixin Deng & Fuling Zhou & Yuhui Sun, 2023. "Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xixi Sun & Yujie Yuan & Qitong Chen & Shiqi Nie & Jiaxuan Guo & Zutian Ou & Min Huang & Zixin Deng & Tiangang Liu & Tian Ma, 2022. "Metabolic pathway assembly using docking domains from type I cis-AT polyketide synthases," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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