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Metabolic pathway assembly using docking domains from type I cis-AT polyketide synthases

Author

Listed:
  • Xixi Sun

    (Chinese Academy of Sciences)

  • Yujie Yuan

    (Chinese Academy of Sciences)

  • Qitong Chen

    (Chinese Academy of Sciences)

  • Shiqi Nie

    (Chinese Academy of Sciences)

  • Jiaxuan Guo

    (Chinese Academy of Sciences
    Wuhan University)

  • Zutian Ou

    (Chinese Academy of Sciences)

  • Min Huang

    (Chinese Academy of Sciences)

  • Zixin Deng

    (Wuhan University
    Shanghai Jiao Tong University
    Wuhan University)

  • Tiangang Liu

    (Wuhan University
    Wuhan University
    Hesheng Tech, Co., Ltd
    Wuhan University)

  • Tian Ma

    (Chinese Academy of Sciences)

Abstract

Engineered metabolic pathways in microbial cell factories often have no natural organization and have challenging flux imbalances, leading to low biocatalytic efficiency. Modular polyketide synthases (PKSs) are multienzyme complexes that synthesize polyketide products via an assembly line thiotemplate mechanism. Here, we develop a strategy named mimic PKS enzyme assembly line (mPKSeal) that assembles key cascade enzymes to enhance biocatalytic efficiency and increase target production by recruiting cascade enzymes tagged with docking domains from type I cis-AT PKS. We apply this strategy to the astaxanthin biosynthetic pathway in engineered Escherichia coli for multienzyme assembly to increase astaxanthin production by 2.4-fold. The docking pairs, from the same PKSs or those from different cis-AT PKSs evidently belonging to distinct classes, are effective enzyme assembly tools for increasing astaxanthin production. This study addresses the challenge of cascade catalytic efficiency and highlights the potential for engineering enzyme assembly.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33272-2
    DOI: 10.1038/s41467-022-33272-2
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    References listed on IDEAS

    as
    1. Li Su & Laurence Hôtel & Cédric Paris & Clara Chepkirui & Alexander O. Brachmann & Jörn Piel & Christophe Jacob & Bertrand Aigle & Kira J. Weissman, 2022. "Engineering the stambomycin modular polyketide synthase yields 37-membered mini-stambomycins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Takeshi Miyazawa & Melissa Hirsch & Zhicheng Zhang & Adrian T. Keatinge-Clay, 2020. "An in vitro platform for engineering and harnessing modular polyketide synthases," Nature Communications, Nature, vol. 11(1), pages 1-7, December.
    3. Wei Kang & Tian Ma & Min Liu & Jiale Qu & Zhenjun Liu & Huawei Zhang & Bin Shi & Shuai Fu & Juncai Ma & Louis Tung Faat Lai & Sicong He & Jianan Qu & Shannon Wing-Ngor Au & Byung Ho Kang & Wilson Chun, 2019. "Modular enzyme assembly for enhanced cascade biocatalysis and metabolic flux," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    4. Lee J. Sweetlove & Alisdair R. Fernie, 2018. "The role of dynamic enzyme assemblies and substrate channelling in metabolic regulation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    5. 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.
    6. Li Su & Laurence Hôtel & Cédric Paris & Clara Chepkirui & Alexander O. Brachmann & Jörn Piel & Christophe Jacob & Bertrand Aigle & Kira J. Weissman, 2022. "Author Correction: Engineering the stambomycin modular polyketide synthase yields 37-membered mini-stambomycins," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    7. Somnath Dutta & Jonathan R. Whicher & Douglas A. Hansen & Wendi A. Hale & Joseph A. Chemler & Grady R. Congdon & Alison R. H. Narayan & Kristina Håkansson & David H. Sherman & Janet L. Smith & Georgio, 2014. "Structure of a modular polyketide synthase," Nature, Nature, vol. 510(7506), pages 512-517, June.
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