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C–N bond formation by a polyketide synthase

Author

Listed:
  • Jialiang Wang

    (Shanghai Jiao Tong University)

  • Xiaojie Wang

    (Shanghai Jiao Tong University
    Shanghai Jikaixing Biotech Inc.)

  • Xixi Li

    (Shanghai Jiao Tong University)

  • LiangLiang Kong

    (Chinese Academy of Sciences)

  • Zeqian Du

    (Shanghai Jiao Tong University)

  • Dandan Li

    (Shanghai Jiao Tong University)

  • Lixia Gou

    (North China University of Science and Technology)

  • Hao Wu

    (Shanghai Jiao Tong University)

  • Wei Cao

    (Shanghai Jiao Tong University)

  • Xiaozheng Wang

    (Shanghai Jiao Tong University)

  • Shuangjun Lin

    (Shanghai Jiao Tong University)

  • Ting Shi

    (Shanghai Jiao Tong University)

  • Zixin Deng

    (Shanghai Jiao Tong University)

  • Zhijun Wang

    (Shanghai Jiao Tong University)

  • Jingdan Liang

    (Shanghai Jiao Tong University)

Abstract

Assembly-line polyketide synthases (PKSs) are molecular factories that produce diverse metabolites with wide-ranging biological activities. PKSs usually work by constructing and modifying the polyketide backbone successively. Here, we present the cryo-EM structure of CalA3, a chain release PKS module without an ACP domain, and its structures with amidation or hydrolysis products. The domain organization reveals a unique “∞”-shaped dimeric architecture with five connected domains. The catalytic region tightly contacts the structural region, resulting in two stabilized chambers with nearly perfect symmetry while the N-terminal docking domain is flexible. The structures of the ketosynthase (KS) domain illustrate how the conserved key residues that canonically catalyze C–C bond formation can be tweaked to mediate C–N bond formation, revealing the engineering adaptability of assembly-line polyketide synthases for the production of novel pharmaceutical agents.

Suggested Citation

  • Jialiang Wang & Xiaojie Wang & Xixi Li & LiangLiang Kong & Zeqian Du & Dandan Li & Lixia Gou & Hao Wu & Wei Cao & Xiaozheng Wang & Shuangjun Lin & Ting Shi & Zixin Deng & Zhijun Wang & Jingdan Liang, 2023. "C–N bond formation by a polyketide synthase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36989-w
    DOI: 10.1038/s41467-023-36989-w
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    References listed on IDEAS

    as
    1. Tom Bretschneider & Joel B. Heim & Daniel Heine & Robert Winkler & Benjamin Busch & Björn Kusebauch & Thilo Stehle & Georg Zocher & Christian Hertweck, 2013. "Vinylogous chain branching catalysed by a dedicated polyketide synthase module," Nature, Nature, vol. 502(7469), pages 124-128, October.
    2. Dominik A. Herbst & Roman P. Jakob & Franziska Zähringer & Timm Maier, 2016. "Correction: Corrigendum: Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases," Nature, Nature, vol. 536(7616), pages 360-360, August.
    3. Dominik A. Herbst & Roman P. Jakob & Franziska Zähringer & Timm Maier, 2016. "Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases," Nature, Nature, vol. 531(7595), pages 533-537, March.
    4. Jonathan R. Whicher & Somnath Dutta & Douglas A. Hansen & Wendi A. Hale & Joseph A. Chemler & Annie M. Dosey & Alison R. H. Narayan & Kristina Håkansson & David H. Sherman & Janet L. Smith & Georgios , 2014. "Structural rearrangements of a polyketide synthase module during its catalytic cycle," Nature, Nature, vol. 510(7506), pages 560-564, June.
    5. Jialiang Wang & Jingdan Liang & Lu Chen & Wei Zhang & Liangliang Kong & Chao Peng & Chen Su & Yi Tang & Zixin Deng & Zhijun Wang, 2021. "Structural basis for the biosynthesis of lovastatin," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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