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AvmM catalyses macrocyclization through dehydration/Michael-type addition in alchivemycin A biosynthesis

Author

Listed:
  • Hong Jie Zhu

    (Nanjing University)

  • Bo Zhang

    (Nanjing University)

  • Wanqing Wei

    (Nanjing University)

  • Shuang He Liu

    (Nanjing University)

  • Lang Xiang

    (Nanjing University)

  • Jiapeng Zhu

    (Nanjing University of Chinese Medicine)

  • Rui Hua Jiao

    (Nanjing University)

  • Yasuhiro Igarashi

    (Toyama Prefectural University)

  • Ghader Bashiri

    (The University of Auckland)

  • Yong Liang

    (Nanjing University)

  • Ren Xiang Tan

    (Nanjing University)

  • Hui Ming Ge

    (Nanjing University)

Abstract

Macrocyclization is an important process that affords morphed scaffold in biosynthesis of bioactive natural products. Nature has adapted diverse biosynthetic strategies to form macrocycles. In this work, we report the identification and characterization of a small enzyme AvmM that can catalyze the construction of a 16-membered macrocyclic ring in the biosynthesis of alchivemycin A (1). We show through in vivo gene deletion, in vitro biochemical assay and isotope labelling experiments that AvmM catalyzes tandem dehydration and Michael-type addition to generate the core scaffold of 1. Mechanistic studies by crystallography, DFT calculations and MD simulations of AvmM reveal that the reactions are achieved with assistance from the special tenuazonic acid like moiety of substrate. Our results thus uncover an uncharacterized macrocyclization strategy in natural product biosynthesis.

Suggested Citation

  • Hong Jie Zhu & Bo Zhang & Wanqing Wei & Shuang He Liu & Lang Xiang & Jiapeng Zhu & Rui Hua Jiao & Yasuhiro Igarashi & Ghader Bashiri & Yong Liang & Ren Xiang Tan & Hui Ming Ge, 2022. "AvmM catalyses macrocyclization through dehydration/Michael-type addition in alchivemycin A biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32088-4
    DOI: 10.1038/s41467-022-32088-4
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    References listed on IDEAS

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    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. Jonathan Dorival & Fanny Risser & Christophe Jacob & Sabrina Collin & Gerald Dräger & Cédric Paris & Benjamin Chagot & Andreas Kirschning & Arnaud Gruez & Kira J. Weissman, 2018. "Insights into a dual function amide oxidase/macrocyclase from lankacidin biosynthesis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    3. Kristina Haslinger & Madeleine Peschke & Clara Brieke & Egle Maximowitsch & Max J. Cryle, 2015. "X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis," Nature, Nature, vol. 521(7550), pages 105-109, May.
    4. Fredarla S. Miller & Kathryn K. Crone & Matthew R. Jensen & Sudipta Shaw & William R. Harcombe & Mikael H. Elias & Michael F. Freeman, 2021. "Conformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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