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Biochemical and structural insights of multifunctional flavin-dependent monooxygenase FlsO1-catalyzed unexpected xanthone formation

Author

Listed:
  • Chunfang Yang

    (Chinese Academy of Sciences
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou)
    Sanya Institute of Ocean Eco-Environmental Engineering
    University of Chinese Academy of Sciences)

  • Liping Zhang

    (Chinese Academy of Sciences
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou)
    Sanya Institute of Ocean Eco-Environmental Engineering)

  • Wenjun Zhang

    (Chinese Academy of Sciences
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou)
    Sanya Institute of Ocean Eco-Environmental Engineering
    University of Chinese Academy of Sciences)

  • Chunshuai Huang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiguang Zhu

    (Chinese Academy of Sciences
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou)
    Sanya Institute of Ocean Eco-Environmental Engineering
    University of Chinese Academy of Sciences)

  • Xiaodong Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wei Liu

    (Chinese Academy of Sciences)

  • Mengran Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bidhan Chandra De

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Changsheng Zhang

    (Chinese Academy of Sciences
    Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou)
    Sanya Institute of Ocean Eco-Environmental Engineering
    University of Chinese Academy of Sciences)

Abstract

Xanthone-containing natural products display diverse pharmacological properties. The biosynthetic mechanisms of the xanthone formation have not been well documented. Here we show that the flavoprotein monooxygenase FlsO1 in the biosynthesis of fluostatins not only functionally compensates for the monooxygenase FlsO2 in converting prejadomycin to dehydrorabelomycin, but also unexpectedly converts prejadomycin to xanthone-containing products by catalyzing three successive oxidations including hydroxylation, epoxidation and Baeyer-Villiger oxidation. We also provide biochemical evidence to support the physiological role of FlsO1 as the benzo[b]-fluorene C5-hydrolase by using nenestatin C as a substrate mimic. Finally, we resolve the crystal structure of FlsO1 in complex with the cofactor flavin adenine dinucleotide close to the “in” conformation to enable the construction of reactive substrate-docking models to understand the basis of a single enzyme-catalyzed multiple oxidations. This study highlights a mechanistic perspective for the enzymatic xanthone formation in actinomycetes and sets an example for the versatile functions of flavoproteins.

Suggested Citation

  • Chunfang Yang & Liping Zhang & Wenjun Zhang & Chunshuai Huang & Yiguang Zhu & Xiaodong Jiang & Wei Liu & Mengran Zhao & Bidhan Chandra De & Changsheng Zhang, 2022. "Biochemical and structural insights of multifunctional flavin-dependent monooxygenase FlsO1-catalyzed unexpected xanthone formation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33131-0
    DOI: 10.1038/s41467-022-33131-0
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    References listed on IDEAS

    as
    1. Islam El-Awaad & Marco Bocola & Till Beuerle & Benye Liu & Ludger Beerhues, 2016. "Bifunctional CYP81AA proteins catalyse identical hydroxylations but alternative regioselective phenol couplings in plant xanthone biosynthesis," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    2. Bidhan Chandra De & Wenjun Zhang & Chunfang Yang & Attila Mándi & Chunshuai Huang & Liping Zhang & Wei Liu & Mark W. Ruszczycky & Yiguang Zhu & Ming Ma & Ghader Bashiri & Tibor Kurtán & Hung-wen Liu &, 2022. "Flavin-enabled reductive and oxidative epoxide ring opening reactions," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Bin Wang & Fang Guo & Jinwei Ren & Guomin Ai & Bertrand Aigle & Keqiang Fan & Keqian Yang, 2015. "Identification of Alp1U and Lom6 as epoxy hydrolases and implications for kinamycin and lomaiviticin biosynthesis," Nature Communications, Nature, vol. 6(1), pages 1-5, November.
    4. Britta Frensch & Thorsten Lechtenberg & Michel Kather & Zeynep Yunt & Martin Betschart & Bernd Kammerer & Steffen Lüdeke & Michael Müller & Jörn Piel & Robin Teufel, 2021. "Enzymatic spiroketal formation via oxidative rearrangement of pentangular polyketides," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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