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O-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis

Author

Listed:
  • Yuchun Zhao

    (Shanghai Jiao Tong University)

  • Xiangyang Liu

    (Shanghai Jiao Tong University)

  • Zhihong Xiao

    (Shanghai Jiao Tong University)

  • Jie Zhou

    (Shanghai Jiao Tong University)

  • Xingyu Song

    (Fudan University)

  • Xiaozheng Wang

    (Shanghai Jiao Tong University)

  • Lijun Hu

    (Jinan University)

  • Ying Wang

    (Jinan University)

  • Peng Sun

    (Second Military Medical University)

  • Wenning Wang

    (Fudan University)

  • Xinyi He

    (Shanghai Jiao Tong University)

  • Shuangjun Lin

    (Shanghai Jiao Tong University)

  • Zixin Deng

    (Shanghai Jiao Tong University)

  • Lifeng Pan

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

  • Ming Jiang

    (Shanghai Jiao Tong University)

Abstract

Diazo compounds are rare natural products possessing various biological activities. Kinamycin and lomaiviticin, two diazo natural products featured by the diazobenzofluorene core, exhibit exceptional potency as chemotherapeutic agents. Despite the extensive studies on their biosynthetic gene clusters and the assembly of their polyketide scaffolds, the formation of the characteristic diazo group remains elusive. l-Glutamylhydrazine was recently shown to be the hydrazine donor in kinamycin biosynthesis, however, the mechanism for the installation of the hydrazine group onto the kinamycin scaffold is still unclear. Here we describe an O-methyltransferase-like protein, AlpH, which is responsible for the hydrazine incorporation in kinamycin biosynthesis. AlpH catalyses a unique SAM-independent coupling of l-glutamylhydrazine and polyketide intermediate via a rare Mannich reaction in polyketide biosynthesis. Our discovery expands the catalytic diversity of O-methyltransferase-like enzymes and lays a strong foundation for the discovery and development of novel diazo natural products through genome mining and synthetic biology.

Suggested Citation

  • Yuchun Zhao & Xiangyang Liu & Zhihong Xiao & Jie Zhou & Xingyu Song & Xiaozheng Wang & Lijun Hu & Ying Wang & Peng Sun & Wenning Wang & Xinyi He & Shuangjun Lin & Zixin Deng & Lifeng Pan & Ming Jiang, 2023. "O-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41062-7
    DOI: 10.1038/s41467-023-41062-7
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    References listed on IDEAS

    as
    1. Masao Ohashi & Fang Liu & Yang Hai & Mengbin Chen & Man-cheng Tang & Zhongyue Yang & Michio Sato & Kenji Watanabe & K. N. Houk & Yi Tang, 2017. "SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis," Nature, Nature, vol. 549(7673), pages 502-506, September.
    2. Guiyun Zhao & Wei Peng & Kaihui Song & Jingkun Shi & Xingyu Lu & Binju Wang & Yi-Ling Du, 2021. "Molecular basis of enzymatic nitrogen-nitrogen formation by a family of zinc-binding cupin enzymes," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Masao Ohashi & Cooper S. Jamieson & Yujuan Cai & Dan Tan & Daiki Kanayama & Man-Cheng Tang & Sarah M. Anthony & Jason V. Chari & Joyann S. Barber & Elias Picazo & Thomas B. Kakule & Shugeng Cao & Neil, 2020. "An enzymatic Alder-ene reaction," Nature, Nature, vol. 586(7827), pages 64-69, October.
    4. 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.
    5. 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.
    6. Kwo-Kwang A. Wang & Tai L. Ng & Peng Wang & Zedu Huang & Emily P. Balskus & Wilfred A. van der Donk, 2018. "Glutamic acid is a carrier for hydrazine during the biosyntheses of fosfazinomycin and kinamycin," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
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