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De novo biosynthesis of antiarrhythmic alkaloid ajmaline

Author

Listed:
  • Jun Guo

    (University of New Brunswick)

  • Di Gao

    (Zhejiang University)

  • Jiazhang Lian

    (Zhejiang University
    Zhejiang University
    Zhejiang University)

  • Yang Qu

    (University of New Brunswick)

Abstract

The antiarrhythmic drug ajmaline is a monoterpenoid indole alkaloid (MIA) isolated from the Ayurvedic plant Rauvolfia serpentina (Indian Snakeroot). Research into the biosynthesis of ajmaline and another renowned MIA chemotherapeutic drug vinblastine has yielded pivotal advancements in the fields of plant specialized metabolism and engineering over recent decades. While the majority of vinblastine biosynthesis has been recently elucidated, the quest for comprehending ajmaline biosynthesis remains incomplete, marked by the absence of two critical enzymes. Here, we show the discovery and characterization of these two elusive reductases, alongside the identification of two physiologically relevant esterases that complete the biosynthesis of ajmaline. We show that ajmaline biosynthesis proceeds with vomilenine 1,2(R)-reduction followed by its 19,20(S)-reduction. This process is further modulated by two root-expressing esterases that deacetylate 17-O-acetylnorajmaline. Expanding upon the successful completion of the ajmaline biosynthetic pathway, we engineer the de novo biosynthesis of ajmaline in Baker’s yeast.

Suggested Citation

  • Jun Guo & Di Gao & Jiazhang Lian & Yang Qu, 2024. "De novo biosynthesis of antiarrhythmic alkaloid ajmaline," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44797-z
    DOI: 10.1038/s41467-024-44797-z
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    1. Benke Hong & Dagny Grzech & Lorenzo Caputi & Prashant Sonawane & Carlos E. Rodríguez López & Mohamed Omar Kamileen & Néstor J. Hernández Lozada & Veit Grabe & Sarah E. O’Connor, 2022. "Biosynthesis of strychnine," Nature, Nature, vol. 607(7919), pages 617-622, July.
    2. Benke Hong & Dagny Grzech & Lorenzo Caputi & Prashant Sonawane & Carlos E. Rodríguez López & Mohamed Omar Kamileen & Néstor J. Hernández Lozada & Veit Grabe & Sarah E. O’Connor, 2022. "Publisher Correction: Biosynthesis of strychnine," Nature, Nature, vol. 608(7924), pages 37-37, August.
    3. Wen Chen & Yonghui Ma & Wenyan He & Yinxia Wu & Yuancheng Huang & Yipeng Zhang & Hongchang Tian & Kai Wei & Xiaodong Yang & Hongbin Zhang, 2022. "Structure units oriented approach towards collective synthesis of sarpagine-ajmaline-koumine type alkaloids," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Evangelos C. Tatsis & Inês Carqueijeiro & Thomas Dugé de Bernonville & Jakob Franke & Thu-Thuy T. Dang & Audrey Oudin & Arnaud Lanoue & Florent Lafontaine & Anna K. Stavrinides & Marc Clastre & Vincen, 2017. "A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    5. Anna Stavrinides & Evangelos C. Tatsis & Lorenzo Caputi & Emilien Foureau & Clare E. M. Stevenson & David M. Lawson & Vincent Courdavault & Sarah E. O'Connor, 2016. "Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    6. Jie Zhang & Lea G. Hansen & Olga Gudich & Konrad Viehrig & Lærke M. M. Lassen & Lars Schrübbers & Khem B. Adhikari & Paulina Rubaszka & Elena Carrasquer-Alvarez & Ling Chen & Vasil D’Ambrosio & Beata , 2022. "A microbial supply chain for production of the anti-cancer drug vinblastine," Nature, Nature, vol. 609(7926), pages 341-347, September.
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