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Peer-reviewedCC BYNature Communications

Nicotine biosynthesis is completed by cryptic activating glucosylation

  • Benjamin T. W. Schwabe1,2
  • Isabelle Angstman3
  • Katharina Vollheyde3
  • Zoe Ingold1,2
  • Jiacheng Li2
  • Ksenia S. Stankevich2,4
  • Christopher D. Spicer2,4
  • Martin A. Fascione2,4
  • Gideon Grogan2
  • Fernando Geu‐Flores3
  • Benjamin R. Lichman5
5 affiliations
  1. 1Centre for Novel Agricultural Products, Department of Biology, University of York, York, UK
  2. 2Department of Chemistry, University of York, York, UK
  3. 3Section for Plant Biochemistry and Copenhagen Plant Science Centre, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark
  4. 4York Biomedical Research Institute, University of York, York, UK
  5. 5Centre for Novel Agricultural Products, Department of Biology, University of York, York, UK. [email protected]
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Abstract

Nicotine is a neuroactive alkaloid produced by tobacco (Nicotiana tabacum) as a defence against herbivory, and an addictive stimulant that has been used by humans for millennia. Despite its significance, the core steps of its biosynthesis have remained elusive. Here, we demonstrate the in vitro reconstruction of a four-enzyme stereoselective biocatalytic cascade that forms (S)-nicotine from nicotinic acid and N-methylpyrrolinium. This cascade includes two glucose-processing enzymes that participate in a cryptic activating glucosylation step. We also reconstruct this pathway in planta and present high resolution X-ray structures of the key carbon-carbon bond forming reductase-oxidase pair bound to their substrate and product, respectively. This work establishes the complete biosynthetic pathway to nicotine, providing new gene targets for controlling alkaloid production in Nicotiana and unlocking enzymatic routes to pyridine alkaloids.

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Cite

BibTeXRIS
BibTeX
@article{schwabe2026nicotine,
  title = {{Nicotine biosynthesis is completed by cryptic activating glucosylation}},
  author = {Benjamin T. W. Schwabe and Isabelle Angstman and Katharina Vollheyde and Zoe Ingold and Jiacheng Li and Ksenia S. Stankevich and Christopher D. Spicer and Martin A. Fascione and Gideon Grogan and Fernando Geu‐Flores and Benjamin R. Lichman},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-72705-0},
  url = {https://doi.org/10.1038/s41467-026-72705-0},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Nicotine biosynthesis is completed by cryptic activating glucosylation
AU  - Benjamin T. W. Schwabe
AU  - Isabelle Angstman
AU  - Katharina Vollheyde
AU  - Zoe Ingold
AU  - Jiacheng Li
AU  - Ksenia S. Stankevich
AU  - Christopher D. Spicer
AU  - Martin A. Fascione
AU  - Gideon Grogan
AU  - Fernando Geu‐Flores
AU  - Benjamin R. Lichman
PY  - 2026
DA  - 2026/05/18
JO  - Nature Communications
DO  - 10.1038/s41467-026-72705-0
UR  - https://doi.org/10.1038/s41467-026-72705-0
AB  - Nicotine is a neuroactive alkaloid produced by tobacco (Nicotiana tabacum) as a defence against herbivory, and an addictive stimulant that has been used by humans for millennia. Despite its significance, the core steps of its biosynthesis have remained elusive. Here, we demonstrate the in vitro reconstruction of a four-enzyme stereoselective biocatalytic cascade that forms (S)-nicotine from nicotinic acid and N-methylpyrrolinium. This cascade includes two glucose-processing enzymes that participate in a cryptic activating glucosylation step. We also reconstruct this pathway in planta and present high resolution X-ray structures of the key carbon-carbon bond forming reductase-oxidase pair bound to their substrate and product, respectively. This work establishes the complete biosynthetic pathway to nicotine, providing new gene targets for controlling alkaloid production in Nicotiana and unlocking enzymatic routes to pyridine alkaloids.
SN  - 2041-1723
ER  -