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Cited by 12Plant biochemistry and biosynthesisPlant tissue culture and regenerationPlant Gene Expression Analysis

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Nicotine biosynthesis is completed by cryptic activating glucosylation

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Schwabe, Benjamin T. W., Angstman, Isabelle M., Vollheyde, Katharina, Ingold, Zoe, Li, Jiacheng, Stankevich, Ksenia S., Spicer, Christopher D., Fascione, Martin A., Grogan, Gideon, Geu-Flores, Fernando, Lichman, Benjamin R.·2026·Nature Communications
DOI 10.1038/s41467-026-72705-0PMC PMC13184244

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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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  • Highly accurate protein structure prediction with AlphaFold

    Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · cited 1×

    “The structures were solved by molecular replacement using MOLREP 68 with the AlphaFold structures AF-P52579-F1-v4andAF-F1T160-F1-v4usedasthemodelsforNaGR and NicGS, respectively (https://alphafold.ebi.ac.uk/) 69 .”

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Metadata

Authors
Schwabe, B. T. W., Angstman, I. M., Vollheyde, K., Ingold, Z., Li, J., Stankevich, K. S., Spicer, C. D., Fascione, M. A., Grogan, G., Geu-Flores, F., & Lichman, B. R.
Affiliations
  • University of York (GB)
  • University of Copenhagen (DK)
Corresponding author
Lichman, Benjamin R.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2026-05-18
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-72705-0
PMC
PMC13184244
OpenAlex
W7161541149
Cited by
12
References
1
Citations by year
2026: 12
FWCI
24.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Research Councils UK (MR/S01862X/1, MR/X010260/1)
  • RCUK | Biotechnology and Biological Sciences Research Council (BB/T007222/1)
  • Det Frie Forskningsråd (5281-00267B)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant tissue culture and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant Gene Expression Analysis
Keywords
nicotine biosynthesis, tobacco, alkaloid biosynthesis, nicotinic acid, C–C bond formation, pyridine alkaloids, X-ray crystal structure
MeSH terms
Alkaloids, Glucose, Glycosylation, Nicotine, Plant Proteins, Nicotiana, Crystallography, X-Ray

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