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<p>Nicotine is a neuroactive alkaloid produced by tobacco (<i>Nicotiana tabacum</i>) 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 (<i>S</i>)-nicotine from nicotinic acid and <i>N</i>-methylpyrrolinium. This cascade includes two glucose-processing enzymes that participate in a cryptic activating glucosylation step. We also reconstruct this pathway <i>in planta</i> 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 <i>Nicotiana</i> and unlocking enzymatic routes to pyridine alkaloids.</p>

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Nicotine biosynthesis is completed by cryptic activating glucosylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Benjamin T. W. Schwabe,
  • Isabelle M. Angstman,
  • Katharina Vollheyde,
  • Zoe Ingold,
  • Jiacheng Li,
  • Ksenia S. Stankevich,
  • Christopher D. Spicer,
  • Martin A. Fascione,
  • Gideon Grogan,
  • Fernando Geu-Flores,
  • Benjamin R. Lichman

摘要

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.