2026/05/18 by Benjamin T. W. Schwabe, Isabelle M. Angstman, Katharina Vollheyde +8 · 1 voice
Agricultural and Biological Sciences · Biochemistry, Genetics and Molecular Biology · #Biochemical and biochemical processes #Nicotinic Acetylcholine Receptors Study #Plant and Biological Electrophysiology Studies
paper · pdf · doi:10.1038/s41467-026-72705-0
openalex publication_date 2026/05/18 · openalex created_date 2026/05/19 · openalex updated_date 2026/07/31
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.