A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A notable example is the >150 Amaryllidaceae alkaloids (AmAs), including galantamine, an FDA-approved treatment for Alzheimer’s disease. We show that while AmAs accumulate to high levels in many daffodil tissues, biosynthesis is localized to nascent, growing tissue at the leaf base. A similar trend is found in the production of steroidal alkaloids (e.g., cyclopamine) in corn lily. This model of active biosynthesis enabled the elucidation of a complete set of biosynthetic genes that can be used to produce AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodils. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes, where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as above-ground tissue develops. • Active biosynthesis of daffodil toxins is concentrated in new tissue • Included is the Alzheimer’s drug galantamine, which accumulates throughout the plant • This toxin production pattern enabled the discovery and engineering of a galantamine pathway • This paradigm for biosynthesis is likely general, e.g., for cyclopamine in corn lily The biosynthetic pathways in plants that yield important and clinically relevant toxins are complicated and difficult to elucidate. Through combined metabolomics, the biosynthetic pathways of a structurally and functionally diverse set of toxins are discovered, suggesting a model for the production of defense metabolites across geophytes.