Fields, E. A.; Kim, C. Y.; Nett, R. S.

The plant kingdom is rich with medicinal natural products that are complex and difficult to access. Discovering how plants build these molecules can be challenging, especially for biosynthetic pathways that have unusual chemical transformations or require intricate coordination among cellular compartments. Here, we leveraged 300 million years of metabolic conservation to uncover how medicinal clubmosses organize extracellular and intracellular alkaloid biosynthesis to produce the Alzheimer's disease therapeutic huperzine A (HupA). We reveal not only scaffold-forming enzymes that form key precursors to hundreds of clubmoss alkaloids, but also an essential transporter that connects metabolism across the plasma membrane to enable complete HupA biosynthesis. Our results demonstrate how ancient evolutionary conservation can be used to identify cryptic biosynthetic components and unexpected cellular organization in plant specialized metabolism.