Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer
 Cephalotaxus hainanensis


 Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer
 Cephalotaxus
 is highly endangered, creating a conflict between biotechnological valorization and preservation of biodiversity. Here, we construct the whole biosynthetic pathway to the 1-phenethylisoquinoline scaffold, as first committed compound for phenylethylisoquinoline alkaloids (PIAs), combining metabolic modeling, and transcriptome mining of 
 Cephalotaxus hainanensis
 to infer the biosynthesis for PIA precursor. We identify a novel protein,
 Ch
 PSS, driving the Pictet–Spengler condensation and show that this enzyme represents the branching point where PIA biosynthesis diverges from the concurrent benzylisoquinoline-alkaloids pathway. We also pinpoint
 Ch
 DBR as crucial step to form 4-hydroxydihydrocinnamaldehyde diverging from lignin biosynthesis. The elucidation of the early PIA pathway represents an important step toward microbe-based production of these pharmaceutically important alkaloids resolving the conflict between biotechnology and preservation of biodiversity.
