Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer <i>Cephalotaxus hainanensis</i>

Abstract

Cephalotaxines harbor great medical potential, but their natural source, the endemic conifer <i>Cephalotaxus</i> 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 <i>Cephalotaxus hainanensis</i> to infer the biosynthesis for PIA precursor. We identify a novel protein, <i>Ch</i>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 <i>Ch</i>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.