Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer <i>Cephalotaxus hainanensis</i>
Fei Qiao, Yuedong He, Yuhao Zhang, Xuefei Jiang, Hanqing Cong, Zhiming Wang, Huapeng Sun, Yibei Xiao, Yucheng Zhao, Peter Nick
Abstract
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.