Enabling sustainable supply of the essential cancer medicines etoposide and teniposide in yeast

Lignans constitute a diverse family of plant metabolites with therapeutic potential. Among them, podophyllotoxin-type aryltetralin lignans serve as precursors for etoposide and teniposide. Etoposide is an essential anticancer medicine approved for first-line treatment of small cell lung cancer, whereas teniposide is used for treatment of leukemia and some brain tumors. Currently, these drugs depend on extraction of precursors from the endangered plant Sinopodophyllum hexandrum , followed by chemical transformations. By identifying key glycosyltransferases and executing more than 60 genetic edits involving 45 heterologous enzymes, the complex biosynthetic pathway of podophyllotoxin-type lignans was reconstructed in yeast. In this study, we established a chemoenzymatic route that streamlines the synthesis of etoposide and teniposide through a single chemical step from biosynthetic precursor 4′-demethyl-epipodophyllotoxin-4 -O- glucoside, which enables a secure supply chain of these essential medicines.