Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III

作者：Conor James McClune, Jack Chun-Ting Liu, Chloe Wick, Ricardo De La Peña, Bernd Markus Lange, Polly Morrell Fordyce, Elizabeth S. Sattely · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09090-z · 被引用次数：88 · 研究领域：Protist diversity and phylogeny、Microbial Natural Products and Biosynthesis、Photosynthetic Processes and Mechanisms

Abstract Plants make complex and potent therapeutic molecules 1,2 , but sourcing these molecules from natural producers or through chemical synthesis is difficult, which limits their use in the clinic. A prominent example is the anti-cancer therapeutic paclitaxel (sold under the brand name Taxol), which is derived from yew trees ( Taxus species) 3 . Identifying the full paclitaxel biosynthetic pathway would enable heterologous production of the drug, but this has yet to be achieved despite half a century of research 4 . Within Taxus ’ large, enzyme-rich genome 5 , we suspected that the paclitaxel pathway would be difficult to resolve using conventional RNA-sequencing and co-expression analyses. Here, to improve the resolution of transcriptional analysis for pathway identification, we developed a strategy we term multiplexed perturbation × single nuclei (mpXsn) to transcriptionally profile cell states spanning tissues, cell types, developmental stages and elicitation conditions. Our data show that paclitaxel biosynthetic genes segregate into distinct expression modules that suggest consecutive subpathways. These modules resolved seven new genes, allowing a de novo 17-gene biosynthesis and isolation of baccatin III, the industrial precursor to Taxol, in Nicotiana benthamiana leaves, at levels comparable with the natural abundance in Taxus needles. Notably, we found that a nuclear transport factor 2 (NTF2)-like protein, FoTO1, is crucial for promoting the formation of the desire...