Paclitaxel, known commercially as Taxol, is a chemotherapeutic diterpenoid compound widely used in anti-cancer therapy. Despite its low natural abundance, production of paclitaxel involves extraction of baccatin III, a precursor, from yew trees followed by chemical synthesis, as a complete chemical synthesis is not commercially viable and biomanufacturing routes are limited by the lack of knowledge of the complete paclitaxel biosynthetic pathway. Now, McClune, Liu et al. have reported a method to transcriptionally profile specific plant cell states to identify candidate genes involved in the paclitaxel biosynthetic pathway, enabling the de novo biosynthesis of baccatin III in the plant species Nicotiana benthamiana.
The researchers first developed a multiplexed perturbation × single nuclei (mpXsn) transcriptomics method to simultaneously screen biosynthetic genes activated in yew plant tissues in response to factors such as hormones and microorganisms. This showed that Taxol genes co-expressed in separated sub-clusters or gene modules. Particularly, in the first module, the team found that an NTF2-like protein — now termed facilitator of taxane oxidation (FoTO1) — interacts with taxadiene 5α-hydroxylase (T5αH), responsible for the first oxidation step in the pathway, and enables yield increase in the crucial first step. Following the same approach, the team identified 7 further genes with related pathway functions, and then reconstituted the 17-gene biosynthesis of baccatin III and 3′-N-debenzoyl-2′-deoxypaclitaxel in N. benthamiana, obtaining yields comparable to those through extraction methods from yew tissues.
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