Scientists identify pathway for key Taxol precursor

The widely used chemotherapy drug paclitaxel, commonly known as Taxol, was first extracted from the Pacific yew tree in 1963. But while plants have figured out how to manufacture the molecule, for chemists, its total synthesis is complex, to say the least.

That’s why most manufacturers synthesize it from precursor molecules extracted from the needles of the English yew tree or use yew cell cultures to brew the full molecule. Now scientists have identified the biosynthetic pathway for one of those key precursors, baccatin III—which means that easier methods of paclitaxel manufacturing could be coming soon (Nature 2025, DOI: 10.1038/s41586-025-09090-z).

Conor McClune, a postdoc in Elizabeth Sattely’s group at Stanford University, says that unpicking paclitaxel production has been “a grand challenge in the field of plant biosynthesis for 25 years.” For one thing, the pathway involves lots of steps, but yew trees also have genomes four times the size of human genomes, and the plants produce many other compounds similar to paclitaxel.

Scientists have previously identified parts of the pathway; Rodney Croteau’s lab discovered much of it by 2006 (Phytochem. Rev., DOI: 10.1007/s11101-005-3748-2). But identifying the remaining enzymes in the pathway has proved difficult. With the discovery of seven new genes in this latest paper and another 2 genes published in Nature Synthesis a couple of months ago, researchers now have a nearly complete understanding of paclitaxel biosynthesis (2025, DOI: 10.1038/s44160-025-00800-z).

To uncover the genes involved in producing paclitaxel in yew trees, McClune and the team first stressed yew needle cells with many chemicals, then extracted the nuclei from those cells and sequenced the RNA in them. This allowed them to identify modules of genes that expressed themselves as RNA under the same conditions that known paclitaxel biosynthesis genes are expressed under.

To validate which genes were actually a part of the paclitaxel biosynthesis pathway, the Stanford researchers engineered them into tobacco plants in sets of five genes at a time. By checking which plant made the next compound in the pathway, the researchers could figure out which gene was responsible for making that compound before repeating the process. McClune says this allowed them to discover another step in the pathway nearly every week, up until they were able to make baccatin III.

McClune says the lab is now working with collaborators to move the pathway into yeast for biomanufacturing.

Susan Roberts, a chemical engineer at Worcester Polytechnic Institute who wasn’t involved with the study, is thrilled with the results and excited about the methodology, but she says she is skeptical that paclitaxel production via yeast or bacterial culture is truly the best approach.

Right now, paclitaxel production via yew plant cell culture is meeting demand for the drug, Roberts says. But she adds that “there’s always new use cases coming out for Taxol,” and she hopes this work will help bring the cost of manufacturing down. She also thinks the data from McClune’s paper could help her engineer better production in yew cell cultures.

But McClune is also interested in using the technique developed to uncover paclitaxel biosynthesis genes to discover other biosynthetic pathways. “I’m a senior postdoc. I’m heading off to start my own group, hopefully soon. There are a couple general directions I want to take this,” he says.