Team Reveals Genetic Blueprint Key to Taxol Synthesis

Taxol, a chemotherapy drug used for treating ovarian, breast, and lung cancers, is primarily derived from yew trees by extracting its precursor, baccatin III. However, the slow growth of yew trees limits the drug’s supply. Taxol’s complex structure also makes synthetic manufacturing costly, prompting scientists to search for the enzymes yew trees use to make Taxol, with the aim of transferring these pathways into more productive organisms like yeast.

“We really need enzymes to build this molecule,” said Conor McClune, first author of a recently published Nature study. “Enzymes are often the most efficient and cleanest way of doing a chemical reaction.” So, McClune and his colleagues developed a new approach to study plant genes, called multiplexed perturbation × single nuclei (mpXsn), which led to the discovery of several key enzymes involved in Taxol biosynthesis. Their findings move researchers closer to producing Taxol in industrial microbes.

The yew tree genome is vast, containing about 50,000 genes, making it challenging to identify those responsible for Taxol production. Before this study, only 12 relevant genes had been found. The Stanford team accelerated their search by stressing yew tree needles to induce defensive compound production, then sequencing nuclei to identify active genes. By observing which genes were activated together, they identified candidates likely involved in Taxol synthesis.

Through experiments with tobacco plants, the researchers discovered eight new critical genes, including FoTO1, which streamlines the production process. These enzymes enabled the plants to produce baccatin III at higher concentrations than yew trees. The team also identified an enzyme for a step between baccatin and Taxol, leaving only two steps missing. Coincidentally, scientists in Copenhagen identified these final steps, bringing the total to 22 genes that may complete the Taxol pathway.

Future plans include confirming the full pathway in tobacco and transferring the genes to microbes for efficient drug production. This method could also advance the discovery of other plant-derived compounds, as many plant enzymes remain unexplored.