Finding a key puzzle piece in paclitaxel biosynthesis

The cancer drug paclitaxel has captured the imaginations of chemists for decades, in part because of its complex polycyclic core with an oxetane ring. Although scientists have synthesized the molecule from basic chemicals, they didn’t have a complete picture of how nature makes it. Now, chemists have identified an enzyme that forms the key intermediate baccatin III. The finding adds a crucial piece to the puzzle of paclitaxel biosynthesis.

Researchers led by Xiaoguang Lei at Peking University and Jianbin Yan at the Chinese Academy of Agricultural Sciences identified a cyctochrome P450 enzyme—which they named taxane oxetanase 1—that installs the oxetane ring in baccatin III. Scientists previously thought that an epoxide forms on a precursor to baccatin III and then rearranges to the oxetane. Lei and Yan’s team discovered that while taxane oxetanase 1 can make that epoxide, it can’t convert the epoxide to the oxetane. Instead, the team suggests that the enzyme makes the oxetane via a mechanism that was previously unknown in enzymes (Science 2024, DOI: 10.1126/science.adj3484).

Sarah E. O’Connor, an expert in natural product biosynthesis at the Max Planck Institute for Chemical Ecology, says the finding answers a long-standing question in plant natural product biosynthesis. “The mechanism by which the critical oxetane ring forms has always been up for debate,” she says in an email.

Lei says the researchers hope to use their recent discovery to make baccatin III on a large scale via synthetic biology.