Emerging Technologies Empowering the Biosynthesis of Paclitaxel

ABSTRACT: Paclitaxel (Taxol) is a clinically important diterpenoid anticancer drug whose industrial production remains constrained by limited Taxus resources and semi-synthetic routes. Driven by the rapid advancement of genome mining and synthetic biology technologies, the past two years have witnessed substantial breakthroughs in elucidating the biosynthetic pathway of paclitaxel. The pathway constitutes an exceptionally complex biosynthetic network comprising approximately 20 enzymatic steps, predominantly catalyzed by cytochrome P450 monooxygenases, 2-oxoglutarate-dependent dioxygenases (ODDs), and acyltransferases. Nevertheless, microbial production of paclitaxel remains highly obstructed, largely due to inefficient catalytic abilities, enzyme promiscuities, and complex metabolic fluxes. This review summarizes recent progress in elucidating the evolutionary origins and catalytic mechanistic basis of the paclitaxel biosynthetic pathway, with particular emphasis on the emerging technologies and catalytic mechanism studies. Furthermore, current challenges and perspectives for constructing efficient artificial biosynthetic pathways are discussed, providing insights into the future biotechnological production of paclitaxel.