Designing an oxidase toolbox for site-directed oxidation of taxanes

Paclitaxel is one of the most prominent drugs for cancer therapy, and its synthesis has long been pursued by scientific community. Although the biosynthetic pathway has been gradually unraveled, its synthetic efficiency remains severely constrained by the low activity and low product selectivity of the hydrolases involved. In this study, an artificial toolbox of oxidases derived from mutants of TteUPO (unspecific peroxygenase from Thielavia terrestris) is developed for site-directed oxidation of taxanes at the C-4, C-6, C-10, C-11, C-12, and C-13 positions. Furthermore, de novo biosynthesis of oxidized taxadiene products is achieved in an engineered E. coli chassis. These findings offer an unconventional strategy for developing an efficient route toward paclitaxel and constructing paclitaxel analogs with different structures for medicinal evaluation.