Reconstitution of early paclitaxel biosynthetic network

Jack Chun-Ting Liu, Ricardo De La Peña, Christian Tocol and Elizabeth S. Sattely ()
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Jack Chun-Ting Liu: Stanford University
Ricardo De La Peña: Stanford University
Christian Tocol: Stanford University
Elizabeth S. Sattely: Stanford University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Paclitaxel is an anticancer therapeutic produced by the yew tree. Over the last two decades, a significant bottleneck in the reconstitution of early paclitaxel biosynthesis has been the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. Here, we structurally characterize four new products of T5αH, many of which appear to be over-oxidation of the primary mono-oxidized products. By tuning the promoter strength for T5αH expression in Nicotiana plants, we observe decreased levels of these proposed byproducts with a concomitant increase in the accumulation of taxadien-5α-ol, the paclitaxel precursor, by three-fold. This enables the reconstitution of a six step biosynthetic pathway, which we further show may function as a metabolic network. Our result demonstrates that six previously characterized Taxus genes can coordinatively produce key paclitaxel intermediates and serves as a crucial platform for the discovery of the remaining biosynthetic genes.

Date: 2024
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DOI: 10.1038/s41467-024-45574-8

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