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Reconstitution of early paclitaxel biosynthetic network

Author

Listed:
  • Jack Chun-Ting Liu

    (Stanford University)

  • Ricardo De La Peña

    (Stanford University)

  • Christian Tocol

    (Stanford University)

  • Elizabeth S. Sattely

    (Stanford University
    Stanford University)

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.

Suggested Citation

  • Jack Chun-Ting Liu & Ricardo De La Peña & Christian Tocol & Elizabeth S. Sattely, 2024. "Reconstitution of early paclitaxel biosynthetic network," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45574-8
    DOI: 10.1038/s41467-024-45574-8
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    References listed on IDEAS

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