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Rewiring Saccharomyces cerevisiae metabolism for optimised Taxol® precursors production

Nowrouzi, Behnaz; Torres-Montero, Pablo; Kerkhoven, Eduard J; Martínez, José L; Rios-Solis, Leonardo; (2024) Rewiring Saccharomyces cerevisiae metabolism for optimised Taxol® precursors production. Metabolic Engineering Communications , 18 , Article e00229. 10.1016/j.mec.2023.e00229. Green open access

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Abstract

Saccharomyces cerevisiae has been conveniently used to produce Taxol® anticancer drug early precursors. However, the harmful impact of oxidative stress by the first cytochrome P450-reductase enzymes (CYP725A4-POR) of Taxol® pathway has hampered sufficient progress in yeast. Here, we evolved an oxidative stress-resistant yeast strain with three-fold higher titre of their substrate, taxadiene. The performance of the evolved and parent strains were then evaluated in galactose-limited chemostats before and under the oxidative stress by an oxidising agent. The interaction of evolution and oxidative stress was comprehensively evaluated through transcriptomics and metabolite profiles integration in yeast enzyme-constrained genome scale model. Overall, the evolved strain showed improved respiration, reduced overflow metabolites production and oxidative stress re-induction tolerance. The cross-protection mechanism also potentially contributed to better heme, flavin and NADPH availability, essential for CYP725A4 and POR optimal activity in yeast. The results imply that the evolved strain is a robust cell factory for future efforts towards Taxol© production.

Type: Article
Title: Rewiring Saccharomyces cerevisiae metabolism for optimised Taxol® precursors production
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.mec.2023.e00229
Publisher version: https://doi.org/10.1016/j.mec.2023.e00229
Language: English
Additional information: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Saccharomyces cerevisiae, Taxol®, Taxadiene, Oxidative Stress, Adaptive Laboratory Evolution
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10182402
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