Rewiring Saccharomyces cerevisiae metabolism for optimised Taxol® precursors production
Journal article, 2024

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.

Saccharomyces cerevisiae

Oxidative stress

Adaptive laboratory evolution

Taxadiene

Taxol®

Author

Behnaz Nowrouzi

Technical University of Denmark (DTU)

Chalmers, Life Sciences, Systems and Synthetic Biology

University of Edinburgh

Pablo Torres-Montero

Technical University of Denmark (DTU)

Eduard Kerkhoven

Novo Nordisk Foundation

Chalmers, Life Sciences, Systems and Synthetic Biology

Jose Luis Martinez Ruiz

Technical University of Denmark (DTU)

Leonardo Rios-Solis

University of Edinburgh

Newcastle University

University College London (UCL)

Metabolic Engineering Communications

2214-0301 (eISSN)

Vol. 18 e00229

Subject Categories

Biochemistry and Molecular Biology

Microbiology

DOI

10.1016/j.mec.2023.e00229

PubMed

38098801

More information

Latest update

12/15/2023