Rewiring Saccharomyces cerevisiae metabolism for optimised Taxol® precursors production

IF 3.7 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Metabolic Engineering Communications Pub Date : 2023-11-15 DOI:10.1016/j.mec.2023.e00229

Behnaz Nowrouzi , Pablo Torres-Montero , Eduard J. Kerkhoven , José L. Martínez , Leonardo Rios-Solis

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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.

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重组酿酒酵母代谢优化紫杉醇®前体生产

酿酒酵母已被方便地用于生产紫杉醇®抗癌药物的早期前体。然而，紫杉醇(Taxol)途径的第一个细胞色素p450 -还原酶(CYP725A4-POR)氧化应激的有害影响阻碍了酵母的充分进展。在这里，我们进化出一种抗氧化应激的酵母菌株，其底物taxadiene的滴度提高了三倍。进化菌株和亲本菌株在氧化应激前和氧化应激下在半乳糖限制的趋化剂中进行了性能评估。在酵母酶约束的基因组尺度模型中，通过转录组学和代谢物谱整合，全面评估了进化与氧化应激的相互作用。总体而言，进化菌株表现出呼吸改善，溢出代谢物产生减少和氧化应激再诱导耐受性。交叉保护机制也可能有助于提高血红素、黄素和NADPH的利用率，这是酵母中CYP725A4和POR优化活性所必需的。结果表明，进化菌株是一个强大的细胞工厂，为未来紫杉醇©生产的努力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Metabolic Engineering Communications Medicine-Endocrinology, Diabetes and Metabolism

CiteScore

13.30

自引率

1.90%

发文量

审稿时长

18 weeks

期刊介绍： Metabolic Engineering Communications, a companion title to Metabolic Engineering (MBE), is devoted to publishing original research in the areas of metabolic engineering, synthetic biology, computational biology and systems biology for problems related to metabolism and the engineering of metabolism for the production of fuels, chemicals, and pharmaceuticals. The journal will carry articles on the design, construction, and analysis of biological systems ranging from pathway components to biological complexes and genomes (including genomic, analytical and bioinformatics methods) in suitable host cells to allow them to produce novel compounds of industrial and medical interest. Demonstrations of regulatory designs and synthetic circuits that alter the performance of biochemical pathways and cellular processes will also be presented. Metabolic Engineering Communications complements MBE by publishing articles that are either shorter than those published in the full journal, or which describe key elements of larger metabolic engineering efforts.