2025-11-17 中国科学院(CAS)
この成果はバイオ製造の効率化・持続可能化という観点から、微生物による高付加価値化学物質の商業生産を一歩前進させるものである。
<関連情報>
- https://english.cas.cn/newsroom/research_news/chem/202511/t20251117_1115869.shtml
- https://www.pnas.org/doi/10.1073/pnas.2515324122
堅牢な酵母細胞工場に向けた経時的寿命のエンジニアリング Engineering chronological lifespan toward a robust yeast cell factory
Zulin Wu, Jiaoqi Gao, Ning Gao, +1 , and Yongjin J. Zhou
Proceedings of the National Academy of Sciences Published:November 10, 2025
DOI:https://doi.org/10.1073/pnas.2515324122
Significance
It is challenging to associate the laboratory-scale shake-flask fermentation with industrial fed-batch production due to cell aging and the accumulation of toxic metabolites in long-term strain cultivation. Here, we comprehensively engineered cellular resistance and longevity to improve chemical production in yeast. This study established a clear connection between chronological lifespan and biosynthesis capacity for improving sclareol production, a precursor for Ambrox synthesis. Rather than classic metabolic engineering, this longevity engineering strategy could be applied in versatile microbial cell factories for sustainable and economical biomanufacturing.
Abstract
Metabolic rewiring helps to construct efficient microbial cell factories; however, these cells suffer from metabolic stress during long-term fed-batch fermentation. Thus, the construction of robust cells is vital for industrial application of microbial cell factories at the laboratory scale. Here, we systematically characterized longevity factors and pathways for biosynthesis of the diterpenoid sclareol and found that weakening nutrient-sensing pathways and enhancing mitophagy synergistically improved sclareol production by 70.3% (20.1 g/L with a yield of 0.046 g/g glucose). Further enhancing central metabolism improved sclareol production to 25.9 g/L with a yield of 0.051 g/g glucose, the highest production achieved in microbes. Omics data demonstrated that the extension of chronological lifespan by upregulating the expression of lifespan-related genes automatically remodeled the cellular metabolism and improved overall cellular robustness for efficient chemical biosynthesis. We also showed that our strategy significantly improved the biosynthesis of other products such as sesquiterpene β-elemene and phenolic acids. Therefore, this study may provide metabolic connections between cell aging and biosynthetic capacity.
