Sucrose-driven carbon redox rebalancing eliminates the Crabtree effect and boosts energy metabolism in yeast

Zhiqiang Xiao, Yifei Zhao, Yongtong Wang, Xinjia Tan, Lian Wang, Jiwei Mao, Siqi Zhang, Qiyuan Lu, Fanglin Hu, Shasha Zuo, Juan Liu () and Yang Shan ()
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Zhiqiang Xiao: Hunan University
Yifei Zhao: Hunan University
Yongtong Wang: Hunan University
Xinjia Tan: Hunan University
Lian Wang: Tianjin University
Jiwei Mao: Chalmers University of Technology
Siqi Zhang: Hunan University
Qiyuan Lu: Hunan University
Fanglin Hu: Hunan University
Shasha Zuo: Hunan University
Juan Liu: Hunan Academy of Agricultural Sciences
Yang Shan: Hunan University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Saccharomyces cerevisiae primarily generates energy through glycolysis and respiration. However, the manifestation of the Crabtree effect results in substantial carbon loss and energy inefficiency, which significantly diminishes product yield and escalates substrate costs in microbial cell factories. To address this challenge, we introduce the sucrose phosphorolysis pathway and delete the phosphoglucose isomerase gene PGI1, effectively decoupling glycolysis from respiration and facilitating the metabolic transition of yeast to a Crabtree-negative state. Additionally, a synthetic energy system is engineered to regulate the NADH/NAD+ ratio, ensuring sufficient ATP supply and maintaining redox balance for optimal growth. The reprogrammed yeast strain exhibits significantly higher yields of various non-ethanol compounds, with lactic acid and 3-hydroxypropionic acid production increasing by 8- to 11-fold comparing to the conventional Crabtree-positive strain. This study describes an approach for overcoming the Crabtree effect in yeast, substantially improving energy metabolism, carbon recovery, and product yields.

Date: 2025
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DOI: 10.1038/s41467-025-60578-8

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