TBI, Université de Toulouse, CNRS, INRAE, INSA, Toulouse, France.
MetaToul-MetaboHUB, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France.
EMBO J. 2023 Aug 1;42(15):e113079. doi: 10.15252/embj.2022113079. Epub 2023 Jun 12.
Acetate, a major by-product of glycolytic metabolism in Escherichia coli and many other microorganisms, has long been considered a toxic waste compound that inhibits microbial growth. This counterproductive auto-inhibition represents a major problem in biotechnology and has puzzled the scientific community for decades. Recent studies have however revealed that acetate is also a co-substrate of glycolytic nutrients and a global regulator of E. coli metabolism and physiology. Here, we used a systems biology strategy to investigate the mutual regulation of glycolytic and acetate metabolism in E. coli. Computational and experimental analyses demonstrate that decreasing the glycolytic flux enhances co-utilization of acetate with glucose. Acetate metabolism thus compensates for the reduction in glycolytic flux and eventually buffers carbon uptake so that acetate, rather than being toxic, actually enhances E. coli growth under these conditions. We validated this mechanism using three orthogonal strategies: chemical inhibition of glucose uptake, glycolytic mutant strains, and alternative substrates with a natively low glycolytic flux. In summary, acetate makes E. coli more robust to glycolytic perturbations and is a valuable nutrient, with a beneficial effect on microbial growth.
乙酸是大肠杆菌和许多其他微生物糖酵解代谢的主要副产物，长期以来被认为是一种有毒的废物化合物，会抑制微生物的生长。这种适得其反的自动抑制作用是生物技术中的一个主要问题，几十年来一直困扰着科学界。然而，最近的研究表明，乙酸也是糖酵解营养物质的共底物，是大肠杆菌代谢和生理学的全局调节剂。在这里，我们使用系统生物学策略来研究大肠杆菌中糖酵解和乙酸代谢的相互调节。计算和实验分析表明，降低糖酵解通量会增强乙酸与葡萄糖的共利用。因此，乙酸代谢会补偿糖酵解通量的减少，最终缓冲碳的摄取，使得乙酸在这些条件下实际上增强了大肠杆菌的生长，而不是有毒。我们使用三种正交策略验证了这一机制：葡萄糖摄取的化学抑制、糖酵解突变株和具有天然低糖酵解通量的替代底物。总之，乙酸使大肠杆菌对糖酵解扰动更具鲁棒性，并且是一种有价值的营养物质，对微生物的生长有有益的影响。
