Overflow metabolism refers to the production of seemingly wasteful by-products by cells during growth on glucose even when oxygen is abundant. Two theories have been proposed to explain acetate overflow in Escherichia coli – global control of the central metabolism and local control of the acetate pathway – but neither accounts for all observations. Here, we develop a kinetic model of E. coli metabolism that quantitatively accounts for observed behaviors and successfully predicts the response of E. coli to new perturbations. We reconcile these theories and clarify the origin, control and regulation of the acetate flux. We also find that, in turns, acetate regulates glucose metabolism by coordinating the expression of glycolytic and TCA genes. Acetate should not be considered a wasteful end-product since it is also a co-substrate and a global regulator of glucose metabolism in E. coli. This has broad implications for our understanding of overflow metabolism.
Transcriptomics data have been deposited in ArrayExpress under accession code E-MTAB-9086.The calibrated kinetic model has been deposited in BioModels database under accession code MODEL2005050001.All the scripts used to perform the simulations, to analyse the models and to generate the figures are provided in the supporting files and at https://github.com/MetaSys-LISBP/acetate_regulationAll data generated or analysed during this study are included in the manuscript and supporting files.
Response of Escherichia coli to acetate concentration during growth on glucoseArrayExpress, E-MTAB-9086.
- Pierre Millard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Michael Doebeli, University of British Columbia, Canada
© 2021, Millard et al.
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