Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli

Chun-Ying Wang, Martin Lempp, Niklas Farke, Stefano Donati, Timo Glatter and Hannes Link ()
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Chun-Ying Wang: Max Planck Institute for Terrestrial Microbiology
Martin Lempp: Max Planck Institute for Terrestrial Microbiology
Niklas Farke: Max Planck Institute for Terrestrial Microbiology
Stefano Donati: Max Planck Institute for Terrestrial Microbiology
Timo Glatter: Max Planck Institute for Terrestrial Microbiology
Hannes Link: Max Planck Institute for Terrestrial Microbiology

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Synthetic metabolic pathways are a burden for engineered bacteria, but the underlying mechanisms often remain elusive. Here we show that the misregulated activity of the transcription factor Cra is responsible for the growth burden of glycerol overproducing E. coli. Glycerol production decreases the concentration of fructose-1,6-bisphoshate (FBP), which then activates Cra resulting in the downregulation of glycolytic enzymes and upregulation of gluconeogenesis enzymes. Because cells grow on glucose, the improper activation of gluconeogenesis and the concomitant inhibition of glycolysis likely impairs growth at higher induction of the glycerol pathway. We solve this misregulation by engineering a Cra-binding site in the promoter controlling the expression of the rate limiting enzyme of the glycerol pathway to maintain FBP levels sufficiently high. We show the broad applicability of this approach by engineering Cra-dependent regulation into a set of constitutive and inducible promoters, and use one of them to overproduce carotenoids in E. coli.

Date: 2021
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DOI: 10.1038/s41467-021-25142-0

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