Reserve Flux Capacity in the Pentose Phosphate Pathway Enables Escherichia coli's Rapid Response to Oxidative Stress.
- Christodoulou D Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland.
- Link H Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Max Planck Institute for Terrestrial Microbiology, Marburg 35043, Germany.
- Fuhrer T Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
- Kochanowski K Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
- Gerosa L Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Laboratory of Systems Pharmacology, Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA.
- Sauer U Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland. Electronic address: sauer@ethz.ch.
- 2018-05-14
Published in:
- Cell systems. - 2018
allosteric regulation
central metabolism
kinetic modeling
metabolomics
oxidative stress
Escherichia coli
Escherichia coli Proteins
Glucosephosphate Dehydrogenase
Glycolysis
Hydrogen Peroxide
Metabolic Flux Analysis
Metabolic Networks and Pathways
NADP
Oxidative Stress
Pentose Phosphate Pathway
Reactive Oxygen Species
English
To counteract oxidative stress and reactive oxygen species (ROS), bacteria evolved various mechanisms, primarily reducing ROS through antioxidant systems that utilize cofactor NADPH. Cells must stabilize NADPH levels by increasing flux through replenishing metabolic pathways like pentose phosphate (PP) pathway. Here, we investigate the mechanism enabling the rapid increase in NADPH supply by exposing Escherichia coli to hydrogen peroxide and quantifying the immediate metabolite dynamics. To systematically infer active regulatory interactions governing this response, we evaluated ensembles of kinetic models of glycolysis and PP pathway, each with different regulation mechanisms. Besides the known inactivation of glyceraldehyde 3-phosphate dehydrogenase by ROS, we reveal the important allosteric inhibition of the first PP pathway enzyme by NADPH. This NADPH feedback inhibition maintains a below maximum-capacity PP pathway flux under non-stress conditions. Relieving this inhibition instantly increases PP pathway flux upon oxidative stress. We demonstrate that reducing cells' capacity to rapidly reroute their flux through the PP pathway increases their oxidative stress sensitivity.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1016/j.cels.2018.04.009
- PMID 29753645
- Persistent URL
- https://sonar.ch/global/documents/153799
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