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Metabolic regulation of the stress response and the cancer cell's Warburg effect
If you have a question about this talk, please contact Florian Markowetz.
Stability of the metabolic network is a premise for life. This stability requires a modular substructure of the metabolic network, which allows that biochemical modules operate and are controlled semi-independently. We use artificial metabolic deficiencies in yeast to study how the network reconfigures after a perturbation. We find, that a surprisingly low number of phenotype variation is represented in quantitative metabolome data, indicating that metabolic network mainly maintains its stability by acting on transcriptome and proteome. To identify metabolic regulators, we recently completed a prototrophic yeast gene deletion collection which is used for systematic metabolic profiling.
In the second part of the talk, I’ll present data about the regulatory function of a metabolic enzyme, pyruvate kinase (PYK), which coordinates the interplay of at least three important parts of metabolism. We found that altered PYK levels regulates respiration. Surprisingly, levels of reactive oxygen species (ROS) do not correlate, and we find that reduced activity of PK enzyme induced resistance to oxidants. This adaptation is attributable to accumulation of the PYK substrate phosphoenolpyruvate (PEP). PEP acts as feedback inhibitor of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition stimulates the pentose phosphate pathway, increased anti-oxidative metabolism, and prevented ROS accumulation. Thus, a metabolic feedback loop, initiated by PYK , mediated by its substrate and acting on TPI , synchronises energy- and redox metabolism when cells respire. Originating from a single catalytic step, this autonomous re-configuration of central carbon metabolism prevents oxidative stress upon shifts between fermentation and respiration.
This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.
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