title: Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells.
abstract: In proliferating cells, a transition from aerobic to anaerobic metabolism is known as the Warburg effect, whose reversal inhibits cancer cell proliferation. Studying its regulator pyruvate kinase (PYK) in yeast, we discovered that central metabolism is self-adapting to synchronize redox metabolism when respiration is activated. Low PYK activity activated yeast respiration. However, levels of reactive oxygen species (ROS) did not increase, and cells gained resistance to oxidants. This adaptation was attributable to accumulation of the PYK substrate phosphoenolpyruvate (PEP). PEP acted as feedback inhibitor of the glycolytic enzyme triosephosphate isomerase (TPI). TPI inhibition stimulated the pentose phosphate pathway, increased antioxidative metabolism, and prevented ROS accumulation. Thus, a metabolic feedback loop, initiated by PYK, mediated by its substrate and acting on TPI, stimulates redox metabolism in respiring cells. Originating from a single catalytic step, this autonomous reconfiguration of central carbon metabolism prevents oxidative stress upon shifts between fermentation and respiration.
authors: Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
authors: Nana-Maria
authors: NM
authors: Grüning
authors: Mark
authors: M
authors: Rinnerthaler
authors: Katharina
authors: K
authors: Bluemlein
authors: Michael
authors: M
authors: Mülleder
authors: Mirjam M C
authors: MM
authors: Wamelink
authors: Hans
authors: H
authors: Lehrach
authors: Cornelis
authors: C
authors: Jakobs
authors: Michael
authors: M
authors: Breitenbach
authors: Markus
authors: M
authors: Ralser
mesh_terms: D049109:Cell Proliferation; D019069:Cell Respiration / Q000502:physiology*; D002853:Chromatography, Liquid; D025461:Feedback, Physiological; D005690:Galactose / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D010427:Pentose Phosphate Pathway; D010728:Phosphoenolpyruvate / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014305:Triose-Phosphate Isomerase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D010728:Phosphoenolpyruvate; D011770:Pyruvate Kinase; D014305:Triose-Phosphate Isomerase; D005947:Glucose; D005690:Galactose