Pyruvate Kinase Triggers a Metabolic Feedback Loop that Controls Redox Metabolism in Respiring Cells

• Published in: Cell metabolism Vol. 14; no. 3; pp. 415 - 427
• Main Authors: Grüning, Nana-Maria, Rinnerthaler, Mark, Bluemlein, Katharina, Mülleder, Michael, Wamelink, Mirjam M.C., Lehrach, Hans, Jakobs, Cornelis, Breitenbach, Michael, Ralser, Markus
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2011; Cell Press
• Subjects: Cell Proliferation; Cell Respiration - physiology; Chromatography, Liquid; Feedback, Physiological; Galactose - metabolism; Gene Expression Regulation, Fungal; Glucose - metabolism; Glycolysis - physiology; Oxidation-Reduction; Oxidative Stress - genetics; Pentose Phosphate Pathway; Phosphoenolpyruvate - metabolism; Polymerase Chain Reaction; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Reactive Oxygen Species - metabolism; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Tandem Mass Spectrometry; Triose-Phosphate Isomerase - genetics; Triose-Phosphate Isomerase - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.06.017

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. [Display omitted] ► Low pyruvate kinase (PYK) activity activates respiration in yeast ► Accumulation of the PYK substrate PEP inhibits the glycolytic enzyme TPI ► TPI inhibition stimulates the pentose phosphate pathway, preventing ROS accumulation ► The PYK-PEP-TPI feedback loop synchronizes respiration and redox metabolism