PMID:21907146

Citation	Grüning, NM, Rinnerthaler, M, Bluemlein, K, Mülleder, M, Wamelink, MM, Lehrach, H, Jakobs, C, Breitenbach, M and Ralser, M (2011) Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab. 14:415-27
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.
Links	PubMed PMC3202625 Online version:10.1016/j.cmet.2011.06.017
Keywords	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
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
YEAST:KPYK1		GO:0004743: pyruvate kinase activity	ECO:0000316:	UniProtKB:P52489	F		Figure 1B and 1C Pyruvate kinase activity of TEFpr-PYK1 and CYCpr-PYK1. TEFpr is a strong promotor, CYCpr is a weak promotor.	complete CACAO 10958
YEAST:KPYK1		GO:0006098: pentose-phosphate shunt	ECO:0000314:		P		Figure 5B Cells with low PYK activity have increased concentrations of PPP intermediates	complete CACAO 10960
YEAST:KPYK2		GO:0004743: pyruvate kinase activity	ECO:0000316:	UniProtKB:P00549	F		Figure 1B and C Pyruvate kinase activity of TEFpr-PYK2 and CYCpr-PYK2. TEFpr is a strong promotor, CYCpr is a weak promotor.	complete CACAO 10959
YEAST:KPYK2		GO:0006098: pentose-phosphate shunt	ECO:0000314:		P		Figure 5B Cells with low PYK activity have increased concentrations of PPP intermediates	complete CACAO 10961

References

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