Quantitative Determinants of Aerobic Glycolysis Identify Flux Through The
RESEARCH ARTICLE elifesciences.org Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step Alexander A Shestov1†, Xiaojing Liu1†, Zheng Ser1, Ahmad A Cluntun2, Yin P Hung3, Lei Huang4, Dongsung Kim2, Anne Le5, Gary Yellen3, John G Albeck6‡, Jason W Locasale1,2,4* 1Division of Nutritional Sciences, Cornell University, Ithaca, United States; 2Field of Biochemistry and Molecular Cell Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States; 3Department of Neurobiology, Harvard Medical School, Boston, United States; 4Field of Computational Biology, Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, United States; 5Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, United States; 6Department of Cell Biology, Harvard Medical School, Boston, United States Abstract Aerobic glycolysis or the Warburg Effect (WE) is characterized by the increased metabolism of glucose to lactate. It remains unknown what quantitative changes to the activity of metabolism are necessary and sufficient for this phenotype. We developed a computational *For correspondence: locasale@ model of glycolysis and an integrated analysis using metabolic control analysis (MCA), cornell.edu metabolomics data, and statistical simulations. We identified and confirmed a novel mode of regulation specific to aerobic glycolysis where flux through GAPDH, the enzyme separating †These authors contributed lower and upper glycolysis, is the rate-limiting step in the pathway and the levels of fructose equally to this work (1,6) bisphosphate (FBP), are predictive of the rate and control points in glycolysis. Strikingly, Present address: ‡Department negative flux control was found and confirmed for several steps thought to be rate-limiting in of Molecular Cell Biology, glycolysis.
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