title: Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step.
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 model of glycolysis and an integrated analysis using metabolic control analysis (MCA), 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 lower and upper glycolysis, is the rate-limiting step in the pathway and the levels of fructose (1,6) bisphosphate (FBP), are predictive of the rate and control points in glycolysis. Strikingly, negative flux control was found and confirmed for several steps thought to be rate-limiting in glycolysis. Together, these findings enumerate the biochemical determinants of the WE and suggest strategies for identifying the contexts in which agents that target glycolysis might be most effective.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, United States.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shestov
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, United States.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ser
authors.affiliation: Field of Biochemistry and Molecular Cell Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Cluntun
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Yin P
authors.initials: YP
authors.lastname: Hung
authors.affiliation: Field of Computational Biology, Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Field of Biochemistry and Molecular Cell Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States.
authors.forename: Dongsung
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, United States.
authors.forename: Anne
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Yellen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Albeck
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, United States.
authors.forename: Jason W
authors.identifier: http://orcid.org/0000-0002-7766-3502
authors.initials: JW
authors.lastname: Locasale
mesh_terms: D019295:Computational Biology / Q000379:methods; D005635:Fructosediphosphates / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism*; D006019:Glycolysis; D045325:HCT116 Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D008956:Models, Chemical; D009010:Monte Carlo Method; D010641:Phenotype; D010766:Phosphorylation
chemical_list: D005635:Fructosediphosphates; D051246:Glucose Transport Proteins, Facilitative; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D005947:Glucose; C029063:fructose-1,6-diphosphate
keywords: biochemistry; glucose; glycolysis; human; human biology; mass spectrometry; mathematical modeling; medicine; metabolism; metabolomics