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Elife. 2014 Jul 9;3. doi: 10.7554/eLife.03342.

Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step.

Author information

1
Division of Nutritional Sciences, Cornell University, Ithaca, United States.
2
Field of Biochemistry and Molecular Cell Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, United States.
3
Department of Neurobiology, Harvard Medical School, Boston, United States.
4
Field of Computational Biology, Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, United States.
5
Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, United States.
6
Department 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 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.

KEYWORDS:

biochemistry; glucose; glycolysis; human; human biology; mass spectrometry; mathematical modeling; medicine; metabolism; metabolomics

PMID:
25009227
PMCID:
PMC4118620
DOI:
10.7554/eLife.03342
[Indexed for MEDLINE]
Free PMC Article
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