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

Alexander A. Shestov, Xiaojing Liu, Zheng Ser, Ahmad A. Cluntun, Yin P. Hung, Lei Huang, Dongsung Kim, Anne Le, Gary Yellen, John Albeck, Jason W. Locasale

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere03342
Pages (from-to)1-18
Number of pages18
JournaleLife
Volume3
Issue numberJuly2014
DOIs
StatePublished - Jul 9 2014

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Glycolysis
Fluxes
Enzymes
Metabolism
Statistical Data Interpretation
Metabolomics
Lactic Acid
Phenotype
Glucose

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Shestov, A. A., Liu, X., Ser, Z., Cluntun, A. A., Hung, Y. P., Huang, L., ... Locasale, J. W. (2014). Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. eLife, 3(July2014), 1-18. [e03342]. https://doi.org/10.7554/eLife.03342

Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. / Shestov, Alexander A.; Liu, Xiaojing; Ser, Zheng; Cluntun, Ahmad A.; Hung, Yin P.; Huang, Lei; Kim, Dongsung; Le, Anne; Yellen, Gary; Albeck, John; Locasale, Jason W.

In: eLife, Vol. 3, No. July2014, e03342, 09.07.2014, p. 1-18.

Research output: Contribution to journalArticle

Shestov, AA, Liu, X, Ser, Z, Cluntun, AA, Hung, YP, Huang, L, Kim, D, Le, A, Yellen, G, Albeck, J & Locasale, JW 2014, 'Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step', eLife, vol. 3, no. July2014, e03342, pp. 1-18. https://doi.org/10.7554/eLife.03342
Shestov AA, Liu X, Ser Z, Cluntun AA, Hung YP, Huang L et al. Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. eLife. 2014 Jul 9;3(July2014):1-18. e03342. https://doi.org/10.7554/eLife.03342
Shestov, Alexander A. ; Liu, Xiaojing ; Ser, Zheng ; Cluntun, Ahmad A. ; Hung, Yin P. ; Huang, Lei ; Kim, Dongsung ; Le, Anne ; Yellen, Gary ; Albeck, John ; Locasale, Jason W. / Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. In: eLife. 2014 ; Vol. 3, No. July2014. pp. 1-18.
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