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

  1. Alex A Shestov
  2. Xiaojing Liu
  3. Zheng Ser
  4. Ahmad A Cluntun
  5. Yin P Hung
  6. Lei Huang
  7. Dongsung Kim
  8. Anne Le
  9. Gary Yellen
  10. John G Albeck
  11. Jason W Locasale  Is a corresponding author
  1. Cornell University, United States
  2. Harvard Medical School, United States
  3. Johns Hopkins University School of Medicine, United States
  4. University of California, Davis, 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.

Article and author information

Author details

  1. Alex A Shestov

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  2. Xiaojing Liu

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  3. Zheng Ser

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  4. Ahmad A Cluntun

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  5. Yin P Hung

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Lei Huang

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  7. Dongsung Kim

    Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  8. Anne Le

    Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Gary Yellen

    Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  10. John G Albeck

    University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  11. Jason W Locasale

    Cornell University, Ithaca, United States
    For correspondence
    locasale@cornell.edu
    Competing interests
    Jason W Locasale, A patent related to this work has been filed..

Reviewing Editor

  1. David M Sabatini, Whitehead Institute and the Massachusetts Institute of Technology, United States

Version history

  1. Received: May 11, 2014
  2. Accepted: July 8, 2014
  3. Accepted Manuscript published: July 9, 2014 (version 1)
  4. Version of Record published: August 1, 2014 (version 2)

Copyright

© 2014, Shestov et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alex A Shestov
  2. Xiaojing Liu
  3. Zheng Ser
  4. Ahmad A Cluntun
  5. Yin P Hung
  6. Lei Huang
  7. Dongsung Kim
  8. Anne Le
  9. Gary Yellen
  10. John G Albeck
  11. Jason W Locasale
(2014)
Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step
eLife 3:e03342.
https://doi.org/10.7554/eLife.03342

Share this article

https://doi.org/10.7554/eLife.03342

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