Article | Published:

Overflow metabolism in Escherichia coli results from efficient proteome allocation

Nature volume 528, pages 99104 (03 December 2015) | Download Citation

Abstract

Overflow metabolism refers to the seemingly wasteful strategy in which cells use fermentation instead of the more efficient respiration to generate energy, despite the availability of oxygen. Known as the Warburg effect in the context of cancer growth, this phenomenon occurs ubiquitously for fast-growing cells, including bacteria, fungi and mammalian cells, but its origin has remained unclear despite decades of research. Here we study metabolic overflow in Escherichia coli, and show that it is a global physiological response used to cope with changing proteomic demands of energy biogenesis and biomass synthesis under different growth conditions. A simple model of proteomic resource allocation can quantitatively account for all of the observed behaviours, and accurately predict responses to new perturbations. The key hypothesis of the model, that the proteome cost of energy biogenesis by respiration exceeds that by fermentation, is quantitatively confirmed by direct measurement of protein abundances via quantitative mass spectrometry.

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Acknowledgements

We are grateful to F. J. Bruggeman, E. O’Brien, U. Sauer, M. H. Saier and members of the Hwa and Sauer laboratories for valuable comments, and J. L. Figueroa for artistic contributions to the model illustration in Box 1. This work was supported by the NIH (grant R01-GM109069) and the Simons Foundation (grant 330378). T.H. additionally acknowledges the support of M. Rössler, the Walter Haefner Foundation and the ETH Foundation. M.B. acknowledges support from SystemsX TPdF. Y.S. acknowledges support from Hong Kong Baptist University (grants FRG2/11-12/159 and SKLP-14-15-P012).

Author information

Author notes

    • Markus Basan
    •  & Sheng Hui

    These authors contributed equally to this work.

Affiliations

  1. Department of Physics, University of California at San Diego, La Jolla, California 92093-0374, USA

    • Markus Basan
    • , Sheng Hui
    • , Hiroyuki Okano
    •  & Terence Hwa
  2. Institute of Molecular Systems Biology, ETH Zürich, 8093 Zürich, Switzerland

    • Markus Basan
  3. Section of Molecular Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093, USA

    • Hiroyuki Okano
    • , Zhongge Zhang
    • , Yang Shen
    •  & Terence Hwa
  4. Department of Integrative Structural and Computational Biology, Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA

    • James R. Williamson
  5. Institute for Theoretical Studies, ETH Zürich, 8092 Zürich, Switzerland

    • Terence Hwa

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Contributions

M.B., S.H., J.R.W. and T.H. designed the study. M.B., S.H., H.O., Z.Z. and Y.S. performed experiments. M.B., S.H. and T.H. analysed the data and developed the model. M.B., S.H., J.R.W. and T.H. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Terence Hwa.

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    Supplementary Information

    This file contains Supplementary Notes 1-4, including Supplementary Figures 1-15, Supplementary Tables 1-6 and Supplementary References.

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https://doi.org/10.1038/nature15765

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