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Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae

Author

Listed:
  • Fernando Alvarez-Vasquez

    (Department of Biochemistry and Molecular Biology
    Medical University of South Carolina)

  • Kellie J. Sims

    (Department of Biochemistry and Molecular Biology
    Medical University of South Carolina)

  • L. Ashley Cowart

    (Department of Biochemistry and Molecular Biology)

  • Yasuo Okamoto

    (Department of Biochemistry and Molecular Biology)

  • Eberhard O. Voit

    (Department of Biochemistry and Molecular Biology
    Medical University of South Carolina
    Georgia Institute of Technology and Emory Medical School)

  • Yusuf A. Hannun

    (Department of Biochemistry and Molecular Biology)

Abstract

Mathematical models have become a necessary tool for organizing the rapidly increasing amounts of large-scale data on biochemical pathways and for advanced evaluation of their structure and regulation. Most of these models have addressed specific pathways using either stoichiometric1 or flux-balance analysis2, or fully kinetic Michaelis–Menten representations3, metabolic control analysis4, or biochemical systems theory5,6,7. So far, the predictions of kinetic models have rarely been tested using direct experimentation. Here, we validate experimentally a biochemical systems theoretical model of sphingolipid metabolism in yeast8. Simulations of metabolic fluxes, enzyme deletion and the effects of inositol (a key regulator of phospholipid metabolism) led to predictions that show significant concordance with experimental results generated post hoc. The model also allowed the simulation of the effects of acute perturbations in fatty-acid precursors of sphingolipids, a situation that is not amenable to direct experimentation. The results demonstrate that modelling now allows testable predictions as well as the design and evaluation of hypothetical ‘thought experiments’ that may generate new metabolomic approaches.

Suggested Citation

  • Fernando Alvarez-Vasquez & Kellie J. Sims & L. Ashley Cowart & Yasuo Okamoto & Eberhard O. Voit & Yusuf A. Hannun, 2005. "Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae," Nature, Nature, vol. 433(7024), pages 425-430, January.
    • Handle: RePEc:nat:nature:v:433:y:2005:i:7024:d:10.1038_nature03232
    DOI: 10.1038/nature03232
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    Cited by:

    1. Yan Tang & David J. Kwiatkowski & Elizabeth P. Henske, 2022. "Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Po-Wei Chen & Luis L Fonseca & Yusuf A Hannun & Eberhard O Voit, 2016. "Analysis of the Involvement of Different Ceramide Variants in the Response to Hydroxyurea Stress in Baker's Yeast," PLOS ONE, Public Library of Science, vol. 11(1), pages 1-20, January.

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