Systems-level analysis of mechanisms regulating yeast metabolic flux

Sean R. Hackett, Vito R.T. Zanotelli, Wenxin Xu, Jonathan Goya, Junyoung O. Park, David H. Perlman, Patrick A. Gibney, David Botstein, John D. Storey, Joshua D. Rabinowitz

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92 Scopus citations

Abstract

Cellular metabolic fluxes are determined by enzyme activities and metabolite abundances. Biochemical approaches reveal the impact of specific substrates or regulators on enzyme kinetics but do not capture the extent to which metabolite and enzyme concentrations vary across physiological states and, therefore, how cellular reactions are regulated.We measured enzyme and metabolite concentrations and metabolic fluxes across 25 steady-state yeast cultures. We then assessed the extent to which flux can be explained by a Michaelis-Menten relationship between enzyme, substrate, product, and potential regulator concentrations. This revealed three previously unrecognized instances of cross-pathway regulation, which we biochemically verified. One of these involved inhibition of pyruvate kinase by citrate, which accumulated and thereby curtailed glycolytic outflow in nitrogen-limited yeast. Overall, substrate concentrations were the strongest driver of the net rates of cellular metabolic reactions, with metabolite concentrations collectively having more than double the physiological impact of enzymes.

Original languageEnglish (US)
Article numberaaf2786
JournalScience
Volume354
Issue number6311
DOIs
StatePublished - Oct 28 2016

All Science Journal Classification (ASJC) codes

  • General

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    Hackett, S. R., Zanotelli, V. R. T., Xu, W., Goya, J., Park, J. O., Perlman, D. H., Gibney, P. A., Botstein, D., Storey, J. D., & Rabinowitz, J. D. (2016). Systems-level analysis of mechanisms regulating yeast metabolic flux. Science, 354(6311), [aaf2786]. https://doi.org/10.1126/science.aaf2786