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Science. 2016 Oct 28;354(6311). pii: aaf2786. Epub 2016 Oct 27.

Systems-level analysis of mechanisms regulating yeast metabolic flux.

Author information

1
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
2
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
3
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
4
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
5
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
6
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Center for Statistics and Machine Learning, Princeton University, Princeton, NJ 08544, USA.
7
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. joshr@genomics.princeton.edu.

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.

Comment in

PMID:
27789812
PMCID:
PMC5414049
DOI:
10.1126/science.aaf2786
[Indexed for MEDLINE]
Free PMC Article

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