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Title: Metabolite concentrations, fluxes and free energies imply efficient enzyme usage

In metabolism, available free energy is limited and must be divided across pathway steps to maintain a negative Δ G throughout. For each reaction, Δ G is log proportional both to a concentration ratio (reaction quotient to equilibrium constant) and to a flux ratio (backward to forward flux). In this paper, we use isotope labeling to measure absolute metabolite concentrations and fluxes in Escherichia coli, yeast and a mammalian cell line. We then integrate this information to obtain a unified set of concentrations and Δ G for each organism. In glycolysis, we find that free energy is partitioned so as to mitigate unproductive backward fluxes associated with Δ G near zero. Across metabolism, we observe that absolute metabolite concentrations and Δ G are substantially conserved and that most substrate (but not inhibitor) concentrations exceed the associated enzyme binding site dissociation constant ( K m or K i). Finally, the observed conservation of metabolite concentrations is consistent with an evolutionary drive to utilize enzymes efficiently given thermodynamic and osmotic constraints.
Authors:
ORCiD logo [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1]
  1. Princeton Univ., Princeton, NJ (United States)
  2. Technion-Israel Institute of Technology, Haifa (Israel)
Publication Date:
Grant/Contract Number:
SC0012461
Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 12; Journal Issue: 7; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Research Org:
Princeton Univ., NJ (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biochemical reaction networks; mass spectrometry; metabolomics; systems biology
OSTI Identifier:
1347119

Park, Junyoung O., Rubin, Sara A., Xu, Yi -Fan, Amador-Noguez, Daniel, Fan, Jing, Shlomi, Tomer, and Rabinowitz, Joshua D.. Metabolite concentrations, fluxes and free energies imply efficient enzyme usage. United States: N. p., Web. doi:10.1038/nchembio.2077.
Park, Junyoung O., Rubin, Sara A., Xu, Yi -Fan, Amador-Noguez, Daniel, Fan, Jing, Shlomi, Tomer, & Rabinowitz, Joshua D.. Metabolite concentrations, fluxes and free energies imply efficient enzyme usage. United States. doi:10.1038/nchembio.2077.
Park, Junyoung O., Rubin, Sara A., Xu, Yi -Fan, Amador-Noguez, Daniel, Fan, Jing, Shlomi, Tomer, and Rabinowitz, Joshua D.. 2016. "Metabolite concentrations, fluxes and free energies imply efficient enzyme usage". United States. doi:10.1038/nchembio.2077. https://www.osti.gov/servlets/purl/1347119.
@article{osti_1347119,
title = {Metabolite concentrations, fluxes and free energies imply efficient enzyme usage},
author = {Park, Junyoung O. and Rubin, Sara A. and Xu, Yi -Fan and Amador-Noguez, Daniel and Fan, Jing and Shlomi, Tomer and Rabinowitz, Joshua D.},
abstractNote = {In metabolism, available free energy is limited and must be divided across pathway steps to maintain a negative ΔG throughout. For each reaction, ΔG is log proportional both to a concentration ratio (reaction quotient to equilibrium constant) and to a flux ratio (backward to forward flux). In this paper, we use isotope labeling to measure absolute metabolite concentrations and fluxes in Escherichia coli, yeast and a mammalian cell line. We then integrate this information to obtain a unified set of concentrations and ΔG for each organism. In glycolysis, we find that free energy is partitioned so as to mitigate unproductive backward fluxes associated with ΔG near zero. Across metabolism, we observe that absolute metabolite concentrations and ΔG are substantially conserved and that most substrate (but not inhibitor) concentrations exceed the associated enzyme binding site dissociation constant (Km or Ki). Finally, the observed conservation of metabolite concentrations is consistent with an evolutionary drive to utilize enzymes efficiently given thermodynamic and osmotic constraints.},
doi = {10.1038/nchembio.2077},
journal = {Nature Chemical Biology},
number = 7,
volume = 12,
place = {United States},
year = {2016},
month = {5}
}