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Title: Near-equilibrium glycolysis supports metabolic homeostasis and energy yield

Abstract

Glycolysis plays a central role in producing ATP and biomass. Its control principles, however, remain incompletely understood. In this work, we create a method that combines 2H and 13C tracers to determine glycolytic thermodynamics. With this method, we show that, in conditions and organisms with relatively slow fluxes, multiple steps in glycolysis are near to equilibrium, reflecting spare enzyme capacity. In Escherichia coli, nitrogen or phosphorus upshift rapidly increases the thermodynamic driving force, deploying the spare enzyme capacity to increase flux. Similarly, respiration inhibition in mammalian cells rapidly increases both glycolytic flux and the thermodynamic driving force. The thermodynamic shift allows flux to increase with only small metabolite concentration changes. Finally, we find that the cellulose-degrading anaerobe Clostridium cellulolyticum exhibits slow, near-equilibrium glycolysis due to the use of pyrophosphate rather than ATP for fructose-bisphosphate production, resulting in enhanced per-glucose ATP yield. Thus, near-equilibrium steps of glycolysis promote both rapid flux adaptation and energy efficiency.

Authors:
ORCiD logo [1];  [2];  [2]; ORCiD logo [3];  [3];  [2]; ORCiD logo [2];  [2];  [4];  [3]; ORCiD logo [3]; ORCiD logo [2]
+ Show Author Affiliations
  1. Univ. of California, Los Angeles, CA (United States); Princeton Univ., NJ (United States)
  2. Princeton Univ., NJ (United States)
  3. Univ. of Wisconsin, Madison, WI (United States)
  4. Princeton Univ., NJ (United States); ExxonMobil Research and Engineering Company, Annandale, NJ (United States)
Publication Date:
Research Org.:
Univ. of Illinois at Urbana-Champaign, IL (United States); Princeton Univ., NJ (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1570470
Grant/Contract Number:  
SC0018420; SC0012461; AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 15; Journal Issue: 10; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Park, Junyoung O., Tanner, Lukas B., Wei, Monica H., Khana, Daven B., Jacobson, Tyler B., Zhang, Zheyun, Rubin, Sara A., Li, Sophia Hsin-Jung, Higgins, Meytal B., Stevenson, David M., Amador-Noguez, Daniel, and Rabinowitz, Joshua D. Near-equilibrium glycolysis supports metabolic homeostasis and energy yield. United States: N. p., 2019. Web. doi:10.1038/s41589-019-0364-9.
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Park, Junyoung O., Tanner, Lukas B., Wei, Monica H., Khana, Daven B., Jacobson, Tyler B., Zhang, Zheyun, Rubin, Sara A., Li, Sophia Hsin-Jung, Higgins, Meytal B., Stevenson, David M., Amador-Noguez, Daniel, & Rabinowitz, Joshua D. Near-equilibrium glycolysis supports metabolic homeostasis and energy yield. United States. https://doi.org/10.1038/s41589-019-0364-9
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Park, Junyoung O., Tanner, Lukas B., Wei, Monica H., Khana, Daven B., Jacobson, Tyler B., Zhang, Zheyun, Rubin, Sara A., Li, Sophia Hsin-Jung, Higgins, Meytal B., Stevenson, David M., Amador-Noguez, Daniel, and Rabinowitz, Joshua D. Mon . "Near-equilibrium glycolysis supports metabolic homeostasis and energy yield". United States. https://doi.org/10.1038/s41589-019-0364-9. https://www.osti.gov/servlets/purl/1570470.
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@article{osti_1570470,
title = {Near-equilibrium glycolysis supports metabolic homeostasis and energy yield},
author = {Park, Junyoung O. and Tanner, Lukas B. and Wei, Monica H. and Khana, Daven B. and Jacobson, Tyler B. and Zhang, Zheyun and Rubin, Sara A. and Li, Sophia Hsin-Jung and Higgins, Meytal B. and Stevenson, David M. and Amador-Noguez, Daniel and Rabinowitz, Joshua D.},
abstractNote = {Glycolysis plays a central role in producing ATP and biomass. Its control principles, however, remain incompletely understood. In this work, we create a method that combines 2H and 13C tracers to determine glycolytic thermodynamics. With this method, we show that, in conditions and organisms with relatively slow fluxes, multiple steps in glycolysis are near to equilibrium, reflecting spare enzyme capacity. In Escherichia coli, nitrogen or phosphorus upshift rapidly increases the thermodynamic driving force, deploying the spare enzyme capacity to increase flux. Similarly, respiration inhibition in mammalian cells rapidly increases both glycolytic flux and the thermodynamic driving force. The thermodynamic shift allows flux to increase with only small metabolite concentration changes. Finally, we find that the cellulose-degrading anaerobe Clostridium cellulolyticum exhibits slow, near-equilibrium glycolysis due to the use of pyrophosphate rather than ATP for fructose-bisphosphate production, resulting in enhanced per-glucose ATP yield. Thus, near-equilibrium steps of glycolysis promote both rapid flux adaptation and energy efficiency.},
doi = {10.1038/s41589-019-0364-9},
journal = {Nature Chemical Biology},
number = 10,
volume = 15,
place = {United States},
year = {2019},
month = {9}
}
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https://doi.org/10.1038/s41589-019-0364-9
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