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Nat Chem Biol. 2019 Oct;15(10):1001-1008. doi: 10.1038/s41589-019-0364-9. Epub 2019 Sep 23.

Near-equilibrium glycolysis supports metabolic homeostasis and energy yield.

Author information

1
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
2
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
3
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
4
Department of Chemistry, Princeton University, Princeton, NJ, USA.
5
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
6
Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI, USA.
7
Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
8
Corporate Strategic Research, ExxonMobil Research and Engineering Company, Annandale, NJ, USA.
9
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA. amadornoguez@wisc.edu.
10
Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI, USA. amadornoguez@wisc.edu.
11
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.
12
Department of Chemistry, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.

Abstract

Glycolysis plays a central role in producing ATP and biomass. Its control principles, however, remain incompletely understood. Here, we develop a method that combines 2H and 13C tracers to determine glycolytic thermodynamics. Using 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.

PMID:
31548693
DOI:
10.1038/s41589-019-0364-9

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