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Metabolite concentrations, fluxes and free energies imply efficient enzyme usage
Open accessAbstract
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). Here 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). The observed conservation of metabolite concentrations is consistent with an evolutionary drive to utilize enzymes efficiently given thermodynamic and osmotic constraints.
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“In general, average metabolite concentrations generated from the model (Figure 6) show reasonable agreement to the values reported by Park et al. (2016) in E. coli, but the cell-to-cell variation in the kinetic models over a cell cycle is broader than the predicted range.”
From Fundamental behaviors emerge from simulations of a living minimal cell (2022) · cites this paper as Park et al. (2016)
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“The main deviation here is again with the FBA reaction where the kinetic parameters result in a free energy drop of roughly 25 kJ/mol which has been reported to be less than 10 kJ/mol (Flamholz et al., 2013; Park et al., 2016).”
From Fundamental behaviors emerge from simulations of a living minimal cell (2022) · cites this paper as Park et al., 2016
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“Other studies have reported overall free energy changes from −30 to −70 kJ/mol (Flamholz et al., 2013; Park et al., 2016)”
From Fundamental behaviors emerge from simulations of a living minimal cell (2022) · cites this paper as Park et al., 2016
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“At the moment, only relative metabolomics data on Syn3A is available, so the metabolite concentrations used to initialize the simulations of the Syn3A WCM were estimated from a scaling of the comprehensive study done on E. coli (Park et al., 2016) and a limited list from M. pneumoniae (Yus et al., 2009).”
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“While such high concentrations have been reported in yeast (Park et al., 2016), they may be inaccurate for Syn3A.”
From Fundamental behaviors emerge from simulations of a living minimal cell (2022) · cites this paper as Park et al., 2016
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MethodBreast Cancer-Derived Lung Metastases Show Increased Pyruvate Carboxylase-Dependent Anaplerosis
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“Aspartate is estimated at ~5–10 mM whereas asparagine is much closer to the KM, at ~100– 200 mM (Chen et al., 2016; Park et al., 2016).”
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“…with the discrepancy between in vitrodetermined maximal enzyme activities in the oxidative PP pathway of approximately 3.2 mmol g 1 h 1 (Fuhrer and Sauer, 2009) and the about 40% lower actual intracellular fluxes of 2.0 mmol g 1 h 1 reported previously (Fuhrer et al., 2005; Park et al., 2016).”
BackgroundInfluentialT Cell Activation Depends on Extracellular Alanine
Ron‐Harel, N., Ghergurovich, J. M., Notarangelo, G., LaFleur, M. W., Tsubosaka, Y., Sharpe, A. H., Rabinowitz, J. D., & Haigis, M. C. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.034 · Cited by 201
“Using estimated mammalian cell concentrations of pyruvate and glutamate under standard tissue culture conditions, we found that the production of alanine from pyruvate is thermodynamically favorable, with delta G 10 KJ/mol by using the Weizmann equilibrium calculator (Flamholz et al., 2012; Park et al., 2016).”
MethodLian, G., Gnanaprakasam, J. R., Wang, T., Wu, R., Chen, X., Liu, L., Shen, Y., Yang, M., Yang, J. J. J., Chen, Y., et al. (2018) · eLife · doi:10.7554/elife.36158 · Cited by 199
“employing extracellular GSH, the utilization of extracellular GSH plays a minor role in regulating GSH homeostasis, since the extracellular levels of GSH are normally three orders of magnitude lower than intracellular GSH concentrations, which are usually in the millimolar range (Kosower and Kosower, 1978; Meister, 19…”
BackgroundAffinity-based capture and identification of protein effectors of the growth regulator ppGpp
Wang, B., Dai, P., Ding, D., Rosario, A. M. D., Grant, R. A., Pentelute, B. L., & Laub, M. T. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0183-4 · Cited by 194
Extraction and Quantitation of Nicotinamide Adenine Dinucleotide Redox Cofactors
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“In this study, we investigated several different extraction methods for the redox cofactors NADPH/NADP+/NADH/ NAD+ from cultured mammalian cells and mammalian tissues.”
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“While such high concentrations have been reported in yeast (Park et al., 2016), they may be inaccurate for Syn3A.”
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BackgroundImproving formaldehyde consumption drives methanol assimilation in engineered E. coli
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A Bird’s-Eye View of Enzyme Evolution: Chemical, Physicochemical, and Physiological Considerations
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Mitochondrial ATP generation is more proteome efficient than glycolysis
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“As such, slight perturbations due to overexpression of enzymes lead to detrimental effects on cell growth and product accumulation (Gupta, Reizman, Reisch, & Prather, 2017; Park et al., 2016).”
BackgroundPark, Y., Pacitto, A., Bayliss, T., Cleghorn, L. A. T., Wang, Z., Hartman, T. E., Arora, K., Ioerger, T. R., Sacchettini, J. C., Rizzi, M., et al. (2016) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.6b00103 · Cited by 96
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ppGpp Coordinates Nucleotide and Amino-Acid Synthesis in E. coli During Starvation
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“Extraction of hydrophilic metabolites: Experimental procedures for metabolite extraction for analysis using hydrophilic chromatography in tandem with mass spectrometry (pHILIC-MS) or anion-exchange chromatography were modified from those described by previously (Park et al., 2016).”
MethodShimizu, K., & Matsuoka, Y. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.12.007 · Cited by 90
Complex regulation in a Comamonas platform for diverse aromatic carbon metabolism
Wilkes, R. A., Waldbauer, J., Carroll, A. L., Nieto‐Domínguez, M., Parker, D. J., Zhang, L., Guss, A. M., & Aristilde, L. (2023) · Nature Chemical Biology · doi:10.1038/s41589-022-01237-7 · Cited by 91
“Importantly, flux directionality through metabolic reactions was determined to be related to negative Gibbs free energy (∆ G ), which is log proportional to both the concentration ratio of product to reactant and the flux ratio of forward to backward flux 24,25 .”
BackgroundNear-equilibrium glycolysis supports metabolic homeostasis and energy yield
Park, J. O., Tanner, L. B., Wei, M. H., Khana, D. B., Jacobson, T. B., Zhang, Z., Rubin, S. A., Li, H., Higgins, M. B., Stevenson, D. M., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0364-9 · Cited by 89
Physical basis of the cell size scaling laws
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“This high value of metabolite concentration is coherent with reported measurements ( Park et al., 2016 ).”
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“However, it remains open whether these responses buffered lower enzyme levels because in vivo kinetic parameters demonstrated that most of the enzymes are saturated (Bennett et al., 2009; Park et al., 2016).”
BackgroundBisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate
Oslund, R., Su, X., Haugbro, M., Kee, J., Esposito, M., David, Y., Wang, B., Ge, E. J., Perlman, D. H., Kang, Y., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2453 · Cited by 85
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Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle
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“This is further supported by the fact that metabolic substrate and inhibitor levels in mammalian cells are typically in the same range as the K m values for the corresponding enzymes (Park et al , 2016).”
Reznik, E., Christodoulou, D., Goldford, J. E., Briars, E. A., Sauer, U., Segrè, D., & Noor, Ε. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.066 · Cited by 82
“As reported by others (Park et al., 2016), in general, KI values tend to be higher than KM values (Figure 4D; Mann-Whitney U test, p value < 0.”
BackgroundResultInfluentialEvolution of glutamatergic signaling and synapses
Moroz, L. L., Nikitin, M. A., Poličar, P. G., Kohn, A. B., & Romanova, D. Y. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108740 · Cited by 81
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In diverse conditions, intrinsic chromatin condensates have liquid-like material properties
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The PEP-pyruvate-oxaloacetate node: variation at the heart of metabolism
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“The reaction is typically considered irreversible, however, recent findings suggest that the rG of PK is not as negative as was previously thought (Park et al. 2016).”
ResultFunctional Roles of Chelated Magnesium Ions in RNA Folding and Function
Yamagami, R., Sieg, J. P., & Bevilacqua, P. C. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00012 · Cited by 81
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“7 mM (40) that is consistent with targeted measurements of GSH in HepG2 cells at 3 mM (41).”
BackgroundLessons on enzyme kinetics from quantitative proteomics
Davidi, D., & Milo, R. (2017) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2017.02.007 · Cited by 72
“[53] provided evidence that in the glycolytic pathway of E.”
BackgroundIntegrating bioinformatics approaches for a comprehensive interpretation of metabolomics datasets
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“Particularly, integrated pathway maps are reported for metabolic flux analysis and tumor metabolism studies [41].”
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“Intracellular metabolite concentrations reported in Park et al. 44 were constrained to be within twofold of the reported values.”
BackgroundMethodReserve Flux Capacity in the Pentose Phosphate Pathway by NADPH Binding Is Conserved across Kingdoms
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“coli is close to zero (Park et al., 2016), represented as red circles in Fig.”
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“The most highly connected enzymes were fructose-bisphosphate aldolase (FbaA) and malate dehydrogenase (MaeB) with eleven interacting metabolites each.”
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Metadata
- Authors
- Park, J. O., Rubin, S. A., Xu, Y.-F., Amador-Noguez, D., Fan, J., Shlomi, T., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Rabinowitz, Joshua D
- Venue
- Nature Chemical Biology
- Published
- 2016-05-02
- Volume
- 12
- Issue
- 7
- Pages
- 482-489
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4912430
- OpenAlex
- W2346094579
- Cited by
- 453
- References
- 60
- Citations by year
- 2026: 39 · 2025: 56 · 2024: 53 · 2023: 50 · 2022: 44 · 2021: 43 · 2020: 40 · 2019: 37 · 2018: 43 · 2017: 34 · 2016: 13
- FWCI
- 22.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (DESC0012461)
- National Institutes of Health
- National Cancer Institute (R01CA163591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- metabolic flux, metabolite concentrations, enzyme catalytic efficiency, isotopic labeling, glycolysis, reaction quotient, equilibrium constants, Escherichia coli, yeast, thermodynamics of metabolism
- MeSH terms
- Animals, Cell Line, Enzymes, Escherichia coli, Saccharomyces cerevisiae, Thermodynamics, Mice
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