Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli
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Absolute metabolite concentrations are critical to a quantitative understanding of cellular metabolism, as concentrations impact both the free energies and rates of metabolic reactions. Here we use LC-MS/MS to quantify more than 100 metabolite concentrations in aerobic, exponentially growing Escherichia coli with glucose, glycerol or acetate as the carbon source. The total observed intracellular metabolite pool was approximately 300 mM. A small number of metabolites dominate the metabolome on a molar basis, with glutamate being the most abundant. Metabolite concentration exceeds K(m) for most substrate-enzyme pairs. An exception is lower glycolysis, where concentrations of intermediates are near the K(m) of their consuming enzymes and all reactions are near equilibrium. This may facilitate efficient flux reversibility given thermodynamic and osmotic constraints. The data and analyses presented here highlight the ability to identify organizing metabolic principles from systems-level absolute metabolite concentration data.
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Predicted metabolite concentrations are within an order of magnitude of E. coli measurements for 100% of metabolites in one dataset and 70% in a newer high-throughput study.
“the predicted metabolite concentrations are within an order of magnitude of concentrations measured in Escherichia coli for 100% of the metabolites in one compilation of data (Sundararaj et al., 2004) and for 70% in a more recent high-throughput study (Bennett et al., 2009; Figure 2F).”
From A Whole-Cell Computational Model Predicts Phenotype from Genotype (2012) · cites this paper as Bennett et al., 2009
The greater diversity of BBAAs produced by purified BlBSH in vitro compared to BlBSH-expressing E. coli is probably a result of different amino acid profiles in E. coli, where alanine is about 100-fold more concentrated than serine.
“However, the greater diversity of BBAAs produced by purified BlBSH in vitro (Fig. 2b) compared to BlBSH-expressing E. coli (Fig. 2c) is probably a result of the different amino acid profiles in E. coli (alanine is present at about a 100-fold greater concentration than serine)23.”
From Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase (2022) · cites this paper as [23]
The Results and Discussion describe measurements of E. coli metabolite concentrations, but the passages found for “alanine,” “serine,” and their concentration ratio give no values for either amino acid. Our copy therefore does not verify the approximately 100-fold comparison for which this paper is cited. (LLM, conf=0.73)
Experimental — accuracy not yet measuredIn model systems, many metabolic enzymes have in vivo Km values higher than their in vitro values and closer to cosubstrate concentrations.
“In model systems, many metabolic enzymes display Km values in vivo that are higher than their corresponding in vitro values and certainly closer to the concentrations of their cosubstrates (Bennett et al., 2009; Yuan et al., 2009).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Bennett et al., 2009
Most enzymes are substrate saturated in E. coli.
“Our observation that active-site competition has an important function in controlling nitrogen assimilation fluxes matches nicely with the recent finding that most enzymes are substrate saturated in E. coli (Bennett et al, 2009).”
From Metabolomics-driven quantitative analysis of ammonia assimilation in E. coli (2009) · cites this paper as Bennett et al, 2009
Active-site competition has an important function in controlling nitrogen assimilation fluxes.
“Our observation that active-site competition has an important function in controlling nitrogen assimilation fluxes matches nicely with the recent finding that most enzymes are substrate saturated in E. coli (Bennett et al, 2009).”
From Metabolomics-driven quantitative analysis of ammonia assimilation in E. coli (2009) · cites this paper as Bennett et al, 2009
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- Authors
- Bennett, B. D., Kimball, E. H., Gao, M., Osterhout, R., Van Dien, S. J., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Genomatica (United States) (US)
- Corresponding author
- Rabinowitz, Joshua D
- Venue
- Nature Chemical Biology
- Published
- 2009-06-28
- Volume
- 5
- Issue
- 8
- Pages
- 593-599
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC2754216
- OpenAlex
- W2004235182
- Cited by
- 1,830
- References
- 48
- Citations by year
- 2026: 79 · 2025: 108 · 2024: 102 · 2023: 121 · 2022: 106 · 2021: 107 · 2020: 128 · 2019: 126 · 2018: 146 · 2017: 133 · 2016: 115 · 2015: 108 · 2014: 118 · 2013: 99 · 2012: 98
- FWCI
- 31.24
- 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)
- Funders
- National Science Foundation
- Foundation for the National Institutes of Health
- American Heart Association
- Arnold and Mabel Beckman Foundation
- National Institute of General Medical Sciences (P50GM071508)
- 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 › Metabolomics and Mass Spectrometry Studies
- Keywords
- Escherichia coli, Michaelis constant, glutamate, glycolysis, carbon source, glucose, glycerol, acetate
- MeSH terms
- Acetates, Binding Sites, Chromatography, Liquid, Escherichia coli, Glucose, Glycerol, Glycolysis, Mass Spectrometry, Thermodynamics, Escherichia coli Proteins, Metabolome
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