Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells
Open accessAbstract
(13)C metabolic flux analysis (MFA) is the most comprehensive means of characterizing cellular metabolic states. Uniquely labeled isotopic tracers enable more focused analyses to probe specific reactions within the network. As a result, the choice of tracer largely determines the precision with which one can estimate metabolic fluxes, especially in complex mammalian systems that require multiple substrates. Here we have experimentally determined metabolic fluxes in a tumor cell line, successfully recapitulating the hallmarks of cancer cell metabolism. Using these data, we computationally evaluated specifically labeled (13)C glucose and glutamine tracers for their ability to precisely and accurately estimate fluxes in central carbon metabolism. These methods enabled us to identify the optimal tracer for analyzing individual fluxes, specific pathways, and central carbon metabolism as a whole. [1,2-(13)C(2)]glucose provided the most precise estimates for glycolysis, the pentose phosphate pathway, and the overall network. Tracers such as [2-(13)C]glucose and [3-(13)C]glucose also outperformed the more commonly used [1-(13)C]glucose. [U-(13)C(5)]glutamine emerged as the preferred isotopic tracer for the analysis of the tricarboxylic acid (TCA) cycle. These results provide valuable, quantitative information on the performance of (13)C-labeled substrates and can aid in the design of more informative MFA experiments in mammalian cell culture.
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PDC and PC both catalyze the flux of pyruvate into the TCA cycle, but their metabolic roles do not appear to be interchangeable.
“Although PDC and PC both catalyze the flux of pyruvate into the TCA cycle, their enzymatic activities can be distinguished by stable isotope tracing26,27, and their metabolic roles do not appear to be interchangeable.”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [26]
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- Authors
- Metallo, C. M., Walther, J. L., & Stephanopoulos, G.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Stephanopoulos, Gregory
- Venue
- Journal of Biotechnology
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 144
- Issue
- 3
- Pages
- 167-174
- ISSN
- 0168-1656 (ISSN-L)
- PMC
- PMC3026314
- OpenAlex
- W2049759143
- Cited by
- 280
- References
- 35
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 11 · 2019: 17 · 2018: 15 · 2017: 22 · 2016: 22 · 2015: 14 · 2014: 18 · 2013: 40 · 2012: 20
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- National Cancer Institute (R01CA160458)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- 13C metabolic flux analysis, isotope tracers, central carbon metabolism, glycolysis, pentose phosphate pathway, TCA cycle, cancer metabolism, cancer cell lines
- MeSH terms
- Algorithms, Carbon, Carbon Isotopes, Computer Simulation, Glucose, Glutamine, Humans, Isotope Labeling, Confidence Intervals, Cell Line, Tumor, Metabolomics
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