The DOI matches its Crossref record; 33 of the 35 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622
Tumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337
ATP citrate lyase inhibition can suppress tumor cell growth
Hatzivassiliou, G., Zhao, F., Bauer, D. E., Andreadis, C., Shaw, A. N., Dhanak, D., Hingorani, S. R., Tuveson, D. A., & Thompson, C. B. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.09.008 · Cited by 1,086
Brick by brick: metabolism and tumor cell growth
DeBerardinis, R. J., Sayed, N., Ditsworth, D., & Thompson, C. B. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.02.003 · Cited by 1,018
Metabolic networks in motion: 13C‐based flux analysis
Sauer, U. (2006) · Molecular Systems Biology · doi:10.1038/msb4100109 · Cited by 681
Munger, J. C., Bennett, B. D., Parikh, A., Feng, X., McArdle, J., RABITZ, H. A., Shenk, T. E., & Rabinowitz, J. D. (2008) · Nature Biotechnology · doi:10.1038/nbt.1500 · Cited by 641
Network Rigidity and Metabolic Engineering in Metabolite Overproduction
Stephanopoulos, G. N., & Vallino, J. J. (1991) · Science · doi:10.1126/science.1904627 · Cited by 601
Self-citationElementary metabolite units (EMU): A novel framework for modeling isotopic distributions
Antoniewicz, M. R., Kelleher, J. K., & Stephanopoulos, G. N. (2006) · Metabolic Engineering · doi:10.1016/j.ymben.2006.09.001 · Cited by 544
Self-citationDetermination of confidence intervals of metabolic fluxes estimated from stable isotope measurements
Antoniewicz, M. R., Kelleher, J. K., & Stephanopoulos, G. N. (2006) · Metabolic Engineering · doi:10.1016/j.ymben.2006.01.004 · Cited by 451
Self-citationQuantifying Reductive Carboxylation Flux of Glutamine to Lipid in a Brown Adipocyte Cell Line
Yoo, H., Antoniewicz, M. R., Stephanopoulos, G., & Kelleher, J. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706494200 · Cited by 301
Self-citationBurgess, S. C., He, T.-T., Yan, Z., Lindner, J., Sherry, A. D., Malloy, C. R., Browning, J. D., & Magnuson, M. A. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.03.004 · Cited by 276
An elementary metabolite unit (EMU) based method of isotopically nonstationary flux analysis
Young, J. D., Walther, J. L., Antoniewicz, M. R., Yoo, H., & Stephanopoulos, G. N. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21632 · Cited by 257
Self-citationIt Is All about MetabolicFluxes
Nielsen, J. (2003) · Journal of Bacteriology · doi:10.1128/jb.185.24.7031-7035.2003 · Cited by 236
Antoniewicz, M. R., Kraynie, D. F., Laffend, L. A., González‐Lergier, J., Kelleher, J. K., & Stephanopoulos, G. N. (2007) · Metabolic Engineering · doi:10.1016/j.ymben.2007.01.003 · Cited by 221
Self-citationAdvances in analysis of microbial metabolic fluxes via 13C isotopic labeling
Tang, Y., Martín, H. G., Myers, S. A., Rodriguez, S., Baidoo, E. E. K., & Keasling, J. D. (2008) · Mass Spectrometry Reviews · doi:10.1002/mas.20191 · Cited by 132
Nöh, K., Wahl, A., & Wiechert, W. (2006) · Metabolic Engineering · doi:10.1016/j.ymben.2006.05.006 · Cited by 97
Hellerstein, M. K. (2004) · Metabolic Engineering · doi:10.1016/j.ymben.2003.10.005 · Cited by 96
Experimental design principles for isotopically instationary 13C labeling experiments
Nöh, K., & Wiechert, W. (2006) · Biotechnology and Bioengineering · doi:10.1002/bit.20803 · Cited by 89
Hofmann, U., Maier, K., Niebel, A., Vacun, G., Reuß, M., & Mauch, K. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21747 · Cited by 81
Boros, L. G., Steinkamp, M. P., Fleming, J. C., Lee, W. P., Cascante, M., & Neufeld, E. J. (2003) · Blood · doi:10.1182/blood-2003-05-1537 · Cited by 75
Measurement of endogenous synthesis of plasma cholesterol in rats and humans using MIDA
Neese, R. A., Faix, D. J., Kletke, C., Wu, K. K., Wang, A. C., Shackleton, C. H. L., & Hellerstein, M. K. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.264.1.e136 · Cited by 71
Kleijn, R. J., Geertman, J.-M. A., Nfor, B. K., Ras, C., Schipper, D., Pronk, J. T., Heijnen, J. J., van Maris, A. J. A., & van Winden, W. A. (2006) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2006.00180.x · Cited by 67
Isotopomer spectral analysis of triglyceride fatty acid synthesis in 3T3-L1 cells
Kharroubi, A., Masterson, T. M., Aldaghlas, T., Kennedy, K. A., & Kelleher, J. K. (1992) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1992.263.4.e667 · Cited by 62
Tang, Y., Martín, H. G., Dehal, P., Deutschbauer, A. M., Llorà, X., Meadows, A. L., Arkin, A. P., & Keasling, J. D. (2008) · Biotechnology and Bioengineering · doi:10.1002/bit.22129 · Cited by 49
Boros, L., Lerner, M. R., Morgan, D. L., Taylor, S. L., Smith, B. J., Postier, R. G., & Brackett, D. J. (2005) · Pancreas · doi:10.1097/01.mpa.0000186524.53253.fb · Cited by 48
Börner, J., Buchinger, S., & Schomburg, D. (2007) · Analytical Biochemistry · doi:10.1016/j.ab.2007.04.036 · Cited by 42
Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells
Sriram, G., Rahib, L., He, J.-S., Campos, A. E., Parr, L. S., Liao, J. C., & Dipple, K. M. (2007) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2007.09.008 · Cited by 41
Chang, Y., Suthers, P. F., & Maranas, C. D. (2008) · Biotechnology and Bioengineering · doi:10.1002/bit.21926 · Cited by 36
Metabolomic and Mass Isotopomer Analysis of Liver Gluconeogenesis and Citric Acid Cycle
Yang, L., Kasumov, T., Kombu, R. S., Zhu, S., Cendrowski, A. V., David, F., Anderson, V. E., Kelleher, J. K., & Brunengraber, H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803455200 · Cited by 30
High-Throughput Screening Platform for Anticancer Therapeutic Drug Cytotoxicity
Sekhon, B. K., Roubin, R. H., Tan, A. C., Chan, W. K., & Sze, D. (2008) · Assay and Drug Development Technologies · doi:10.1089/adt.2008.148 · Cited by 26
Planning optimal measurements of isotopomer distributions for estimation of metabolic fluxes
Rantanen, A., Mielikäinen, T., Rousu, J., Maaheimo, H., & Ukkonen, E. (2006) · Bioinformatics · doi:10.1093/bioinformatics/btl069 · Cited by 24
Holleran, A. L., Fiskum, G. M., & Kelleher, J. K. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.6.e945 · Cited by 9
Cited by
Sorted by citations
The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791
Self-citationGlucose feeds the TCA cycle via circulating lactate
Hui, S., Ghergurovich, J. M., Morscher, R. J., Jang, C., Teng, X., Lu, W., Esparza, L. A., Reya, T., Zhan, L., Yanxiang Guo, J., et al. (2017) · Nature · doi:10.1038/nature24057 · Cited by 1,721
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
