MetaboTools: A comprehensive toolbox for analysis of genome-scale metabolic models

Aurich, Maike K.; Fleming, Ronan M. T.; Thiele, Ines

doi:10.3389/fphys.2016.00327

Title: MetaboTools: A comprehensive toolbox for analysis of genome-scale metabolic models

Journal Article · Wed Aug 03 00:00:00 EDT 2016 · Frontiers in Physiology

DOI:https://doi.org/10.3389/fphys.2016.00327· OSTI ID:1326674

Aurich, Maike K. ^[1]; Fleming, Ronan M. T. ^[1]; Thiele, Ines ^[1]

Univ. of Luxembourg, Esch-sur-Alzette (Luxembourg)

Metabolomic data sets provide a direct read-out of cellular phenotypes and are increasingly generated to study biological questions. Previous work, by us and others, revealed the potential of analyzing extracellular metabolomic data in the context of the metabolic model using constraint-based modeling. With the MetaboTools, we make our methods available to the broader scientific community. The MetaboTools consist of a protocol, a toolbox, and tutorials of two use cases. The protocol describes, in a step-wise manner, the workflow of data integration, and computational analysis. The MetaboTools comprise the Matlab code required to complete the workflow described in the protocol. Tutorials explain the computational steps for integration of two different data sets and demonstrate a comprehensive set of methods for the computational analysis of metabolic models and stratification thereof into different phenotypes. The presented workflow supports integrative analysis of multiple omics data sets. Importantly, all analysis tools can be applied to metabolic models without performing the entire workflow. Taken together, the MetaboTools constitute a comprehensive guide to the intra-model analysis of extracellular metabolomic data from microbial, plant, or human cells. In conclusion, this computational modeling resource offers a broad set of computational analysis tools for a wide biomedical and non-biomedical research community.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Univ. of Luxembourg, Esch-sur-Alzette (Luxembourg)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); European Union (EU)

Grant/Contract Number:: SC0010429; 668738

OSTI ID:: 1326674

Journal Information:: Frontiers in Physiology, Vol. 7; ISSN 1664-042X

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 24 works

Citation information provided by
Web of Science

References (57)

Reconstruction of Genome-Scale Active Metabolic Networks for 69 Human Cell Types and 16 Cancer Types Using INIT Agren, Rasmus; Bordel, Sergio; Mardinoglu, Adil PLoS Computational Biology, Vol. 8, Issue 5 https://doi.org/10.1371/journal.pcbi.1002518	journal	May 2012
Identification of anticancer drugs for hepatocellular carcinoma through personalized genome‐scale metabolic modeling Agren, Rasmus; Mardinoglu, Adil; Asplund, Anna Molecular Systems Biology, Vol. 10, Issue 3 https://doi.org/10.1002/msb.145122	journal	March 2014
Contextualization Procedure and Modeling of Monocyte Specific TLR Signaling Aurich, Maike K.; Thiele, Ines PLoS ONE, Vol. 7, Issue 12 https://doi.org/10.1371/journal.pone.0049978	journal	December 2012
Prediction of intracellular metabolic states from extracellular metabolomic data Aurich, Maike K.; Paglia, Giuseppe; Rolfsson, Óttar Metabolomics, Vol. 11, Issue 3 https://doi.org/10.1007/s11306-014-0721-3	journal	August 2014
Getting the right answers: understanding metabolomics challenges Beisken, Stephan; Eiden, Michael; Salek, Reza M. Expert Review of Molecular Diagnostics, Vol. 15, Issue 1 https://doi.org/10.1586/14737159.2015.974562	journal	October 2014
Integration of expression data in genome-scale metabolic network reconstructions Blazier, Anna S.; Papin, Jason A. Frontiers in Physiology, Vol. 3 https://doi.org/10.3389/fphys.2012.00299	journal	January 2012
Using the reconstructed genome-scale human metabolic network to study physiology and pathology: Key Symposium: Modelling human metabolism Bordbar, A.; Palsson, B. O. Journal of Internal Medicine, Vol. 271, Issue 2 https://doi.org/10.1111/j.1365-2796.2011.02494.x	journal	January 2012
Insight into human alveolar macrophage and M. tuberculosis interactions via metabolic reconstructions Bordbar, Aarash; Lewis, Nathan E.; Schellenberger, Jan Molecular Systems Biology, Vol. 6, Issue 1 https://doi.org/10.1038/msb.2010.68	journal	January 2010
Model‐driven multi‐omic data analysis elucidates metabolic immunomodulators of macrophage activation Bordbar, Aarash; Mo, Monica L.; Nakayasu, Ernesto S. Molecular Systems Biology, Vol. 8, Issue 1 https://doi.org/10.1038/msb.2012.21	journal	January 2012
MetExplore: a web server to link metabolomic experiments and genome-scale metabolic networks Cottret, L.; Wildridge, D.; Vinson, F. Nucleic Acids Research, Vol. 38, Issue Web Server https://doi.org/10.1093/nar/gkq312	journal	May 2010
Cell culture metabolomics: applications and future directions Čuperlović-Culf, Miroslava; Barnett, David A.; Culf, Adrian S. Drug Discovery Today, Vol. 15, Issue 15-16 https://doi.org/10.1016/j.drudis.2010.06.012	journal	August 2010
ChEBI: a database and ontology for chemical entities of biological interest Degtyarenko, K.; de Matos, P.; Ennis, M. Nucleic Acids Research, Vol. 36, Issue Database https://doi.org/10.1093/nar/gkm791	journal	December 2007
Glutamine‐driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia Fan, Jing; Kamphorst, Jurre J.; Mathew, Robin Molecular Systems Biology, Vol. 9, Issue 1 https://doi.org/10.1038/msb.2013.65	journal	January 2013
Pathomx: an interactive workflow-based tool for the analysis of metabolomic data Fitzpatrick, Martin A.; McGrath, Catherine M.; Young, Stephen P. BMC Bioinformatics, Vol. 15, Issue 1 https://doi.org/10.1186/s12859-014-0396-9	journal	December 2014
Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase Frezza, Christian; Zheng, Liang; Folger, Ori Nature, Vol. 477, Issue 7363 https://doi.org/10.1038/nature10363	journal	August 2011
Exometabolome analysis reveals hypoxia at the up-scaling of a Saccharomyces cerevisiae high-cell density fed-batch biopharmaceutical process Fu, Zhibiao; Verderame, Thomas D.; Leighton, Julie M. Microbial Cell Factories, Vol. 13, Issue 1 https://doi.org/10.1186/1475-2859-13-32	journal	January 2014
Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep08183	journal	February 2015
Computationally efficient flux variability analysis Gudmundsson, Steinn; Thiele, Ines BMC Bioinformatics, Vol. 11, Issue 1 https://doi.org/10.1186/1471-2105-11-489	journal	September 2010
Comparative evaluation of open source software for mapping between metabolite identifiers in metabolic network reconstructions: application to Recon 2 Haraldsdóttir, Hulda S.; Thiele, Ines; Fleming, Ronan MT Journal of Cheminformatics, Vol. 6, Issue 1 https://doi.org/10.1186/1758-2946-6-2	journal	January 2014
Transparency in metabolic network reconstruction enables scalable biological discovery Heavner, Benjamin D.; Price, Nathan D. Current Opinion in Biotechnology, Vol. 34 https://doi.org/10.1016/j.copbio.2014.12.010	journal	August 2015
Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation Jain, M.; Nilsson, R.; Sharma, S. Science, Vol. 336, Issue 6084 https://doi.org/10.1126/science.1218595	journal	May 2012
Individualized therapy of HHT driven by network analysis of metabolomic profiles Jamshidi, Neema; Miller, Franklin J.; Mandel, Jess BMC Systems Biology, Vol. 5, Issue 1 https://doi.org/10.1186/1752-0509-5-200	journal	January 2011
Computational reconstruction of tissue‐specific metabolic models: application to human liver metabolism Jerby, Livnat; Shlomi, Tomer; Ruppin, Eytan Molecular Systems Biology, Vol. 6, Issue 1 https://doi.org/10.1038/msb.2010.56	journal	January 2010
The model organism as a system: integrating 'omics' data sets Joyce, Andrew R.; Palsson, Bernhard Ø. Nature Reviews Molecular Cell Biology, Vol. 7, Issue 3 https://doi.org/10.1038/nrm1857	journal	March 2006
Metabolomics and systems biology: making sense of the soup Kell, D. Current Opinion in Microbiology, Vol. 7, Issue 3 https://doi.org/10.1016/j.mib.2004.04.012	journal	June 2004
The dynamic range of the human metabolome revealed by challenges Krug, Susanne; Kastenmüller, Gabi; Stückler, Ferdinand The FASEB Journal, Vol. 26, Issue 6 https://doi.org/10.1096/fj.11-198093	journal	June 2012
Global Profiling of Metabolic Adaptation to Hypoxic Stress in Human Glioblastoma Cells Kucharzewska, Paulina; Christianson, Helena C.; Belting, Mattias PLOS ONE, Vol. 10, Issue 1 https://doi.org/10.1371/journal.pone.0116740	journal	January 2015
Constraining the metabolic genotype–phenotype relationship using a phylogeny of in silico methods Lewis, Nathan E.; Nagarajan, Harish; Palsson, Bernhard O. Nature Reviews Microbiology, Vol. 10, Issue 4 https://doi.org/10.1038/nrmicro2737	journal	February 2012
Systematic Evaluation of Methods for Integration of Transcriptomic Data into Constraint-Based Models of Metabolism Machado, Daniel; Herrgård, Markus PLoS Computational Biology, Vol. 10, Issue 4 https://doi.org/10.1371/journal.pcbi.1003580	journal	April 2014
Integration of clinical data with a genome‐scale metabolic model of the human adipocyte Mardinoglu, Adil; Agren, Rasmus; Kampf, Caroline Molecular Systems Biology, Vol. 9, Issue 1 https://doi.org/10.1038/msb.2013.5	journal	January 2013
Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease Mardinoglu, Adil; Agren, Rasmus; Kampf, Caroline Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms4083	journal	January 2014
Defining the Human Adipose Tissue Proteome To Reveal Metabolic Alterations in Obesity Mardinoglu, Adil; Kampf, Caroline; Asplund, Anna Journal of Proteome Research, Vol. 13, Issue 11 https://doi.org/10.1021/pr500586e	journal	September 2014
Updates in metabolomics tools and resources: 2014-2015: General Misra, Biswapriya B.; van der Hooft, Justin J. J. ELECTROPHORESIS, Vol. 37, Issue 1 https://doi.org/10.1002/elps.201500417	journal	November 2015
Connecting extracellular metabolomic measurements to intracellular flux states in yeast Mo, Monica L.; Palsson, Bernhard Ø; Herrgård, Markus J. BMC Systems Biology, Vol. 3, Issue 1 https://doi.org/10.1186/1752-0509-3-37	journal	January 2009
KEGG: Kyoto Encyclopedia of Genes and Genomes Ogata, H.; Goto, S.; Sato, K. Nucleic Acids Research, Vol. 27, Issue 1 https://doi.org/10.1093/nar/27.1.29	journal	January 1999
What is flux balance analysis? Orth, Jeffrey D.; Thiele, Ines; Palsson, Bernhard Ø Nature Biotechnology, Vol. 28, Issue 3 https://doi.org/10.1038/nbt.1614	journal	March 2010
Monitoring metabolites consumption and secretion in cultured cells using ultra-performance liquid chromatography quadrupole–time of flight mass spectrometry (UPLC–Q–ToF-MS) Paglia, Giuseppe; Hrafnsdóttir, Sigrún; Magnúsdóttir, Manuela Analytical and Bioanalytical Chemistry, Vol. 402, Issue 3 https://doi.org/10.1007/s00216-011-5556-4	journal	December 2011
Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits Petersen, Ann-Kristin; Zeilinger, Sonja; Kastenmüller, Gabi Human Molecular Genetics, Vol. 23, Issue 2 https://doi.org/10.1093/hmg/ddt430	journal	September 2013
Uniform Sampling of Steady-State Flux Spaces: Means to Design Experiments and to Interpret Enzymopathies Price, Nathan D.; Schellenberger, Jan; Palsson, Bernhard O. Biophysical Journal, Vol. 87, Issue 4 https://doi.org/10.1529/biophysj.104.043000	journal	October 2004
Membrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease Sahoo, Swagatika; Aurich, Maike K.; Jonsson, Jon J. Frontiers in Physiology, Vol. 5 https://doi.org/10.3389/fphys.2014.00091	journal	March 2014
Metabolomics for Functional Genomics, Systems Biology, and Biotechnology Saito, Kazuki; Matsuda, Fumio Annual Review of Plant Biology, Vol. 61, Issue 1 https://doi.org/10.1146/annurev.arplant.043008.092035	journal	June 2010
Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0 Schellenberger, Jan; Que, Richard; Fleming, Ronan M. T. Nature Protocols, Vol. 6, Issue 9 https://doi.org/10.1038/nprot.2011.308	journal	August 2011
GIM3E: condition-specific models of cellular metabolism developed from metabolomics and expression data Schmidt, Brian J.; Ebrahim, Ali; Metz, Thomas O. Bioinformatics, Vol. 29, Issue 22 https://doi.org/10.1093/bioinformatics/btt493	journal	August 2013
Integrating Transcriptomics with Metabolic Modeling Predicts Biomarkers and Drug Targets for Alzheimer's Disease Stempler, Shiri; Yizhak, Keren; Ruppin, Eytan PLoS ONE, Vol. 9, Issue 8 https://doi.org/10.1371/journal.pone.0105383	journal	August 2014
A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2 Thiele, Ines; Hyduke, Daniel R.; Steeb, Benjamin BMC Systems Biology, Vol. 5, Issue 1 https://doi.org/10.1186/1752-0509-5-8	journal	January 2011
A protocol for generating a high-quality genome-scale metabolic reconstruction Thiele, Ines; Palsson, Bernhard Ø Nature Protocols, Vol. 5, Issue 1 https://doi.org/10.1038/nprot.2009.203	journal	January 2010
Candidate Metabolic Network States in Human Mitochondria: IMPACT OF DIABETES, ISCHEMIA, AND DIET Thiele, I.; Price, N. D.; Vo, T. D. Journal of Biological Chemistry, Vol. 280, Issue 12 https://doi.org/10.1074/jbc.M409072200	journal	November 2004
A community-driven global reconstruction of human metabolism Thiele, Ines; Swainston, Neil; Fleming, Ronan M. T. Nature Biotechnology, Vol. 31, Issue 5 https://doi.org/10.1038/nbt.2488	journal	March 2013
rBioNet: A COBRA toolbox extension for reconstructing high-quality biochemical networks Thorleifsson, S. G.; Thiele, I. Bioinformatics, Vol. 27, Issue 14 https://doi.org/10.1093/bioinformatics/btr308	journal	May 2011
Improved metabolite identification with MIDAS and MAGMa through MS/MS spectral dataset-driven parameter optimization Verdegem, Dries; Lambrechts, Diether; Carmeliet, Peter Metabolomics, Vol. 12, Issue 6 https://doi.org/10.1007/s11306-016-1036-3	journal	April 2016
Fast Reconstruction of Compact Context-Specific Metabolic Network Models Vlassis, Nikos; Pacheco, Maria Pires; Sauter, Thomas PLoS Computational Biology, Vol. 10, Issue 1 https://doi.org/10.1371/journal.pcbi.1003424	journal	January 2014
HMDB 3.0—The Human Metabolome Database in 2013 Wishart, David S.; Jewison, Timothy; Guo, An Chi Nucleic Acids Research, Vol. 41, Issue D1 https://doi.org/10.1093/nar/gks1065	journal	November 2012
A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2 Thiele, I.; Hyduke, D. R.; Steeb, B. BioMed Central https://doi.org/10.5451/unibas-ep19143	text	January 2011
Linkage of Organic Anion Transporter-1 to Metabolic Pathways through Integrated “Omics”-driven Network and Functional Analysis Ahn, Sun-Young; Jamshidi, Neema; Mo, Monica L. Journal of Biological Chemistry, Vol. 286, Issue 36 https://doi.org/10.1074/jbc.m111.272534	journal	July 2011
Use of Randomized Sampling for Analysis of Metabolic Networks Schellenberger, Jan; Palsson, Bernhard Ø. Journal of Biological Chemistry, Vol. 284, Issue 9 https://doi.org/10.1074/jbc.r800048200	journal	October 2008
Discrimination of Modes of Action of Antifungal Substances by Use of Metabolic Footprinting Allen, J.; Davey, H. M.; Broadhurst, D. Applied and Environmental Microbiology, Vol. 70, Issue 10 https://doi.org/10.1128/aem.70.10.6157-6165.2004	journal	October 2004
Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer Yizhak, Keren; Gaude, Edoardo; Le Dévédec, Sylvia eLife, Vol. 3 https://doi.org/10.7554/elife.03641	journal	November 2014

Cited By (8)

Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0 Heirendt, Laurent; Arreckx, Sylvain; Pfau, Thomas Nature Protocols, Vol. 14, Issue 3 https://doi.org/10.1038/s41596-018-0098-2	journal	February 2019
Use of genome-scale models to get new insights into the marine actinomycete genus Salinispora Contador, Carolina A.; Rodríguez, Vida; Andrews, Barbara A. BMC Systems Biology, Vol. 13, Issue 1 https://doi.org/10.1186/s12918-019-0683-1	journal	January 2019
Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease Heinken, Almut; Ravcheev, Dmitry A.; Baldini, Federico Microbiome, Vol. 7, Issue 1 https://doi.org/10.1186/s40168-019-0689-3	journal	May 2019
A benchmark-driven approach to reconstruct metabolic networks for studying cancer metabolism Jamialahmadi, Oveis; Hashemi-Najafabadi, Sameereh; Motamedian, Ehsan PLOS Computational Biology, Vol. 15, Issue 4 https://doi.org/10.1371/journal.pcbi.1006936	journal	April 2019
Extracellular Microbial Metabolomics: The State of the Art Pinu, Farhana; Villas-Boas, Silas Metabolites, Vol. 7, Issue 3 https://doi.org/10.3390/metabo7030043	journal	August 2017
Towards a widespread adoption of metabolic modeling tools in biopharmaceutical industry: a process systems biology engineering perspective Richelle, Anne; David, Blandine; Demaegd, Didier npj Systems Biology and Applications, Vol. 6, Issue 1 https://doi.org/10.1038/s41540-020-0127-y	journal	March 2020
The Virtual Metabolic Human database: integrating human and gut microbiome metabolism with nutrition and disease Noronha, Alberto; Modamio, Jennifer; Jarosz, Yohan Nucleic Acids Research, Vol. 47, Issue D1 https://doi.org/10.1093/nar/gky992	journal	October 2018
A systems approach reveals distinct metabolic strategies among the NCI-60 cancer cell lines Aurich, Maike K.; Fleming, Ronan M. T.; Thiele, Ines PLOS Computational Biology, Vol. 13, Issue 8 https://doi.org/10.1371/journal.pcbi.1005698	journal	August 2017

Similar Records

Genome-Scale ¹³C Fluxomics Modeling for Metabolic Engineering of Saccharomyces cerevisiae.

Book · Tue Nov 13 00:00:00 EST 2018 · OSTI ID:1326674

Ando, David; García Martín, Héctor

Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation

Journal Article · Tue Dec 22 00:00:00 EST 2015 · mSystems · OSTI ID:1326674

Noecker, Cecilia; Eng, Alexander; Srinivasan, Sujatha; +6 more

Cognitive analysis of metabolomics data for systems biology

Journal Article · Fri Jan 22 00:00:00 EST 2021 · Nature Protocols · OSTI ID:1326674

Majumder, Erica L.-W.; Billings, Elizabeth M.; Benton, H. Paul; +9 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
97 MATHEMATICS AND COMPUTING
constraint-based reconstruction and analysis (COBRA)
metabolomics
metabolism
metabolic modeling
metabolic phenotypes
protocol
modelanalysis

Title: MetaboTools: A comprehensive toolbox for analysis of genome-scale metabolic models

Citation Formats

References (57)

Cited By (8)

Similar Records

Related Subjects