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Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions
Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain; A.N.Belozersky Institute of Physico-Chemical Biology, Moscow, Russia.
Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain;; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS),Centro de Investigación Biomédica en Red de Enfermedade Respiratorias (CIBERES) Universitat de Barcelona, Barcelona, Spain.
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2011 (English)In: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 5, article id 175Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution.

RESULTS: The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells.

CONCLUSIONS: The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution indicates the presence of a separate pool of hexose phosphates that is channeled towards glycogen synthesis.

Place, publisher, year, edition, pages
London, United kingdom: BioMed Central, 2011. Vol. 5, article id 175
National Category
Medical and Health Sciences Bioinformatics (Computational Biology)
Identifiers
URN: urn:nbn:se:oru:diva-63655DOI: 10.1186/1752-0509-5-175ISI: 000301740700001PubMedID: 22034837Scopus ID: 2-s2.0-80054972207OAI: oai:DiVA.org:oru-63655DiVA, id: diva2:1169219
Funder
EU, European Research Council
Note

Funding Agencies:

Spanish Government 

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion of Spanish Government 

European Regional Development Fund (ERDF) "Una manera de hacer Europa" ISCIII-RTICC 

Generalitat de Catalunya-AGAUR 

Foundation Marato 

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-05-08Bibliographically approved

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Oresic, Matej

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