Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions

Igor Marin de Mas, Vitaly A. Selivanov (Corresponding Author), Silvia Marin, Josep Roca, Matej Orešič, Loranne Agius, Marta Cascante (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

15 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number175
JournalBMC Systems Biology
Volume5
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Glycogen
Metabolism
Hexoses
Glucose
Fluxes
Phosphates
Metabolites
Isomers
Phosphate
Lactic Acid
Metabolome
Metabolic Networks and Pathways
Model Discrimination
Isotopes
Software
Radioactive tracers
Pathway
Cell
Experimental Data
Liver

Cite this

de Mas, I. M., Selivanov, V. A., Marin, S., Roca, J., Orešič, M., Agius, L., & Cascante, M. (2011). Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions. BMC Systems Biology, 5, [175]. https://doi.org/10.1186/1752-0509-5-175
de Mas, Igor Marin ; Selivanov, Vitaly A. ; Marin, Silvia ; Roca, Josep ; Orešič, Matej ; Agius, Loranne ; Cascante, Marta. / Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions. In: BMC Systems Biology. 2011 ; Vol. 5.
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abstract = "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.",
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de Mas, IM, Selivanov, VA, Marin, S, Roca, J, Orešič, M, Agius, L & Cascante, M 2011, 'Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions', BMC Systems Biology, vol. 5, 175. https://doi.org/10.1186/1752-0509-5-175

Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions. / de Mas, Igor Marin; Selivanov, Vitaly A. (Corresponding Author); Marin, Silvia; Roca, Josep; Orešič, Matej; Agius, Loranne; Cascante, Marta (Corresponding Author).

In: BMC Systems Biology, Vol. 5, 175, 2011.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions

AU - de Mas, Igor Marin

AU - Selivanov, Vitaly A.

AU - Marin, Silvia

AU - Roca, Josep

AU - Orešič, Matej

AU - Agius, Loranne

AU - Cascante, Marta

PY - 2011

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N2 - 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.

AB - 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.

U2 - 10.1186/1752-0509-5-175

DO - 10.1186/1752-0509-5-175

M3 - Article

VL - 5

JO - BMC Systems Biology

JF - BMC Systems Biology

SN - 1752-0509

M1 - 175

ER -