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DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

Baroukh C, Muñoz-Tamayo R, Steyer JP, Bernard O - PLoS ONE (2014)

Bottom Line: Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed.DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles.It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

View Article: PubMed Central - PubMed

Affiliation: INRA UR050, Laboratoire des Biotechnologies de l'Environnement, Narbonne, France; INRIA-BIOCORE, Sophia-Antipolis, France.

ABSTRACT
Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

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Stoichiometric matrix K' describing the bioprocess obtained after formation and reduction of metabolic sub-networks.K' as a much lower dimension (16×8) than the starting metabolic network (157×162). Lines of K' correspond to kept metabolites whereas columns correspond to macroscopic reactions obtained thanks to elementary flux mode analysis on each sub-networks. K' can be divided into sub-matrices KS' (in red), KA' (in orange) and KB' (in green), according to the lines corresponding to substrates S, intracellular metabolites allowed to accumulate A and functional biomass B.
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pone-0104499-g005: Stoichiometric matrix K' describing the bioprocess obtained after formation and reduction of metabolic sub-networks.K' as a much lower dimension (16×8) than the starting metabolic network (157×162). Lines of K' correspond to kept metabolites whereas columns correspond to macroscopic reactions obtained thanks to elementary flux mode analysis on each sub-networks. K' can be divided into sub-matrices KS' (in red), KA' (in orange) and KB' (in green), according to the lines corresponding to substrates S, intracellular metabolites allowed to accumulate A and functional biomass B.

Mentions: After splitting the network into sub-networks and obtaining the EFMs for each sub-network, a reduced model described by 16 metabolites and 8 macroscopic reactions was obtained. The number of macroscopic reactions is similar to the model of Guest et al [34], where 10 lumped metabolic reactions were obtained. Mathematically, these first two steps of the DRUM approach translated into a reduced stoichiometric matrix K' (Figure 5) of much lower dimension (16×8) than the starting one (157×162). The definition of the reaction kinetics is the final building block of DRUM. For each macroscopic reaction obtained after the reduction step, simple proportional kinetics were assumed (Table 1).


DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

Baroukh C, Muñoz-Tamayo R, Steyer JP, Bernard O - PLoS ONE (2014)

Stoichiometric matrix K' describing the bioprocess obtained after formation and reduction of metabolic sub-networks.K' as a much lower dimension (16×8) than the starting metabolic network (157×162). Lines of K' correspond to kept metabolites whereas columns correspond to macroscopic reactions obtained thanks to elementary flux mode analysis on each sub-networks. K' can be divided into sub-matrices KS' (in red), KA' (in orange) and KB' (in green), according to the lines corresponding to substrates S, intracellular metabolites allowed to accumulate A and functional biomass B.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126706&req=5

pone-0104499-g005: Stoichiometric matrix K' describing the bioprocess obtained after formation and reduction of metabolic sub-networks.K' as a much lower dimension (16×8) than the starting metabolic network (157×162). Lines of K' correspond to kept metabolites whereas columns correspond to macroscopic reactions obtained thanks to elementary flux mode analysis on each sub-networks. K' can be divided into sub-matrices KS' (in red), KA' (in orange) and KB' (in green), according to the lines corresponding to substrates S, intracellular metabolites allowed to accumulate A and functional biomass B.
Mentions: After splitting the network into sub-networks and obtaining the EFMs for each sub-network, a reduced model described by 16 metabolites and 8 macroscopic reactions was obtained. The number of macroscopic reactions is similar to the model of Guest et al [34], where 10 lumped metabolic reactions were obtained. Mathematically, these first two steps of the DRUM approach translated into a reduced stoichiometric matrix K' (Figure 5) of much lower dimension (16×8) than the starting one (157×162). The definition of the reaction kinetics is the final building block of DRUM. For each macroscopic reaction obtained after the reduction step, simple proportional kinetics were assumed (Table 1).

Bottom Line: Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed.DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles.It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

View Article: PubMed Central - PubMed

Affiliation: INRA UR050, Laboratoire des Biotechnologies de l'Environnement, Narbonne, France; INRIA-BIOCORE, Sophia-Antipolis, France.

ABSTRACT
Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

Show MeSH
Related in: MedlinePlus