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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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Fluxes between the 6 sub-networks at different time of the day.Fluxes were estimated thanks to model simulations. They were normalized per moles of carbon consumed or produced. Thickness of arrows depends on intensity of the flux. At the beginning of the night (t = 0 h), carbohydrates and lipids are already consumed so as to continue functional biomass growth. Most of carbohydrates and lipids are directly invested for biomass and only few of their carbons are used for PEP synthesis. At the end of the night (t = 12 h), the metabolism is slow, because very few carbons are left for growth and energy. At midday (t = 18 h), when light intensity is at its maximum, slightly less than a third of incoming carbons goes to functional biomass (28,6%). The rest of it is stored into carbohydrates (37,1%) and lipids (34,2%). After one day (t = 24 h), the biological systems has similar fluxes to the beginning (t = 0 h), showing the cyclic behavior of the metabolic network of a unicellular photoautotrophic microalgae submitted to a day/night cycle.
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pone-0104499-g006: Fluxes between the 6 sub-networks at different time of the day.Fluxes were estimated thanks to model simulations. They were normalized per moles of carbon consumed or produced. Thickness of arrows depends on intensity of the flux. At the beginning of the night (t = 0 h), carbohydrates and lipids are already consumed so as to continue functional biomass growth. Most of carbohydrates and lipids are directly invested for biomass and only few of their carbons are used for PEP synthesis. At the end of the night (t = 12 h), the metabolism is slow, because very few carbons are left for growth and energy. At midday (t = 18 h), when light intensity is at its maximum, slightly less than a third of incoming carbons goes to functional biomass (28,6%). The rest of it is stored into carbohydrates (37,1%) and lipids (34,2%). After one day (t = 24 h), the biological systems has similar fluxes to the beginning (t = 0 h), showing the cyclic behavior of the metabolic network of a unicellular photoautotrophic microalgae submitted to a day/night cycle.

Mentions: Model simulation reproduces accurately experimental data (see Figure 1). In particular, the model correctly represents lipids and carbohydrates accumulation during the day and their consumption during the night (Figure 1D). The distribution of fluxes during a classical day/night cycle is displayed in Figure 6 and in Video S1.


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)

Fluxes between the 6 sub-networks at different time of the day.Fluxes were estimated thanks to model simulations. They were normalized per moles of carbon consumed or produced. Thickness of arrows depends on intensity of the flux. At the beginning of the night (t = 0 h), carbohydrates and lipids are already consumed so as to continue functional biomass growth. Most of carbohydrates and lipids are directly invested for biomass and only few of their carbons are used for PEP synthesis. At the end of the night (t = 12 h), the metabolism is slow, because very few carbons are left for growth and energy. At midday (t = 18 h), when light intensity is at its maximum, slightly less than a third of incoming carbons goes to functional biomass (28,6%). The rest of it is stored into carbohydrates (37,1%) and lipids (34,2%). After one day (t = 24 h), the biological systems has similar fluxes to the beginning (t = 0 h), showing the cyclic behavior of the metabolic network of a unicellular photoautotrophic microalgae submitted to a day/night cycle.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104499-g006: Fluxes between the 6 sub-networks at different time of the day.Fluxes were estimated thanks to model simulations. They were normalized per moles of carbon consumed or produced. Thickness of arrows depends on intensity of the flux. At the beginning of the night (t = 0 h), carbohydrates and lipids are already consumed so as to continue functional biomass growth. Most of carbohydrates and lipids are directly invested for biomass and only few of their carbons are used for PEP synthesis. At the end of the night (t = 12 h), the metabolism is slow, because very few carbons are left for growth and energy. At midday (t = 18 h), when light intensity is at its maximum, slightly less than a third of incoming carbons goes to functional biomass (28,6%). The rest of it is stored into carbohydrates (37,1%) and lipids (34,2%). After one day (t = 24 h), the biological systems has similar fluxes to the beginning (t = 0 h), showing the cyclic behavior of the metabolic network of a unicellular photoautotrophic microalgae submitted to a day/night cycle.
Mentions: Model simulation reproduces accurately experimental data (see Figure 1). In particular, the model correctly represents lipids and carbohydrates accumulation during the day and their consumption during the night (Figure 1D). The distribution of fluxes during a classical day/night cycle is displayed in Figure 6 and in Video S1.

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