Costa2014 - Computational Model of L. lactis Metabolism

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Short description
Costa2014 - Computational Model of L. lactis Metabolism

This model is described in the article:

Costa RS, Hartmann A, Gaspar P, Neves AR, Vinga S.
Mol Biosyst 2014 Mar; 10(3): 628-639

Abstract:

Biomedical research and biotechnological production are greatly benefiting from the results provided by the development of dynamic models of microbial metabolism. Although several kinetic models of Lactococcus lactis (a Lactic Acid Bacterium (LAB) commonly used in the dairy industry) have been developed so far, most of them are simplified and focus only on specific metabolic pathways. Therefore, the application of mathematical models in the design of an engineering strategy for the production of industrially important products by L. lactis has been very limited. In this work, we extend the existing kinetic model of L. lactis central metabolism to include industrially relevant production pathways such as mannitol and 2,3-butanediol. In this way, we expect to study the dynamics of metabolite production and make predictive simulations in L. lactis. We used a system of ordinary differential equations (ODEs) with approximate Michaelis-Menten-like kinetics for each reaction, where the parameters were estimated from multivariate time-series metabolite concentrations obtained by our team through in vivo Nuclear Magnetic Resonance (NMR). The results show that the model captures observed transient dynamics when validated under a wide range of experimental conditions. Furthermore, we analyzed the model using global perturbations, which corroborate experimental evidence about metabolic responses upon enzymatic changes. These include that mannitol production is very sensitive to lactate dehydrogenase (LDH) in the wild type (W.T.) strain, and to mannitol phosphoenolpyruvate: a phosphotransferase system (PTS(Mtl)) in a LDH mutant strain. LDH reduction has also a positive control on 2,3-butanediol levels. Furthermore, it was found that overproduction of mannitol-1-phosphate dehydrogenase (MPD) in a LDH/PTS(Mtl) deficient strain can increase the mannitol levels. The results show that this model has prediction capability over new experimental conditions and offers promising possibilities to elucidate the effect of alterations in the main metabolism of L. lactis, with application in strain optimization.

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Format
SBML (L2V4)
Related Publication
  • An extended dynamic model of Lactococcus lactis metabolism for mannitol and 2,3-butanediol production.
  • Costa RS, Hartmann A, Gaspar P, Neves AR, Vinga S
  • Molecular bioSystems , 3/ 2014 , Volume 10 , pages: 628-639
  • Instituto de Engenharia de Sistemas e Computadores, Investigac√£o e Desenvolvimento (INESC-ID), R Alves Redol 9, 1000-029 Lisboa, Portugal. rcosta@kdbio.inesc-id.pt.
  • Biomedical research and biotechnological production are greatly benefiting from the results provided by the development of dynamic models of microbial metabolism. Although several kinetic models of Lactococcus lactis (a Lactic Acid Bacterium (LAB) commonly used in the dairy industry) have been developed so far, most of them are simplified and focus only on specific metabolic pathways. Therefore, the application of mathematical models in the design of an engineering strategy for the production of industrially important products by L. lactis has been very limited. In this work, we extend the existing kinetic model of L. lactis central metabolism to include industrially relevant production pathways such as mannitol and 2,3-butanediol. In this way, we expect to study the dynamics of metabolite production and make predictive simulations in L. lactis. We used a system of ordinary differential equations (ODEs) with approximate Michaelis-Menten-like kinetics for each reaction, where the parameters were estimated from multivariate time-series metabolite concentrations obtained by our team through in vivo Nuclear Magnetic Resonance (NMR). The results show that the model captures observed transient dynamics when validated under a wide range of experimental conditions. Furthermore, we analyzed the model using global perturbations, which corroborate experimental evidence about metabolic responses upon enzymatic changes. These include that mannitol production is very sensitive to lactate dehydrogenase (LDH) in the wild type (W.T.) strain, and to mannitol phosphoenolpyruvate: a phosphotransferase system (PTS(Mtl)) in a LDH mutant strain. LDH reduction has also a positive control on 2,3-butanediol levels. Furthermore, it was found that overproduction of mannitol-1-phosphate dehydrogenase (MPD) in a LDH/PTS(Mtl) deficient strain can increase the mannitol levels. The results show that this model has prediction capability over new experimental conditions and offers promising possibilities to elucidate the effect of alterations in the main metabolism of L. lactis, with application in strain optimization.
Contributors
Rafael Costa

Metadata information

is
BioModels Database MODEL1503180000
BioModels Database BIOMD0000000572
isDescribedBy
PubMed 24413179
isDerivedFrom
PubMed 22325620
PubMed 11932446
PubMed 21841021
PubMed 15006767
PubMed 873604
PubMed 15345435
isVersionOf
Curation status
Curated
  • Model originally submitted by : Rafael Costa
  • Submitted: Mar 18, 2015 10:08:38 AM
  • Last Modified: Mar 26, 2015 4:41:43 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Mar 26, 2015 4:41:43 PM
    • Submitted by: Rafael Costa
    • With comment: Current version of Costa2014 - Computational Model of L. lactis Metabolism
  • Version: 1 public model Download this version
    • Submitted on: Mar 18, 2015 10:08:38 AM
    • Submitted by: Rafael Costa
    • With comment: Original import of Costa2014 - Computational Model of L. lactis Metabolism
Curator's comment:
(added: 26 Mar 2015, 16:41:04, updated: 26 Mar 2015, 16:41:04)
Figure 2 of the reference publication has been reproduced here: time course simulation for main metabolites for 120 minutes. The simulation was done using Copasi v4.14 (Build 89) and the plot was generated using Gnuplot. The Copasi file of the model with simulation settings for the whole Figure 3 can be downloaded from the below link: