Costa2014 - Computational Model of L. lactis Metabolism

Costa2014 - Computational Model of L. lactis
Metabolism

This model is described in the article:

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.
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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