title: Monte-Carlo modeling of the central carbon metabolism of Lactococcus lactis: insights into metabolic regulation.
abstract: Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, medium- and large-scale metabolic networks models.
authors.affiliation: Manchester Institute of Biotechnology, School of Chemical Engineering and Analytical Sciences (CEAS), Manchester Centre for Integrative Systems Biology (MCISB), The University of Manchester, Manchester, United Kingdom.
authors.forename: Ettore
authors.initials: E
authors.lastname: Murabito
authors.affiliation: Manchester Institute of Biotechnology, School of Chemical Engineering and Analytical Sciences (CEAS), Manchester Centre for Integrative Systems Biology (MCISB), The University of Manchester, Manchester, United Kingdom.
authors.forename: Malkhey
authors.initials: M
authors.lastname: Verma
authors.affiliation: Molecular Microbial Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Bekker
authors.affiliation: Systems Bioinformatics IBIVU and Netherlands Institute for Systems Biology (NISB), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bellomo
authors.affiliation: Manchester Institute of Biotechnology, School of Chemical Engineering and Analytical Sciences (CEAS), Manchester Centre for Integrative Systems Biology (MCISB), The University of Manchester, Manchester, United Kingdom; Synthetic Systems Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands; Molecular Cell Physiology, FALW, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
authors.affiliation: Systems Bioinformatics IBIVU and Netherlands Institute for Systems Biology (NISB), VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Teusink
authors.affiliation: CzechGlobe - Global Change Research Center, Academy of Sciences of the Czech Republic, Brno, Czech Republic; Humboldt-University Berlin, Institute for Theoretical Biology, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Steuer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D050260:Carbohydrate Metabolism; D003198:Computer Simulation; D025461:Feedback, Physiological; D005635:Fructosediphosphates / Q000378:metabolism; D013294:Lactococcus lactis / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method
chemical_list: D005635:Fructosediphosphates; D000255:Adenosine Triphosphate; C029063:fructose-1,6-diphosphate