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J. Biol. Chem., Vol. 281, Issue 52, 40041-40048, December 29, 2006

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Analysis of Growth of Lactobacillus plantarum WCFS1 on a Complex Medium Using a Genome-scale Metabolic Model^*

Bas Teusink^¶1, Anne Wiersma, Douwe Molenaar, Christof Francke^¶, Willem M. de Vos, Roland J. Siezen^¶, and Eddy J. Smid

From the Wageningen Centre for Food Sciences, Wageningen NL-6700AN, NIZO Food Research, Ede NL-6710BA, and ^¶Centre for Molecular and Biomolecular Informatics, Radboud University, Nijmegen 6710BA, The Netherlands

A genome-scale metabolic model of the lactic acid bacterium Lactobacillus plantarum WCFS1 was constructed based on genomic content and experimental data. The complete model includes 721 genes, 643 reactions, and 531 metabolites. Different stoichiometric modeling techniques were used for interpretation of complex fermentation data, as L. plantarum is adapted to nutrient-rich environments and only grows in media supplemented with vitamins and amino acids. (i) Based on experimental input and output fluxes, maximal ATP production was estimated and related to growth rate. (ii) Optimization of ATP production further identified amino acid catabolic pathways that were not previously associated with free-energy metabolism. (iii) Genome-scale elementary flux mode analysis identified 28 potential futile cycles. (iv) Flux variability analysis supplemented the elementary mode analysis in identifying parallel pathways, e.g. pathways with identical end products but different co-factor usage. Strongly increased flexibility in the metabolic network was observed when strict coupling between catabolic ATP production and anabolic consumption was relaxed. These results illustrate how a genome-scale metabolic model and associated constraint-based modeling techniques can be used to analyze the physiology of growth on a complex medium rather than a minimal salts medium. However, optimization of biomass formation using the Flux Balance Analysis approach, reported to successfully predict growth rate and by product formation in Escherichia coli and Saccharomyces cerevisiae, predicted too high biomass yields that were incompatible with the observed lactate production. The reason is that this approach assumes optimal efficiency of substrate to biomass conversion, and can therefore not predict the metabolically inefficient lactate formation.

Received for publication, June 29, 2006 , and in revised form, October 20, 2006.

^* This work was supported by the Kluyver Centre for Genomics of Industrial Fermentation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental materials I-IV.

¹ To whom correspondence should be addressed: P.O. Box 20, 6710BA Ede, The Netherlands. Tel.: 31-318-659-674; Fax: 31-318-650-400; E-mail: Bas.Teusink{at}nizo.nl.

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