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J. Biol. Chem., Vol. 283, Issue 10, 6347-6358, March 7, 2008

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Arginine Biosynthesis in Escherichia coli

EXPERIMENTAL PERTURBATION AND MATHEMATICAL MODELING^*

Marina Caldara¹, Geneviève Dupont¹²³, Frédéric Leroy^¶4, Albert Goldbeter², Luc De Vuyst^¶5, and Raymond Cunin⁵⁶

From the Laboratory of Microbiology and Genetics, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Unitéde Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, B-1050 Brussels, and ^¶Laboratory of Industrial Microbiology and Food Biotechnology, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium

A basic challenge in cell biology is to understand how interconnected metabolic pathways are regulated to provide the adequate cellular outcome when changing levels of metabolites and enzyme expression. In Escherichia coli, the arginine and pyrimidine biosynthetic pathways are connected through a common metabolite provided by a single enzyme. The different elements of the arginine biosynthetic system of Escherichia coli, including the connection with pyrimidine biosynthesis, and the principal regulatory mechanisms operating at genetic and enzymatic levels were integrated in a mathematical model using a molecular kinetic approach combined with a modular description of the system. The model was then used to simulate a set of perturbed conditions as follows: genetic derepression, feedback resistance of the first enzymatic step, and low constitutive synthesis of the intermediate carbamyl phosphate. In all cases, an excellent quantitative agreement between simulations and experimental results was found. The model was used to gain further insight into the function of the system, including the synergy between the different regulations. The outcome of combinations of perturbations on cellular arginine concentration was predicted accurately, establishing the model as a powerful tool for the design of arginine-overproducing strains.

Received for publication, July 18, 2007 , and in revised form, December 4, 2007.

^* 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 Experimental Procedures, Table SI, Equation S1, and a figure.

¹ Both authors contributed equally to this work.

² Supported by Fonds de la Recherche Scientifique Médicale Grant 3.4636.04, the European Union through the Network of Excellence BioSim Contract LSHB-CT-2004-005137, and the Belgian Programme on Interuniversity Attraction Poles, initiated by the Belgian Federal Science Policy Office, Project P6/22 (BIOMAGNET).

³ Maître de Recherche at the Belgian Fonds National de la Recherche Scientifique.

⁴ Postdoctoral fellow of the FWO-Vlaanderen.

⁵ Supported by Research Council of the Vrije Universiteit Brussel Grant OZR837 and the Fund for Scientific Research-Flanders, FWO-Vlaanderen, G.0041.03.

⁶ To whom correspondence should be addressed. Tel.: 32-2-6291341; Fax: 32-2-629-1345; E-mail: rcunin{at}vub.ac.be.

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