Reconstruction and Analysis of the Genetic and Metabolic Regulatory Networks of the Central Metabolism of Bacillus Subtilis

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Reconstruction and Analysis of the Genetic and Metabolic Regulatory Networks of the Central Metabolism of Bacillus Subtilis Reconstruction and analysis of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis. Anne Goelzer, Fadia Bekkal Brikci, Isabelle Martin-Verstraete, Philippe Noirot, Philippe Bessières, Stéphane Aymerich, Vincent Fromion To cite this version: Anne Goelzer, Fadia Bekkal Brikci, Isabelle Martin-Verstraete, Philippe Noirot, Philippe Bessières, et al.. Reconstruction and analysis of the genetic and metabolic regulatory networks of the cen- tral metabolism of Bacillus subtilis.. BMC Systems Biology, BioMed Central, 2008, 2 (20), pp.20. 10.1186/1752-0509-2-20. hal-00315553 HAL Id: hal-00315553 https://hal.archives-ouvertes.fr/hal-00315553 Submitted on 2 Jul 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. BMC Systems Biology BioMed Central Research article Open Access Reconstruction and analysis of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis Anne Goelzer1, Fadia Bekkal Brikci1, Isabelle Martin-Verstraete2,3, Philippe Noirot4, Philippe Bessières1, Stéphane Aymerich5 and Vincent Fromion*1 Address: 1Unité Mathématique, Informatique et Génomes, Institut National Recherche Agronomique, UR1077, F-78350 Jouy-en-Josas, France, 2Unité de Génétique des Génomes Bactériens, Institut Pasteur, URA CNRS 2171, 28, rue du Docteur Roux, 75724 Paris Cedex 15, France, 3Unité de Formation et de Recherche de Biochimie, Université Paris 7-Denis Diderot, 2 place Jussieu, 75251 Paris, France, 4Unité Génétique Microbienne, Institut National Recherche Agronomique, F-78350 Jouy-en-Josas, France and 5Microbiologie et Génétique Moléculaire, Institut National Recherche Agronomique Paris-Grignon, CNRS (UMR2585) INRA (UMR1238), F-78850 Thiverval-Grignon, France Email: Anne Goelzer - [email protected]; Fadia Bekkal Brikci - [email protected]; Isabelle Martin-Verstraete - [email protected]; Philippe Noirot - [email protected]; Philippe Bessières - [email protected]; Stéphane Aymerich - [email protected]; Vincent Fromion* - [email protected] * Corresponding author Published: 26 February 2008 Received: 25 October 2007 Accepted: 26 February 2008 BMC Systems Biology 2008, 2:20 doi:10.1186/1752-0509-2-20 This article is available from: http://www.biomedcentral.com/1752-0509/2/20 © 2008 Goelzer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Few genome-scale models of organisms focus on the regulatory networks and none of them integrates all known levels of regulation. In particular, the regulations involving metabolite pools are often neglected. However, metabolite pools link the metabolic to the genetic network through genetic regulations, including those involving effectors of transcription factors or riboswitches. Consequently, they play pivotal roles in the global organization of the genetic and metabolic regulatory networks. Results: We report the manually curated reconstruction of the genetic and metabolic regulatory networks of the central metabolism of Bacillus subtilis (transcriptional, translational and post- translational regulations and modulation of enzymatic activities). We provide a systematic graphic representation of regulations of each metabolic pathway based on the central role of metabolites in regulation. We show that the complex regulatory network of B. subtilis can be decomposed as sets of locally regulated modules, which are coordinated by global regulators. Conclusion: This work reveals the strong involvement of metabolite pools in the general regulation of the metabolic network. Breaking the metabolic network down into modules based on the control of metabolite pools reveals the functional organization of the genetic and metabolic regulatory networks of B. subtilis. Background ing knowledge as a first step towards systems biology, Recently, the reconstruction and analysis of genome-scale which we define as the study of the interactions between genetic and metabolic regulatory networks has become an the components of biological systems to understand how area of active research. It requires the integration of exist- these interactions give rise to the function and behavior of Page 1 of 18 (page number not for citation purposes) BMC Systems Biology 2008, 2:20 http://www.biomedcentral.com/1752-0509/2/20 the system. Genetic and metabolic networks have been regulatory network of Escherichia coli [19]. Moreover, by constructed for Helicobacter pylori [1], Haemophilus influen- introducing the notion of local and global regulation, we zae [2], Lactococcus lactis [3], Escherichia coli [4], and Homo reveal that the complex regulatory network can be broken sapiens [5], by incorporating the description of chemical down into sets of locally regulated modules, which are reactions into a stoichiometric matrix. Transcriptional reg- coordinated by global regulators. Local regulations ensure ulation by regulatory proteins has been included in the that the control of elementary pathways through genetic last update of the model of Saccharomyces cerevisiae [6,7]. and/or enzymatic regulation depends upon the level of However, most of these models do not explicitly include key metabolites. The regulation of tryptophan synthesis regulation mediated by metabolites, with the exception of by tryptophan through the TRAP regulatory protein is an the most recent version of the EcoCyc database [8]. example of such a local regulation. In contrast, global reg- Metabolites can modulate the activity of transcription fac- ulations ensure the coordination between these elemen- tors and enzymes and are therefore key regulators. tary pathways in response to environmental changes. For example, CcpA inhibits several pathways during glycolytic Reconstruction of the metabolic network and its associ- growth conditions. The integration of these local/global ated regulatory network contributes to resolving various levels and the use of the classification of sensing signals in problems such as unravelling how the bacterium coordi- [19] lead to recover the main physiological aspects of nates its genetic and metabolic networks to adapt to envi- metabolism of Bacillus subtilis. Finally, the notion of local ronmental changes [9,10] and elucidating the global and global regulation allows the graphic representation of organization of the regulatory network [11,12]. Such any metabolic pathway and its various regulatory mecha- work will also help develop tools and concepts to handle nisms. and to analyze the inherent complexity of biological func- tions. As this represents one of the central issues of the sys- Results tems biology approach, metabolic networks have been the Model construction focus of in depth studies [13,14], and various tools have Our aim was to study the general organization of the met- been developed to unravel the organization of these abolic functions of B. subtilis, to identify the components highly complex networks [15,16]. involved in their regulations and to unravel how these reg- ulations coordinate metabolism (involving various degra- Here, we report the reconstruction of the genetic and met- dative and biosynthesis pathways of anabolism and abolic regulatory network for the Gram-positive bacte- catabolism). Pathways involved in the metabolic func- rium Bacillus subtilis. B. subtilis has been studied for over tions can be classified as "minor" or "major" according to 40 years and is one of the best-characterized bacteria, eas- the flux through the pathway. Typically, the "major" met- ily amenable to genetic and physiological studies. The abolic pathways are those involved in the production of publication of the B. subtilis genome sequence [17] and energy, redox power, and metabolic precursors of pro- subsequent international programmes of systematic gene teins, RNA, DNA, membrane and cell wall. The "minor" disruption, functional analysis and regulatory network metabolic pathways include the de novo synthesis of cofac- studies [18], makes this microorganism a prime candidate tors and secondary metabolites (including vitamins, coen- to develop systems biology. Our model includes the bio- zymes, and antibiotics). Most minor metabolic pathways chemical reactions of the metabolic network and all the are linear and poorly connected with other pathways, known levels of regulation involved in metabolic path- whereas major metabolic pathways are highly intercon- ways: transcriptional, translational, post-translational and nected with other pathways, implying coordinated regula- modulation of enzymatic activities. To obtain the most tory mechanisms. We focused on the major metabolic complete view of the interplay between the metabolic net- pathways of B. subtilis, and in particular: central carbon work and genetic regulation, the description of each regu-
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