Comparison of metabolite production capability indices generated by network analysis methods.
ABSTRACT A framework of constraint-based reconstruction and analysis (COBRA) is used for modeling large-scale metabolic networks. In COBRA, extreme pathway and optimization analyses are commonly used to study the properties of networks. While the results of both methods are completely consistent, extreme pathway analysis is considered to be better because of its wider representational ability. In this study, we assessed these two methods by computational knockout experiments. We examined a simple pathway model and found that the extreme pathway method led to misguided conclusions in specific cases, while optimization analysis calculated the correct knockout effects. We also investigated the Escherichia coli metabolic pathway model, and found that these methods result in inconsistent interpretations of the network properties. IN CONCLUSION: it has been claimed that these two methods result in the same producible metabolites, but we found a difference in individual results for a biological pathway. Our results could provide helpful guidance for when to use the methods, particularly extreme pathway analysis.
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ABSTRACT: A genome-scale metabolic model of Helicobacter pylori 26695 was constructed from genome sequence annotation, biochemical, and physiological data. This represents an in silico model largely derived from genomic information for an organism for which there is substantially less biochemical information available relative to previously modeled organisms such as Escherichia coli. The reconstructed metabolic network contains 388 enzymatic and transport reactions and accounts for 291 open reading frames. Within the paradigm of constraint-based modeling, extreme-pathway analysis and flux balance analysis were used to explore the metabolic capabilities of the in silico model. General network properties were analyzed and compared to similar results previously generated for Haemophilus influenzae. A minimal medium required by the model to generate required biomass constituents was calculated, indicating the requirement of eight amino acids, six of which correspond to essential human amino acids. In addition a list of potential substrates capable of fulfilling the bulk carbon requirements of H. pylori were identified. A deletion study was performed wherein reactions and associated genes in central metabolism were deleted and their effects were simulated under a variety of substrate availability conditions, yielding a number of reactions that are deemed essential. Deletion results were compared to recently published in vitro essentiality determinations for 17 genes. The in silico model accurately predicted 10 of 17 deletion cases, with partial support for additional cases. Collectively, the results presented herein suggest an effective strategy of combining in silico modeling with experimental technologies to enhance biological discovery for less characterized organisms and their genomes.Journal of Bacteriology 09/2002; 184(16):4582-93. · 3.19 Impact Factor
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ABSTRACT: Structural analysis of cellular interaction networks contributes to a deeper understanding of network-wide interdependencies, causal relationships, and basic functional capabilities. While the structural analysis of metabolic networks is a well-established field, similar methodologies have been scarcely developed and applied to signaling and regulatory networks. We propose formalisms and methods, relying on adapted and partially newly introduced approaches, which facilitate a structural analysis of signaling and regulatory networks with focus on functional aspects. We use two different formalisms to represent and analyze interaction networks: interaction graphs and (logical) interaction hypergraphs. We show that, in interaction graphs, the determination of feedback cycles and of all the signaling paths between any pair of species is equivalent to the computation of elementary modes known from metabolic networks. Knowledge on the set of signaling paths and feedback loops facilitates the computation of intervention strategies and the classification of compounds into activators, inhibitors, ambivalent factors, and non-affecting factors with respect to a certain species. In some cases, qualitative effects induced by perturbations can be unambiguously predicted from the network scheme. Interaction graphs however, are not able to capture AND relationships which do frequently occur in interaction networks. The consequent logical concatenation of all the arcs pointing into a species leads to Boolean networks. For a Boolean representation of cellular interaction networks we propose a formalism based on logical (or signed) interaction hypergraphs, which facilitates in particular a logical steady state analysis (LSSA). LSSA enables studies on the logical processing of signals and the identification of optimal intervention points (targets) in cellular networks. LSSA also reveals network regions whose parametrization and initial states are crucial for the dynamic behavior. We have implemented these methods in our software tool CellNetAnalyzer (successor of FluxAnalyzer) and illustrate their applicability using a logical model of T-Cell receptor signaling providing non-intuitive results regarding feedback loops, essential elements, and (logical) signal processing upon different stimuli. The methods and formalisms we propose herein are another step towards the comprehensive functional analysis of cellular interaction networks. Their potential, shown on a realistic T-cell signaling model, makes them a promising tool.BMC Bioinformatics 02/2006; 7:56. · 3.02 Impact Factor
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ABSTRACT: A phenotype mechanism is classically derived through the study of a set of mutants and comparison of their biochemical capabilities. One method of comparing mutant capabilities is to characterize producible and knocked out metabolites. However such an effect is difficult to manually assess, especially for a large biochemical network and a complex media. Current algorithmic approaches towards analyzing metabolic networks either do not address this specific property or are computationally infeasible on the genome-scale. We have developed a novel genome-scale computational approach that identifies the full set of biochemical species that are knocked out from the metabolome following a gene deletion. Results from this approach are combined with data from in vivo mutant screens to examine the essentiality of metabolite production for a phenotype. This approach can also be a useful tool for metabolic network annotation validation and refinement in newly sequenced organisms. Combining an in silico genome-scale model of Escherichia coli metabolism with in vivo survival data, we uncover possible essential roles for several cell membranes, cell walls, and quinone species. We also identify specific biomass components whose production appears to be non-essential for survival, contrary to the assumptions of previous models. Programs are available upon request from the authors in the form of Matlab script files. http://www.cis.upenn.edu/biocomp/manuscripts/bioinformatics_bti245/supp-info.html.Bioinformatics 06/2005; 21(9):2008-16. · 5.32 Impact Factor