Modular decomposition of metabolic reaction networks based on flux analysis and pathway projection

Abstract

Motivation: The rational decomposition of biochemical networks into sub-structures has emerged as a useful approach to study the design of these complex systems. A biochemical network is characterized by an inhomogeneous connectivity distribution, which gives rise to several organizational features, including modularity. To what extent the connectivity-based modules reflect the functional organization of the network remains to be further explored. In this work, we examine the influence of physiological perturbations on the modular organization of cellular metabolism. Results: Modules were characterized for two model systems, liver and adipocyte primary metabolism, by applying an algorithm for topdown partition of directed graphs with non-uniform edge weights. The weights were set by the engagement of the corresponding reactions as expressed by the flux distribution. For the base case of the fasted rat liver, three modules were found, carrying out the following biochemical transformations: ketone body production, glucose synthesis and transamination. This basic organization was further modified when different flux distributions were applied that describe the liver's metabolic response to whole body inflammation. For the fully mature adipocyte, only a single module was observed, integrating all of the major pathways needed for lipid storage.

Identification of Potential Pathway Mediation Targets in Toll-like Receptor Signaling

“…However, since ExPa analysis becomes computationally challenging in large-scale, mass-balanced networks [21], we could not apply this method to the TLR network. In contrast, network modularization has been established as a method for reducing large-scale networks into more manageable units [22]–[24]. Another approach for reducing network complexity is to focus on input–output relationships [20],[25].…”

Genome-scale metabolic analysis of Clostridium thermocellum for bioethanol production

“…By means of the quasi-steady state assumption, i.e., that metabolite concentrations are constant over short time scales, the reaction list can be used to define a space of possible steady state behaviors for the metabolic network. This solution space can then be probed by a growing number of methods to obtain specific predictions of the organism's behavior [4,7-9]. The most commonly employed method is flux balance analysis (FBA).…”

Stoichiometry Based Steady-State Hepatic Flux Analysis: Computational and Experimental Aspects

“…Since an exergonic reaction can be a driving-force for an endergonic reaction if these two reactions are coupled in the same pathway, elementary modes were also used to formulate thermodynamic feasibility constraints for hepatic metabolic network to reduce the feasible range of intracellular fluxes [63,66,84,85,86,87]. The Gibbs free energy of the pathway is the summation of the Gibbs free energies of reactions involved in that pathway which should be less than or equal to zero.…”