Motivated by recent progress on the interplay between graph theory, dynamics, and systems theory, we revisit the analysis of chemical reaction networks described by mass action kinetics. For reaction networks possessing a thermodynamic equilibrium we derive a compact formulation exhibiting at the same time the structure of the complex graph and the stoichiometry of the network, and which admits a direct thermodynamical interpretation. This formulation allows us to easily characterize the set of equilibria and their stability properties. Furthermore, we develop a framework for interconnection of chemical reaction networks. Finally we discuss how the established framework leads to a new approach for model reduction.

BackgroundIn this paper we propose a model reduction method for biochemical reaction networks governed by a variety of reversible and irreversible enzyme kinetic rate laws, including reversible Michaelis-Menten and Hill kinetics. The method proceeds by a stepwise reduction in the number of complexes, defined as the left and right-hand sides of the reactions in the network. It is based on the Kron reduction of the weighted Laplacian matrix, which describes the graph structure of the complexes and reactions in the network. It does not rely on prior knowledge of the dynamic behaviour of the network and hence can be automated, as we demonstrate. The reduced network has fewer complexes, reactions, variables and parameters as compared to the original network, and yet the behaviour of a preselected set of significant metabolites in the reduced network resembles that of the original network. Moreover the reduced network largely retains the structure and kinetics of the original model.ResultsWe apply our method to a yeast glycolysis model and a rat liver fatty acid beta-oxidation model. When the number of state variables in the yeast model is reduced from 12 to 7, the difference between metabolite concentrations in the reduced and the full model, averaged over time and species, is only 8%. Likewise, when the number of state variables in the rat-liver beta-oxidation model is reduced from 42 to 29, the difference between the reduced model and the full model is 7.5%.ConclusionsThe method has improved our understanding of the dynamics of the two networks. We found that, contrary to the general disposition, the first few metabolites which were deleted from the network during our stepwise reduction approach, are not those with the shortest convergence times. It shows that our reduction approach performs differently from other approaches that are based on time-scale separation. The method can be used to facilitate fitting of the parameters or to embed a detailed model of interest in a more coarse-grained yet realistic environment.

Abstract-Oxidative stress contributes to the pathogenesis of atherosclerosis. p22phox -based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242T CYBA polymorphism, whereas others have not. Because vascular p22 phox is identical to neutrophil p22 phox , we studied the association between the C242T, A640G, and Ϫ930 A/G CYBA polymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7Ϯ0.7, 7.9Ϯ0.6, and 5.9Ϯ1.2 mol/L per minute per 10 6 neutrophils for the C242T CC, CT, and TT genotypes, respectively (PϽ0.05). In contrast, the A640G and the Ϫ930

In this paper we derive a compact mathematical formulation describing the dynamics of chemical reaction networks that are complex-balanced and are governed by mass action kinetics. The formulation is based on the graph of (substrate and product) complexes and the stoichiometric information of these complexes, and crucially uses a balanced weighted Laplacian matrix. It is shown that this formulation leads to elegant methods for characterizing the space of all equilibria for complex-balanced networks and for deriving stability properties of such networks. We propose a method for model reduction of complex-balanced networks, which is similar to the Kron reduction method for electrical networks and involves the computation of Schur complements of the balanced weighted Laplacian matrix

Studies with dietary supplementation of various types of fibers have shown beneficial effects on symptoms of the metabolic syndrome. Short-chain fatty acids (SCFAs), the main products of intestinal bacterial fermentation of dietary fiber, have been suggested to play a key role. Whether the concentration of SCFAs or their metabolism drives these beneficial effects is not yet clear. In this study we investigated the SCFA concentrations and in vivo host uptake fluxes in the absence or presence of the dietary fiber guar gum. C57Bl/6J mice were fed a high-fat diet supplemented with 0%, 5%, 7.5% or 10% of the fiber guar gum. To determine the effect on SCFA metabolism, 13C-labeled acetate, propionate or butyrate were infused into the cecum of mice for 6 h and the isotopic enrichment of cecal SCFAs was measured. The in vivo production, uptake and bacterial interconversion of acetate, propionate and butyrate were calculated by combining the data from the three infusion experiments in a single steady-state isotope model. Guar gum treatment decreased markers of the metabolic syndrome (body weight, adipose weight, triglycerides, glucose and insulin levels and HOMA-IR) in a dose-dependent manner. In addition, hepatic mRNA expression of genes involved in gluconeogenesis and fatty acid synthesis decreased dose-dependently by guar gum treatment. Cecal SCFA concentrations were increased compared to the control group, but no differences were observed between the different guar gum doses. Thus, no significant correlation was found between cecal SCFA concentrations and metabolic markers. In contrast, in vivo SCFA uptake fluxes by the host correlated linearly with metabolic markers. We argue that in vivo SCFA fluxes, and not concentrations, govern the protection from the metabolic syndrome by dietary fibers.

A treatment of a chemical reaction network theory is given from the perspective of nonlinear network dynamics, in particular of consensus dynamics. By starting from the complex-balanced assumption, the reaction dynamics governed by mass action kinetics can be rewritten into a form which allows for a very simple derivation of a number of key results in the chemical reaction network theory, and which directly relates to the thermodynamics and port-Hamiltonian formulation of the system. Central in this formulation is the definition of a balanced Laplacian matrix on the graph of chemical complexes together with a resulting fundamental inequality. This immediately leads to the characterisation of the set of equilibria and their stability. Furthermore, the assumption of complex balancedness is revisited from the point of view of Kirchhoff's matrix tree theorem. Both the form of the dynamics and the deduced behaviour are very similar to consensus dynamics, and provide additional perspectives to the latter. Finally, using the classical idea of extending the graph of chemical complexes by a 'zero' complex, a complete steady-state stability analysis of mass action kinetics reaction networks with constant inflows and mass action kinetics outflows is given, and a unified framework is provided for structure-preserving model reduction of this important class of open reaction networks

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The characterization of the notions of complex and detailed balancing for mass action kinetics chemical reaction networks is revisited from the perspective of algebraic graph theory, in particular Kirchhoff's Matrix Tree theorem for directed weighted graphs. This yields an elucidation of previously obtained results, in particular with respect to the Wegscheider conditions, and a new necessary and sufficient condition for complex balancing, which can be verified constructively.