Steady states and stability in metabolic networks without regulation

Abstract

Metabolic networks are often extremely complex. Despite intensive efforts many details of these networks, e.g., exact kinetic rates and parameters of metabolic reactions, are not known, making it difficult to derive their properties. Considerable effort has been made to develop theory about properties of steady states in metabolic networks that are valid for any values of parameters. General results on uniqueness of steady states and their stability have been derived with specific assumptions on reaction kinetics, stoichiometry and network topology. For example, deep results have been obtained under the assumptions of mass-action reaction kinetics, continuous flow stirred tank reactors (CFSTR), concordant reaction networks and others. Nevertheless, a general theory about properties of steady states in metabolic networks is still missing. Here we make a step further in the quest for such a theory. Specifically, we study properties of steady states in metabolic networks with monotonic kinetics in relation to their stoichiometry (simple and general) and the number of metabolites participating in every reaction (single or many). Our approach is based on the investigation of properties of the Jacobian matrix. We show that stoichiometry, network topology, and the number of metabolites that participate in every reaction have a large influence on the number of steady states and their stability in metabolic networks. Specifically, metabolic networks with single-substrate-single-product reactions have disconnected steady states, whereas in metabolic networks with multiple-substrates-multiple-product reactions manifolds of steady states arise. Metabolic networks with simple stoichiometry have either a unique globally asymptotically stable steady state or asymptotically stable manifolds of steady states. In metabolic networks with general stoichiometry the steady states are not always stable and we provide conditions for their stability. In order to demonstrate the biological relevance we illustrate the results on the examples of the TCA cycle, the mevalonate pathway and the Calvin cycle.

Keywords: Local stability; Manifold; Metabolism; Robustness.