Multi-equilibrium property of metabolic networks: Exclusion of multi-stability for SSN metabolic modules

It is a fundamental and important problem whether or not a metabolic network can admit multiple equilibria in a living organism. Due to the complexity of the metabolic network, it is generally a difficult task to study the problem as a whole from both analytical and numerical viewpoints. In this paper, a structure-oriented modularization research framework is proposed to analyze the multi-stability of metabolic networks. We first decompose a metabolic network into four types of basic building blocks (called metabolic modules) according to the particularity of its structure, and then focus on one type of these basic building blocks— the single substrate and single product with no inhibition (SSN) module, by deriving a nonlinear ordinary differential equation (ODE) model based on the Hill kinetics. We show that the injectivity of the vector field of the ODE model is equivalent to the nonsingularity of its Jacobian matrix, which enables us equivalently to convert an unverifiable sufficient condition for the absence of multiple equilibria of an SSN module into a verifiable one. Moreover, we prove that this sufficient condition holds for the SSN module in a living organism. Such a theoretical result not only provides a general framework for modeling metabolic networks, but also shows that the SSN module in a living organism cannot be multi-stable. Copyright 2011 John Wiley & Sons, Ltd.