Presentation Information
[C04-04]Regulation of Metabolite Concentrations in the Fasting Mouse Liver Characterized by Thermodynamic Profiling of Metabolic Reactions
*Takumi Abekawa1, Satoshi Ohno2, Shinya Kuroda1 (1. The University of Tokyo (Japan), 2. Institute of Science Tokyo (Japan))
Keywords:
Metabolism,Gibbs free energy,Enzymatic kinetics
Understanding homeostasis in living organisms requires elucidation of the behavior of biochemical reactions known as metabolism. The concentrations of metabolites, which are substrates and products of those reactions, fluctuate depending on physiological conditions and are therefore important targets of investigation. One important perspective for interpreting metabolite concentrations is Gibbs free energy change of reaction (ΔrG′), a thermodynamic property that depends on metabolite concentrations.
According to the second law of thermodynamics, in physiological environments characterized by open systems under constant temperature and pressure, where both matter and energy are exchanged with the surroundings, chemical reactions proceed in the direction that decreases Gibbs free energy, reaching equilibrium when ΔrG′ is zero. Thus, ΔrG′ serves as an important thermodynamic indicator of how far a metabolic reaction is from equilibrium. Defined as the difference in Gibbs free energy between the products and reactants, ΔrG′ is inherently dependent on metabolite concentrations, as the Gibbs free energy of a metabolite is a function of its concentration.
In addition to its physical significance, ΔrG′ can be integrated with information on enzyme saturation to infer biologically meaningful properties such as the Flux Control Coefficient (FCC), which quantifies how a transient perturbation in a reaction rate affects the steady-state flux of the entire metabolic system i.e. rate-limiting degree.
In this study, we computed ΔrG′ during fasting time courses in mouse liver using metabolomics data, focusing on the metabolic shift from glycolysis to gluconeogenesis. During fasting, we observed that ΔrG′ tended to be tightly maintained in reactions near equilibrium, despite large fluctuations in the concentrations of participating metabolites. In contrast, such maintenance of ΔrG′ was not evident in reactions far from equilibrium. Calculation of FCCs based on the obtained ΔrG′ revealed that the range of metabolite concentration changes observed in mouse liver falls within a regime that preserves candidates of rate-limiting step characterized by large FCCs, which are constrained by ΔrG′.
To our knowledge, this is the first study to examine ΔrG′ of each reaction in different metabolic state across any cell type, and our findings thus uncover a novel aspect of the regulation of metabolite concentration.
According to the second law of thermodynamics, in physiological environments characterized by open systems under constant temperature and pressure, where both matter and energy are exchanged with the surroundings, chemical reactions proceed in the direction that decreases Gibbs free energy, reaching equilibrium when ΔrG′ is zero. Thus, ΔrG′ serves as an important thermodynamic indicator of how far a metabolic reaction is from equilibrium. Defined as the difference in Gibbs free energy between the products and reactants, ΔrG′ is inherently dependent on metabolite concentrations, as the Gibbs free energy of a metabolite is a function of its concentration.
In addition to its physical significance, ΔrG′ can be integrated with information on enzyme saturation to infer biologically meaningful properties such as the Flux Control Coefficient (FCC), which quantifies how a transient perturbation in a reaction rate affects the steady-state flux of the entire metabolic system i.e. rate-limiting degree.
In this study, we computed ΔrG′ during fasting time courses in mouse liver using metabolomics data, focusing on the metabolic shift from glycolysis to gluconeogenesis. During fasting, we observed that ΔrG′ tended to be tightly maintained in reactions near equilibrium, despite large fluctuations in the concentrations of participating metabolites. In contrast, such maintenance of ΔrG′ was not evident in reactions far from equilibrium. Calculation of FCCs based on the obtained ΔrG′ revealed that the range of metabolite concentration changes observed in mouse liver falls within a regime that preserves candidates of rate-limiting step characterized by large FCCs, which are constrained by ΔrG′.
To our knowledge, this is the first study to examine ΔrG′ of each reaction in different metabolic state across any cell type, and our findings thus uncover a novel aspect of the regulation of metabolite concentration.