A Proposed Principle of Kinetic-Thermodynamic Coupling in the Glycolytic Pathway and Its Application to the Regulation of Glycolysis by PKM2

Metabolic regulation is governed by two fundamental principles: enzyme kinetics and chemical thermodynamics. These principles play distinct yet complementary roles, thermodynamics determines the energetic favorability of reactions, while kinetics governs the rates at which these reactions proceed. Glycolysis serves as a classical model for understanding these regulatory mechanisms. However, the interaction between enzyme kinetics and thermodynamics within the glycolytic pathway, specifically, the relationship among glycolytic flux, the rate of each enzymatic step, intermediate concentrations, and the Gibbs free energy changes of individual reactions, has long been overlooked. In this study, I propose a principle of kinetic-thermodynamic coupling in the glycolytic pathway. This principle explains how the rates of individual steps, the concentrations of intermediates, and the Gibbs free energy changes are coordinated such that the flux through each step remains equal and constant, while preserving the steady-state distribution of intermediate concentration. To demonstrate its utility, the principle is applied to the regulation of glycolysis by PKM2. In this context, it offers a precise framework for understanding how PKM2 activity, intermediate concentrations, and Gibbs free energy values are intricately coordinated during transitions between steady states. Based on this framework, mathematical expressions are derived for association of PKM2 activity with thermodynamic properties of glycolytic pathway, for PKM2 flux control and concentration control coefficients, and for the total mass transfer, duration, and average rate during transitions between steady states. This kinetic-thermodynamic model offers a novel biochemical perspective that fills a critical gap in our understanding of glycolysis and its regulation.