A Theoretical Framework for Kinetic-Thermodynamic Coupling in the Regulation of Glycolysis by PKM2

Metabolic regulation is governed by enzyme kinetics and chemical thermodynamics, yet their interplay remains underexplored. We previously demonstrated experimentally that kinetic-thermodynamic coupling stabilizes glycolytic flux despite marked perturbations of enzymes such as PKM2, PGK1, GAPDH, and LDH. Building on these findings, I present a theoretical framework for kinetic-thermodynamic coupling in the glycolytic pathway. This framework shows how enzyme rates, intermediate concentrations, and Gibbs free energy values are coordinated to sustain equal flux through each enzymatic step. Using PKM2 as a model, mathematical expressions are derived that link its activity to the thermodynamic landscape of glycolysis, quantify its flux and concentration control coefficients, and describe the transient phase between steady states in terms of mass transfer, duration, and velocity. The analysis reveals that glycolysis is not only adaptable but also intrinsically self-stabilizing. This work provides a unifying biochemical principle for understanding glycolytic regulation — and, more broadly, metabolic regulation.