EXCESS-SUBSTRATE INHIBITION IN ENZYMOLOGY AND HIGH-DOSE INHIBITION IN PHARMACOLOGY - A REINTERPRETATION

A kinetic model, called the Recovery Model, which incorporates an obligatory recovery phase of fixed duration (t(r)) in the operation cycle of a macromolecule (enzyme, receptor) is proposed. Binding of a ligand (substrate, agonist) during t(r) disturbs the recovery process and causes inhibition (substrate inhibition, agonist autoinhibition). A quantitative stochastic analysis of a minimal version of the Recovery Model reveals that (1) plotting the response versus the logarithm of the ligand concentration never yields a strictly symmetrical bell-shaped dose-response curve, (2) the position and shape of the descent of the dose-response curve can vary greatly in dependence of the kinetic parameters of the system, and (3) a minimal steepness of the descent with a Hill coefficient of 1 exists provided that the response can be totally inhibited by high ligand concentrations. The Recovery Model is equally applicable to macromolecules that can bind single or multiple ligands, and suggests new ways to explain such diverse phenomena as partial agonism, pulse generation, desensitization, memory effects and ultrasensitivity. In addition, substrate inhibition and agonist autoinhibition are regarded as phenomena closely related to other kinds of non-Michaelian behaviour because of a common temporal mechanism, namely the temporal interference of arriving ligand molecules with timing-sensitive phases of the operation cycle.