Interaction of two inhibitors which act on different enzymes of a metabolic pathway

Abstract

An analysis of the interaction of two inhibitors which act on different enzymes of a generalized metabolic pathway is presented. The steady-state kinetic behaviour of the pathway is treated in terms of the operation of a single component enzyme, E, with which one inhibitor interacts directly. The other inhibitor is assumed to act on an enzyme prior to E, and affects E only by decreasing the concentration of its substrate. Whether the interaction of the two inhibitors is synergistic, independent or antagonistic is determined from a comparison of the effect of the direct inhibitor upon the apparent kinetic order of its target enzyme with its effect on the fractional substrate decrement produced by the remote inhibitor. The analysis is applied to three model pathways whose component reactions are catalyzed by enzymes operating with Michaelis-Menten-Henri kinetics with particular emphasis on conditions where the interaction is synergistic. It is found that synergism will in many cases result from the fact that a competitive inhibitor of a Michaelis-Menten-Henri enzyme will increase the apparent kinetic order of the reaction, making its rate more sensitive to the substrate decrease resulting from the action of a remote inhibitor. Cases are also described where synergism can result solely from one inhibitor increasing the fractional substrate decrement caused by the other. In all cases where a synergistic interaction was found in the model pathways a necessary condition was that the configuration of the pathway should be such that each inhibitor, acting alone, must be capable of reducing the pathway velocity. A brief description of the properties of metabolic pathways which are susceptible to inhibition at multiple points is presented.