FAST-SLOW ANALYSIS OF A MODEL FOR THE STIMULATION OF ENZYMATIC ACTIVITY BY A COMPETITIVE INHIBITOR

Competitive inhibitors can, paradoxically, stimulate an enzymatic reaction at low to moderate doses. Competitive inhibition of an enzyme occurs when an inhibitor binds to the enzyme’s binding site and blocks the enzyme’s target molecule from binding. We recently proposed a detailed but straightforward mass action model for competitive inhibition of phosphoglycerate kinase 1 (PGK1) by Terazosin (TZ). This straightforward model predicts an increased reaction rate at low or moderate TZ doses, suggesting that stimulation is an intrinsic feature of competitive inhibition in enzymes with two products. This mechanism can aid in development of novel therapies, particularly since enzyme activators are more rare and difficult to design than inhibitors. Here we propose a three time scale reduction of that detailed model and show that the resulting rate equation retains three essential attributes of competitive inhibitor stimulation. These attributes are the biphasic dose response, the dependence on the relative rates of product dissociation from the binary and ternary complexes, and the parameter region where stimulation is possible.