Noncompetitive inhibition bisubstrate reaction

The modality of compounds that inhibit enzymes catalyzing bisubstrate reactions will differ with respect to the two substrates of the reaction, and the pattern of inhibition will depend on the reaction mechanism of the enzyme. Thus, when we use terms like competitive, noncompetitive, or uncompetitive inhibition, we must... 

In this chapter we described the thermodynamics of enzyme-inhibitor interactions and defined three potential modes of reversible binding of inhibitors to enzyme molecules. Competitive inhibitors bind to the free enzyme form in direct competition with substrate molecules. Noncompetitive inhibitors bind to both the free enzyme and to the ES complex or subsequent enzyme forms that are populated during catalysis. Uncompetitive inhibitors bind exclusively to the ES complex or to subsequent enzyme forms. We saw that one can distinguish among these inhibition modes by their effects on the apparent values of the steady state kinetic parameters Umax, Km, and VmdX/KM. We further saw that for bisubstrate reactions, the inhibition modality depends on the reaction mechanism used by the enzyme. Finally, we described how one may use the dissociation constant for inhibition (Kh o.K or both) to best evaluate the relative affinity of different inhibitors for ones target enzyme, and thus drive compound optimization through medicinal chemistry efforts. 

As a mle, a noncompetitive inhibition occurs only if there are more than one substrate or product (Todhunter, 1979 Fromm, 1995). For example, a noncompetitive inhibition will take place in a random bisubstrate reaction, when an inhibitor competes with one substrate while the other substrate is varied. Thus, the equilibria shown below describe a Rapid Equilibrium Random bisubstrate system in which an inhibitor competes with A but allows B to bind. 

We shall turn now to much more realistic cases of bisubstrate reactions. The proper way to study a substrate inhibition in bisubstrate reactions is to vary a noninhibitory substrate, at differing high levels of the inhibitory one and see whether the slopes, intercepts, or both of reciprocal plots show the inhibitory effects (Cleland, 1979). These cases are then called competitive, uncompetitive, and noncompetitive substrate inhibition, respectively. 

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