Anticompetitive inhibition

If an inhibitor binds only to the glycosyl-enzyme intermediate of a retaining glycosidase, then uncompetitive (sometimes more informatively called anticompetitive) inhibition is observed. The rate law is that of eqn. (5.29). It should be noted that, like the analogous case of substrate inhibition described by eqn. (5.17), Ki is Ad[(k+2 + k+3)/k+2], where is the dissociation constant of the glycosyl-enzyme intermediate. 

GLYCOSYL TRANSFER - MODIFICATION OF TOOLS FROM SMALL-MOLECULE PHYSICAL ORGANIC CHEMISTRY AND NEW TOOLS FROM PROTEIN CHEMISTRY 

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Inhibition can be analysed visually by double reciprocal plots (Figure 5.12). In the case of competitive inhibition, 1/v versus 1/[S] plots at various values of P] give a series of lines all intersecting at 1 /[S] = 0, 1/v = 1/ Fmax, whereas in the case of anticompetitive inhibition, the 1/v versus 1/[S] plots at various values of P] are all parallel. The fascination of double reciprocal plots was such that a further form of inhibition, where the lines all intersected at 1/v = 0, 1/[S] = — 1/ Am was defined and confusingly termed non-competitive inhibition the physical situation, rarely encountered in practice, was that inhibitor bound equally to E and ES. The rate law is that of eqn. (5.30). In practice, inhibition which is neither cleanly competitive nor cleanly uncompetitive is best described by the mixed inhibition eqn. (5.31). 

Figure 5.12 Double reciprocal plots, drawn to scale, for (a) competitive and (b) anticompetitive inhibition.

Anticompetitive inhibition can be simply explained if the inhibitor can become attached to ES but not to E. 

In addition to the above, there is mixed inhibition, which exists if i increases or decreases as substrate concentration increases, but not to the same extent as for the pure competitive or anticompetitive cases,... 

A considerable medicinal chemistry effort has gone into devising inhibitors of aldose reductase their inhibition shows a dominant or even exclusive anticompetitive component when measured as inhibitors of aldose reduction, since they form tight complexes of the form E.NAD.I the inhibition is competitive when alditol oxidation is measured. 

Sometimes the degree of inhibition is increased as the substrate concentration is increased. Here we shall refer to this behavior as anticompetitive. (The terms coupling and uncompetitive are also applied to this type of behavior.)... 

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