Dead-End Inhibition

Dead-end inhibition of an enzyme occurs when a compound, usually a structural analogue of a substrate, combines at the active site of the enzyme, but does not undergo reaction. The resulting complex can only dissociate back to the components from which it was formed. Dead-end inhibitors are useful for determining kinetic reaction mechanisms because dead-end inhibition patterns can be characteristic of a particular mechanism. Rules have been formulated for the qualitative prediction of such inhibition patterns (1) and these rules can be summarized as follows:

1. A dead-end inhibitor affects the slope of a double-reciprocal plot when   the inhibitor and the variable substrate combine with the same enzyme form or   a reversible connection exists between the points of addition of the inhibitor and the variable substrate. Such a reversible connection exists only when the variable substrate adds after the inhibitor.

2. A dead-end inhibitor affects the intercept of a double-reciprocal plot when the inhibitor and variable substrate combine with different forms of enzyme and saturation with the variable substrate does not overcome the inhibition. Intercept effects will always be observed unless steps between the points of addition of the variable substrate and the inhibitor are at thermodynamic equilibrium.

The results of the application of the rules to kinetic mechanisms for Bi–Bi reaction mechanisms are given in Table 1. Further examples are given in Competitive inhibition, Noncompetitive Inhibition, Product Inhibition, Substrate Inhibition, and Uncompetitive inhibition.

Table 1. Dead-end Inhibition Patterns for Bi–Bi Reaction Mechanisms ^a

^a The mechanisms are illustrated under Kinetic mechanisms. C = linear competitive inhibition. NC = linear noncompetitive inhibition. UC = linear uncompetitive inhibition.

References

1. W. W. Cleland (1963) Biochim. Biophys. Acta 67, 188–196.