Transition state, slow, tight-binding

This article describes various approaches to inhibition of enzyme catalysis. Reversible inhibition includes competitive, uncompetitive, mixed inhibition, noncompetitive inhibition, transition state, and slow tight-binding inhibition. Irreversible inhibition approaches include affinity labeling and mechanism-based enzyme inhibition. The kinetics of the various inhibition approaches are summarized, and examples of each type of Inhibition are presented. 

Example of a Transition State Analog Inhibitor that Exhibits Slow Tight-Binding inhibition... 

Transition-state inhibitors, especially those with peptidyl or peptidomimetic extensions, are slow-binding inhibitors, and the protease-inhibitor binding mechanism includes one or more weakly bound intermediates before the formation of the tightly bound E I complex. This slow-binding inhibition is a hallmark of inhibitors that bind in the active site in a substrate-like manner. In this way, transition-state analogs mimic the association... 

A tenfold change in the equilibrium constant corresponds to a standard free-energy change (AG°0 of 1.36 kcal/mol (1.36 comes from 2.303 RT). If a mutant enzyme binds a substrate, S, 100-fold as tightly as does the native enzyme, more Gibbs free energy of activation (AGf) is needed to convert S to Sf (transition state). In fact, the AG is increased by 2.72 kcal/mol (2.303 RT log 100) and the velocity of the reaction will be slowed down by a factor of 100. 

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