Substrate B

ch2 o

normally catalyzes the hydrolysis of peptide bonds next to aromatic amino acids. The substrates shown in Figure 1 are convenient smaller models for the natural substrates (long polypeptides and proteins). The additional chemical groups added in each substrate (A to B to C) are shaded. As the table shows, the interaction between the enzyme and these added functional groups has a minimal effect on Km (taken here as a reflection of Kd) but a large, positive effect on kcat and kcat/Km. This is what we would expect if the interaction contributed largely to stabilization of the transition state. The results also demonstrate that the rate of a reaction can be affected greatly by enzymesubstrate interactions that are physically remote from the covalent bonds that are altered in the enzyme-catalyzed reaction. Chymotrypsin is described in more detail in the text.

A complementary experimental approach is to modify the enzyme, eliminating certain enzyme-substrate interactions by replacing specific amino acid residues through site-directed mutagenesis (see Fig. 9-12). Results from such experiments again demonstrate the importance of binding energy in stabilizing the transition state.

Transition-State Analogs

Even though transition states cannot be observed directly, chemists can often predict the approximate structure of a transition state based on accumulated knowledge about reaction mechanisms. The transition state is by definition transient and so unstable that direct measurement of the binding interaction between this species and the enzyme is impossible. In some

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