Hydrolysis nucleophilic acyl substitution proteins

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that then undergoes hydrolysis. 

Knowing how the protein chain is folded is a key element in understanding how an enzyme catalyzes a reaction. Biochemical processes are usually related to the core reaction types of organic chemistry and involve similar key intermediates. The reactions, however, are much faster and more selective. In proposing an enzyme-catalyzed mechanism for a reaction such as amide or ester hydrolysis, it is customary to assume it proceeds by way of a tetrahedral intermediate, then modify the usual nucleophilic acyl substitution mechanism by assigning various catalytic functions to selected amino acid side chains of the enzyme. 

Figure 37.2. Catalysis by the enzyme chymotrypsin of the cleavage of one peptide bond in a protein a proposed mechanism. Histidine and pro-tonated histidine act as general base and acid in two successive nucleophilic substitution reactions (a) cleavage of protein with formation of acyl enzyme and liberation of one protein fragment (6) hydrolysis of acyl enzyme with regeneration of the enzyme and liberation of the other protein fragment.

---