Do cleavages of amides by serine proteases occur through a stepwise pathway involving tetrahedral intermediates?

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Abstract
The mechanism of the serine protease-catalyzed cleavage of amides (acylation) was examined in terms of the basicity of the functional groups participating in the catalysis. The reaction apparently does not proceed via a stepwise pathway, unlike the cleavage of esters and anilides, which start with general base-catalyzed formation of the tetrahedral intermediate followed by its general acid-catalyzed breakdown. Instead, the proton abstracted from the hydroxyl group of the serine by the imidazolyl group of the histidine is donated to the N atom of the leaving group of the amide before the bond between the carbonyl C atom of the amide and the attacking serine O atom is completed. Reactions proceed by a SN2-like reaction through the cooperation of acid catalysis by the imidazolyl cation and nucleophilic attack by the serine. The mechanisms of the enzymatic hydrolyses of anilides and esters proceed through a discrete tetrahedral intermediate, but the enzymatic hydrolyses of amides probably do not.