Fig. 5.

Model comparing carboxypeptidase A and ACE. In this schematic, the active sites of carboxypeptidase A and ACE are compared. The pockets in the enzyme represent side chain binding sites within the active sites of the enzymes. In ACE, these pockets are often labeled S₁, S₁′, and S₂′ based on their position relative to the zinc molecule. The + indicate positive charges and X-H represents a potential hydrogen bond. Interactions stabilizing substrates or inhibitors are indicated with dots. The substrate amino bond hydrolyzed by the enzymes is indicated with a bent line. Initial thinking about ACE inhibitors was derived from work showing that benzylsuccinic acid was an inhibitor of carboxypeptidase A (Byers and Wolfenden, 1973). A major advance was the use of a sulfhydryl group to bind to the zinc molecule (Ondetti and Cushmen, 1981). The figure also shows the structure of the ACE inhibitor lisinopril, which has a high affinity for ACE due to interaction with the S₁ pocket, in addition to the zinc atom and other structural features of ACE. Adapted with permission from Cushman et al. (1977). Copyright (1978) American Chemical Society.