Small-molecule inhibitor: benzylsuccinic acid

Name

History: It was reported by Byers & Wolfenden (1972) and Byers & Wolfenden (1973) that L-benzylsuccinate is an inhibitor of carboxypeptidase A.
Peptidases inhibited: L-Benzylsuccinate inhibits carboxypeptidase A (K_i 0.45 microM: Byers & Wolfenden, 1973) and much more weakly, <#tubulinyl-Tyr carboxypeptidase#U9E.002#> (K_i >20 mM: Webster & Oxford, 1996). Racemic benzylsuccinate inhibits thermolysin (K_i 3.8 mM: Bolognesi & Matthews, 1979), and it was eventually shown that it is the D-isomer that binds (Hausrath et al., 1994). Benzylsuccinate also forms a complex with human procarboxypeptidase A2 (Garcia-Saez et al., 1997). Wheat serine carboxypeptidase II is inhibited by L-benzylsuccinate with K_i 0.2 mM (Bullock et al., 1994).
Mechanism: Inhibition is reversible. Crystal structures (see Literature) show that the mode of binding to metallopeptidases is similar to that of other carboxyalkyl compounds (Hausrath et al., 1994). The structure of the complex with the serine-type wheat carboxypeptidase II has also been elucidated crystallographically (Bullock et al., 1994).

Inhibitor class: This is a compound in the carboxylate class of reversible metallopeptidase inhibitors. In these, the active site zinc of the enzyme is generally coordinated by a carboxylate of the inhibitor, and this interaction contributes to inhibitory potency. Reviewed by Patchett & Cordes (1985) and Powers & Harper (1986), pp. 268 - 277 (who provide a table of K_i values).
Reviews: Powers & Harper (1986), pp. 264-268. Hausrath et al. (1994)