Small-molecule inhibitor: clasto-lactacystin beta-lactone

Name

History: Fenteany et al. (1994) reported that a beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line, and that it inhibits the peptidase activities of the proteasome: Fenteany et al., 1995). Since then, lactacystin and clasto-lactacystin beta-lactone have been widely used in experiments on the activities of the proteasome.
Peptidases inhibited: Lactacystin has been regarded as highly specific for the peptidase activities of the proteasome, e.g. archaean proteasome: Ditzel et al., 1997). Nevertheless, inhibition of several serine carboxypeptidases in family S10 and of tripeptidyl peptidase II has also been reported (Ostrowska et al., 2000; Satoh et al., 2004; Hilbi et al., 2000). Lactacystin also inhibitschlamydial protease-like activity factor (Huang et al., 2008[20081222A083]).
Mechanism: Lactacystin loses N-acetylcysteine in aqueous solutions to form clasto-lactacystin beta-lactone, which penetrates cell membranes and reacts covalently with the proteasome. The beta-lactone ring is attacked by the beta-hydroxy group of N-terminal threonine residues of catalytically-active beta-subunits of the proteasome. k_obs/[I] = 675 M^-1s^-1 for the chymotrypsin-like T01.012 and 30 M^-1s^-1 for the trypsin-like T01.011; reaction with the glutamyl peptidase component (T01.010) is weak (3.7 M^-1s^-1) (Powers et al., 2002, p. 4714).