G. Fenteany et al., INHIBITION OF PROTEASOME ACTIVITIES AND SUBUNIT-SPECIFIC AMINO-TERMINAL THREONINE MODIFICATION BY LACTACYSTIN, Science, 268(5211), 1995, pp. 726-731
Lactacystin is a Streptomyces metabolite that inhibits cell cycle prog
ression and induces neurite outgrowth in a murine neuroblastoma cell l
ine. Tritium-labeled lactacystin was used to identify the 20S proteaso
me as its specific cellular target. Three distinct peptidase activitie
s of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidy
lglutamyl-peptide hydrolyzing activities) were inhibited by lactacysti
n, the first two irreversibly and all at different rates. None of five
other proteases were inhibited, and the ability of lactacystin analog
s to inhibit cell cycle progression and induce neurite outgrowth corre
lated with their ability to inhibit the proteasome. Lactacystin appear
s to modify covalently the highly conserved amino-terminal threonine o
f the mammalian proteasome subunit X (also called MB1), a close homolo
g of the LMP7 proteasome subunit encoded by the major histocompatibili
ty complex. This threonine residue may therefore have a catalytic role
, and subunit X/MB1 may be a core component of an amino-terminal-threo
nine protease activity of the proteasome.