1. Inhibition of Achromobacter protease I by lysinal derivatives
F Sakiyama, M Soejima, T Masaki, S Tsunasawa, T Tanaka Biosci Biotechnol Biochem . 1992 Oct;56(10):1604-7. doi: 10.1271/bbb.56.1604.
Z-Val-, Z-Pro-, Z-Leu-Leu-, and Z-Leu-Pro-lysinals and BZ-DL-lysinal were chemically synthesized and tested as novel inhibitors for Achromobacter protease I (API), a lysine-specific serine protease. Among the lysinal derivatives tested, Z-Val-lysinal was the most potent competitive inhibitor, its Ki being estimated as 6.5 nM in an esterolytic assay with Tos-Lys-OMe. In an amidolytic assay, Z-Leu-Leu-lysinal was the most potent inhibitor and the apparent mode of inhibition was non-competitive. The Kis of the other lysinal derivatives in both esterolytic and amidolytic assays were more than 10(3) times lower than that of leupeptin. Z-Val-lysinol, lacking the aldehyde group, was a poor competitive inhibitor. These results suggest that acyl-, acylaminoacyl-, and acylpeptidyllysinals function as a transition-state inhibitor for Achromobacter protease I.
2. Therapeutic proteasome inhibition in experimental acute pancreatitis
Csaba Somlai, Ilona Varga, Gábor Tóth, Tamás Letoha, Tamás Takács, Csaba Vizler, László Tiszlavicz, József Kaszaki, László Pecze, Liliána Z Fehér World J Gastroenterol . 2007 Sep 7;13(33):4452-7. doi: 10.3748/wjg.v13.i33.4452.
Aim:To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.Methods:Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 microg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.Results:Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-kappaB (NF-kappaB). Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.Conclusion:Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.
3. Apoptosis induction resulting from proteasome inhibition
H Ito, K Shinohara, S Toné, S Kawashima, H Nakano, M Tomioka Biochem J . 1996 Jul 15;317 ( Pt 2)(Pt 2):385-8. doi: 10.1042/bj3170385.
Proteases are known to be involved in the apoptotic pathway. We report here that benzyloxycarbonyl (Z)-Leu-Leu-leucinal(ZLLLal), a leupeptin analogue, can induce apoptosis in MOLT-4 and L5178Y cells. ZLLLal is a cell-permeant inhibitor of proteasome. Among the protease inhibitors tested, only calpain inhibitor I (acetyl-Leu-Leu-norleucinal) and ZLLLal caused a marked induction of apoptosis in MOLT-4 cells. In contrast Z-Leu-leucinal, a specific inhibitor of calpain, did not induce apoptosis. When MOLT-4 cells were incubated in the presence of ZLLLal, p53 accumulated in the cells. These results strongly suggest that inhibition of proteasome induces p53-dependent apoptosis and that proteasome can protect cell from apoptosis.
