Computational modeling of the potential interactions of the proteasome β5 subunit and catechol-Ο-methyltransferase-resistant EGCG analogs

Abstract

Abstract. (-)-Epigallocatechin gallate [(-)-EGCG] has beenimplicated in cancer chemoprevention and has been shown as an inhibitor of tumor proteasomal chymotrypsin-like activity in vitro and in vivo. However, EGCG is subjected to rapid biotransforming modifications such as methylation by catechol-O-methyltransferase (COMT) that limits its action. We recently reported that structure 7, an EGCG analog which should be resistant to COMT-mediated methylation and inactivation in cells, was able to inhibit the activity of purified 20S proteasome and cellular 26S proteasome. However, the involved molecular mechanism is unknown. Herein, we applied computational solution to understand the possible interaction between EGCG analogs including structure 7 and the proteasome ß5 subunit which is responsible for the chymotrypsin-like activity. We report that the ester carbonyls at C2 and C3 carbon atoms may be the active sites for nucleophilic attack in structure 7 and 5. Equally spaced carbon atoms in COMT-resistant structure 7 give more stable conformation and lower docked free energy than other EGCG analogs. The absence of a second gallate group in structure 16 and 21 significantly decreases the ability to inhibit the proteasome.

Epigenetic targets of bioactive dietary components for cancer prevention and therapy

“…Recently, Moiseeva et al ( 2007 ) showed that low-dose long-term exposure of bioactive components such as EGCG and genistein results in epigenetic alterations of gene expression, reduced growth, and increased cellular apoptosis in breast cancer cells. Furthermore, there are several synthetic analogs of EGCG that have been shown to have strong anti-cancer activity with more efficacy and stability than EGCG under physiological conditions (Kanwar et al 2010 ; Huo et al 2010 ; Landis-Piwowar et al 2007 ). However, their epigenetic roles in cancer prevention and therapy have not yet been reported.…”