Molecular modelling study of the mechanism of high-potency inhibition of human catechol-O-methyltransferase by (-)-epigallocatechin-3-O-gallate.
The molecular mechanism of inhibition of human catechol-O-methyltransferase (COMT) by (-)-epigallocatechin-3-O-gallate (EGCG), which is a modest substrate of COMT but an ultra-potent inhibitor of this enzyme, was studied. EGCG has an IC(50) value of 70 nM for inhibiting human liver COMT-mediated O-methylation of 2-hydroxyestradiol, which was 210-760 times more potent than catechin, epigallocatechin and epicatechin. Kinetic analyses showed that EGCG had a strong component of non-competitive inhibition of the O-methylation of 2-hydroxyestradiol. Computational molecular modelling studies showed that the B- and D-rings of EGCG can bind tightly to the human COMT in four different modes (i.e. D-para-OH, D-meta-OH, B-para-OH, and B-meta-OH). The binding geometry of EGCG in these binding modes was found to be less than ideal to form perfect Mg(2+) coordination for the catalysis of its own methylation. It is concluded that the very tight binding interaction of EGCG with COMT makes it a potent non-competitive inhibitor, but its imperfect geometry makes it a poor substrate for methylation by this enzyme.
Zhu
B T
BT
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. BTZhu@kumc.edu
Shim
J-Y
JY
Nagai
M
M
Bai
H-W
HW
D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000737:chemistry*; D065098:Catechol O-Methyltransferase Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008745:Methylation; D008958:Models, Molecular; D051381:Rats; D013552:Swine
D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D002392:Catechin; C045651:epigallocatechin gallate; D002394:Catechol O-Methyltransferase