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Xenobiotica
the fate of foreign compounds in biological systems
Volume 38, 2008 - Issue 2
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Research Article

Molecular modelling study of the mechanism of high-potency inhibition of human catechol-O-methyltransferase by (–)-epigallocatechin-3-O-gallate

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Pages 130-146 | Received 15 Aug 2007, Accepted 12 Oct 2007, Published online: 22 Sep 2008
 

Abstract

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 IC50 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 Mg2+ 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.

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