Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: Structure-activity relationship and molecular-modeling studies

@article{citeulike:2945733, abstract = {(-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. We previously demonstrated that EGCG was both a substrate and potent inhibitor of human liver cytosolic catechol-O-methyltransferease (COMT). We now report the structure-activity relationship for the inhibition of COMT-catalyzed O-methylation of catecholestrogens in human liver cytosol by tea catechins and some of their metabolites. The most potent inhibitors were catechins with a galloyl-type D-ring, including EGCG (IC50 = 0.07 [mu]M), 4''-O-methyl-EGCG (IC50 = 0.10 [mu]M), 4',4''-di-O-methyl-EGCG (4',4''-DiMeEGCG) (IC50 = 0.15 [mu]M), and (-)-epicatechin-3-gallate (ECG) (IC50 = 0.20 [mu]M). Catechins without the D-ring showed two to three orders of magnitude less inhibitory potency. Enzyme kinetic analyses revealed that EGCG behaved as a mixed inhibitor, whereas 4',4''-di-O-methyl-EGCG exhibited competitive kinetics for the S-adenosylmethionine (SAM), and noncompetitive kinetics for the catechol binding site. These compounds may represent a new type of COMT inhibitor. In silico molecular-modeling studies using a homology model of human COMT were conducted to aid in the understanding the catalytic and inhibitory mechanisms. Either D-ring or B-ring of EGCG could be accommodated to the substrate binding pocket of human COMT. However, the close proximity (2.6 \r{A}) of 4''-OH to the critical residue Lys144, the higher acidity of the hydroxyl groups of the D-ring, and the hydrophobic interactions between the D-ring and residues in the binding pocket greatly facilitated the interaction of the D-ring with the enzyme, and resulted in increased inhibitory potency. These results provide mechanistic insight into the inhibition of COMT by commonly consumed tea catechins.}, author = {Chen, Dapeng and Wang, Ching Y. and Lambert, Joshua D. and Ai, Ni and Welsh, William J. and Yang, Chung S. }, citeulike-article-id = {2945733}, doi = {http://dx.doi.org/10.1016/j.bcp.2005.01.024}, journal = {Biochemical Pharmacology}, keywords = {comt}, month = {May}, number = {10}, pages = {1523--1531}, posted-at = {2008-06-30 20:54:25}, priority = {2}, title = {Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: Structure-activity relationship and molecular-modeling studies}, url = {http://dx.doi.org/10.1016/j.bcp.2005.01.024}, volume = {69}, year = {2005} }

TY - JOUR ID - citeulike:2945733 L3 - citeulike-article-id:2945733 TI - Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: Structure-activity relationship and molecular-modeling studies JF - Biochemical Pharmacology VL - 69 IS - 10 SP - 1523 EP - 1531 N2 - (-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. We previously demonstrated that EGCG was both a substrate and potent inhibitor of human liver cytosolic catechol-O-methyltransferease (COMT). We now report the structure-activity relationship for the inhibition of COMT-catalyzed O-methylation of catecholestrogens in human liver cytosol by tea catechins and some of their metabolites. The most potent inhibitors were catechins with a galloyl-type D-ring, including EGCG (IC50 = 0.07 [mu]M), 4''-O-methyl-EGCG (IC50 = 0.10 [mu]M), 4',4''-di-O-methyl-EGCG (4',4''-DiMeEGCG) (IC50 = 0.15 [mu]M), and (-)-epicatechin-3-gallate (ECG) (IC50 = 0.20 [mu]M). Catechins without the D-ring showed two to three orders of magnitude less inhibitory potency. Enzyme kinetic analyses revealed that EGCG behaved as a mixed inhibitor, whereas 4',4''-di-O-methyl-EGCG exhibited competitive kinetics for the S-adenosylmethionine (SAM), and noncompetitive kinetics for the catechol binding site. These compounds may represent a new type of COMT inhibitor. In silico molecular-modeling studies using a homology model of human COMT were conducted to aid in the understanding the catalytic and inhibitory mechanisms. Either D-ring or B-ring of EGCG could be accommodated to the substrate binding pocket of human COMT. However, the close proximity (2.6 Å) of 4''-OH to the critical residue Lys144, the higher acidity of the hydroxyl groups of the D-ring, and the hydrophobic interactions between the D-ring and residues in the binding pocket greatly facilitated the interaction of the D-ring with the enzyme, and resulted in increased inhibitory potency. These results provide mechanistic insight into the inhibition of COMT by commonly consumed tea catechins. KW - comt AU - Chen, Dapeng AU - Wang, Ching AU - Lambert, Joshua AU - Ai, Ni AU - Welsh, William AU - Yang, Chung PY - 2005/05/15/ UR - http://dx.doi.org/10.1016/j.bcp.2005.01.024 ER -