Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies |
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Authors: | Chen Dapeng Wang Ching Y Lambert Joshua D Ai Ni Welsh William J Yang Chung S |
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Institution: | Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA. |
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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 (IC(50)=0.07 microM), 4'-O-methyl-EGCG (IC(50)=0.10 microM), 4',4'-di-O-methyl-EGCG (4',4'-DiMeEGCG) (IC(50)=0.15 microM), and (-)-epicatechin-3-gallate (ECG) (IC(50)=0.20 microM). 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 (2.6A) 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. |
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Keywords: | EGCG (-)-epigallocatechin-3-gallate ECG (-)-epicatechin-3-gallate EGC (-)-epigallocatechin EC (-)-epicatechin EGCG-7-Gluc (-)-EGCG-7-O-glucuronide (and similar abbreviations for other glucuronidates) 4′-MeEGC 4′-O-methyl-EGC 4″-MeEGCG 4″-O-methyl-EGCG 4′ 4″-DiMeEGCG 4’ 4″-di-O-methyl-EGCG 2-OH-E2 2-hydroxyestradiol 4-OH-E2 4-hydroxyestradiol COMT catechol-O-methyltransferase SAM S-adenosylmethionine SAH l-homocysteine" target="_blank">S-adenosyl-l-homocysteine L-DOPA 3 l-phenylalanine" target="_blank">4-dihydroxy-l-phenylalanine HPLC-ECD high-performance liquid chromatography-electrochemical detector |
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