期刊
BIOCHEMICAL PHARMACOLOGY
卷 69, 期 10, 页码 1523-1531出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2005.01.024
关键词
catechol-O-methyltransferase; tea catechins; epigallocatechin-3-gailate; catecholestrogens; methylation; molecular modeling
资金
- NCI NIH HHS [CA88691] Funding Source: Medline
(-)-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 angstrom) of 4-OH to the critical residue Lys 144, 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. (c) 2005 Elsevier Inc. All rights reserved.
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