کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9001667 | 1118544 | 2005 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: Structure-activity relationship and molecular-modeling studies
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کلمات کلیدی
COMT2-OH-E2S-adenosyl-l-homocysteineHPLC–ECDSAH(–)-epigallocatechin-3-gallate(–)-epicatechinEpigallocatechin-3-gallateEGCSAMEGCGCatechol-O-methyltransferase4-OH-E22-hydroxyestradiol - 2-هیدروکسی استرادیول3,4-dihydroxy-l-phenylalanine - 3،4-دی هیدروکسیل-فنیل آلانین4-Hydroxyestradiol - 4-هیدروکسی استرادیولl-DOPA - L-DOPAS-adenosylmethionine - اس-ادنوزیل متیونینECG - الکتروکاردیوگرام یا نوار قلبMethylation - متیلاسیونMolecular modeling - مدل سازی مولکولیCatecholestrogens - کاتهولستروژنهاTea catechins - کاکتچین چای
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
(-)-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 μM), 4â³-O-methyl-EGCG (IC50 = 0.10 μM), 4â²,4â³-di-O-methyl-EGCG (4â²,4â³-DiMeEGCG) (IC50 = 0.15 μM), and (-)-epicatechin-3-gallate (ECG) (IC50 = 0.20 μM). 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 4â²,4â³-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 Ã
) of 4â³-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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 69, Issue 10, 15 May 2005, Pages 1523-1531
Journal: Biochemical Pharmacology - Volume 69, Issue 10, 15 May 2005, Pages 1523-1531
نویسندگان
Dapeng Chen, Ching Y. Wang, Joshua D. Lambert, Ni Ai, William J. Welsh, Chung S. Yang,