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Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA (W.J.L., B.T.Z.); and J. L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (J.-Y.S.)
In the present investigation, we studied the modulating effects of several tea catechins and bioflavonoids on DNA methylation catalyzed by prokaryotic SssI DNA methyltransferase (DNMT) and human DNMT1. We found that each of the tea polyphenols [catechin, epicatechin, and (–)-epigallocatechin-3-O-gallate (EGCG)] and bioflavonoids (quercetin, fisetin, and myricetin) inhibited SssI DNMT- and DNMT1-mediated DNA methylation in a concentration-dependent manner. The IC50 values for catechin, epicatechin, and various flavonoids ranged from 1.0 to 8.4 µM, but EGCG was a more potent inhibitor, with IC50 values ranging from 0.21 to 0.47 µM. When epicatechin was used as a model inhibitor, kinetic analyses showed that this catechol-containing dietary polyphenol inhibited enzymatic DNA methylation in vitro largely by increasing the formation of S-adenosyl-L-homocysteine (a potent noncompetitive inhibitor of DNMTs) during the catechol-O-methyltransferase-mediated O-methylation of this dietary catechol. In comparison, the strong inhibitory effect of EGCG on DNMT-mediated DNA methylation was independent of its own methylation and was largely due to its direct inhibition of the DNMTs. This inhibition is strongly enhanced by Mg2+. Computational modeling studies showed that the gallic acid moiety of EGCG plays a crucial role in its high-affinity, direct inhibitory interaction with the catalytic site of the human DNMT1, and its binding with the enzyme is stabilized by Mg2+. The modeling data on the precise molecular mode of EGCG's inhibitory interaction with human DNMT1 agrees perfectly with our experimental finding.
Received for publication October 15, 2004.
Accepted for publication July 21, 2005.
Address correspondence to: Dr. Bao Ting Zhu, Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Room 617, Coker Life Sciences Building, 700 Sumter Street, Columbia, SC 29208. E-mail: btzhu{at}cop.sc.edu
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