Journal
BIOCHEMISTRY-MOSCOW
Volume 75, Issue 9, Pages 1115-1125Publisher
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S000629791009004X
Keywords
pyrimidine-2(1H)-one; covalent intermediate; competitive inhibition; eukaryotic DNA methyltransferase
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Funding
- Russian Foundation for Basic Research (RFBR) [08-04-01096, 10-04-00809]
- CRDF-RFBR [RUB1-2919-MO-07/08-04-91109]
- Presidium of the Russian Academy of Sciences
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Here we studied the inhibition of the catalytic domain of Dnmt3a methyltransferase (Dnmt3a-CD) by DNA duplexes containing the mechanism-based inhibitor pyrimidine-2(1H)-one (P) instead of the target cytosine. It has been shown that conjugates of Dnmt3a-CD with P-DNA (DNA containing pyrimidine-2(1H)-one) are not stable to heating at 65A degrees C in 0.1% SDS. The yield of covalent intermediate increases in the presence of the regulatory factor Dnmt3L. The importance of the DNA minor groove for covalent intermediate formation during the methylation reaction catalyzed by Dnmt3a-CD has been revealed. P-DNA was shown to inhibit Dnmt3a-CD; the IC50 is 830 nM. The competitive mechanism of inhibition of Dnmt3a-CD by P-DNA has been elucidated. It is suggested that therapeutic effect of zebularine could be achieved by inhibition of not only Dnmt1 but also Dnmt3a.
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