The Effect of Antitumor Antibiotic Olivomycin A and Its New Semi-synthetic Derivative Olivamide on the Activity of Murine DNA Methyltransferase Dnmt3aстатья
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Аннотация:Olivomycin A is a highly active antitumor drug that belongs to the family of
aureolic acid antibiotics. The antitumor effect of olivomycin A is related to its ability to
bind to the DNA minor groove in GC-rich regions as Mg2+
-coordinated complexes.
Characterization of cellular targets of olivomycin A and its mechanism of action is
crucial for the successful application of this antibiotic in clinical practice and
development of semi-synthetic derivatives with improved pharmacological properties.
Previously, we have shown that minor groove ligands are able to disrupt the key
epigenetic process of DNA methylation. In this paper, we have studied the impact of
olivomycin A and its improved semi-synthetic analogue N,N-dimethylaminoethylamide
of 1-des-(2,3-dihydroxy-n-butyroyl)-1-carboxy-olivomycin A (olivamide) on the
functioning of de novo DNA methyltransferase (MTase) Dnmt3a (enzyme that carries
out methylation of cytosine residues in the DNA CG-sites in eukaryotic cells) using an
in vitro system consisting of the murine Dnmt3a catalytic domain and a 30-mer DNA
duplex containing four consecutive GC pairs. We have shown that olivomycin A and
olivamide inhibit Dnmt3a with IC50 of 6 ± 1 and 7.1 ± 0.7 M, respectively. Neither
olivomycin A nor olivamide interfered with the formation of the specific enzyme–
substrate complex; however, olivomycin A prevented formation of the covalent DNA–
Dnmt3a intermediate that is necessary for the methylation reaction to proceed. The
inhibitory effects of olivomycin A and olivamide can be explained by the disruption of
the enzyme catalytic loop movement through the DNA minor groove (the reaction stage
that precedes the covalent bond formation between DNA and the enzyme). The results
of this work indicate the epigenetic contribution to the antitumor effect of aureolic acid
group antibiotics.