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Biochemistry (Moscow)

, Volume 84, Issue 1, pp 62–70 | Cite as

The Effect of Antitumor Antibiotic Olivomycin A and Its New Semi-synthetic Derivative Olivamide on the Activity of Murine DNA Methyltransferase Dnmt3a

  • A. V. SergeevEmail author
  • A. N. Tevyashova
  • A. P. Vorobyov
  • E. S. Gromova
Article
  • 2 Downloads

Abstract

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,Ndimethylaminoethylamide of 1′-des-(2,3-dihydroxy-n-butyroyl)-1′-carboxy-olivomycin A (olivamide) on the functioning of de novo DNA methyltransferase 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 μM, 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.

Keywords

DNA methylation olivomycin A olivamide minor groove ligands DNA methyltransferase Dnmt3a inhibition of methylation 

Abbreviation

AA

aureolic acid

AdoHcy

S-adenosyl-L-homocysteine

AdoMet

S-adenosyl-L-methionine

MTase

DNA methyltransferase

P

fluorescence polarization

Z

pyrimidin-2-one

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Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • A. V. Sergeev
    • 1
    Email author
  • A. N. Tevyashova
    • 2
    • 3
  • A. P. Vorobyov
    • 1
  • E. S. Gromova
    • 1
  1. 1.Faculty of ChemistryLomonosov Moscow State UniversityMoscowRussia
  2. 2.Gause Institute of New AntibioticsMoscowRussia
  3. 3.D. Mendeleev University of Chemical Technology of RussiaMoscowRussia

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