Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1

Tatyana A. Kurgina, Stanislav I. Shram, Mikhail M. Kutuzov, Tatyana V. Abramova, Tatyana A. Shcherbakova, Ekaterina A. Maltseva, Vladimir V. Poroikov, Olga I. Lavrik, Vytas K. Švedas, Dmitry K. Nilov

Research output: Contribution to journalArticlepeer-review

Abstract

Previously, we have found that a nucleic acid metabolite, 7-methylguanine (7mGua), produced in the body can have an inhibitory effect on the poly(ADP-ribose) polymerase 1 (PARP1) enzyme, an important pharmacological target in anticancer therapy. In this work, using an original method of analysis of PARP1 activity based on monitoring fluorescence anisotropy, we studied inhibitory properties of 7mGua and its metabolite, 8-hydroxy-7-methylguanine (8h7mGua). Both compounds inhibited PARP1 enzymatic activity in a dose-dependent manner, however, 8h7mGua was shown to be a stronger inhibitor. The IC50 values for 8h7mGua at different concentrations of the NAD+ substrate were found to be 4 times lower, on average, than those for 7mGua. The more efficient binding of 8h7mGua in the PARP1 active site is explained by the presence of an additional hydrogen bond with the Glu988 catalytic residue. Experimental and computational studies did not reveal the effect of 7mGua and 8h7mGua on the activity of other DNA repair enzymes, indicating selectivity of their inhibitory action.

Translated title of the contributionИнгибиторное действие 7-метилгуанина и его метаболита 8-гидрокси-7-метилгуанина на поли(ADP-рибозо)полимеразу 1 человека
Original languageEnglish
Pages (from-to)823-831
Number of pages9
JournalBiochemistry (Moscow)
Volume87
Issue number8
DOIs
Publication statusPublished - Aug 2022

Keywords

  • 7-methylguanine
  • 8-hydroxy-7-methylguanine
  • DNA repair
  • inhibitor
  • poly(ADP-ribose) polymerase

OECD FOS+WOS

  • 1.06 BIOLOGICAL SCIENCES
  • 1.06.CQ BIOCHEMISTRY & MOLECULAR BIOLOGY

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