TY - JOUR

T1 - Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1

AU - Kurgina, Tatyana A.

AU - Shram, Stanislav I.

AU - Kutuzov, Mikhail M.

AU - Abramova, Tatyana V.

AU - Shcherbakova, Tatyana A.

AU - Maltseva, Ekaterina A.

AU - Poroikov, Vladimir V.

AU - Lavrik, Olga I.

AU - Švedas, Vytas K.

AU - Nilov, Dmitry K.

N1 - Funding Information: This study was financially supported by the Russian Science Foundation (project no. 19-74-10072) and by the Russian Foundation for Basic Research (isolation and purification of APE1 and Polβ enzymes, project no. 20-34-90095). Computer-aided prediction of biological activity was carried out in the framework of the Program for Basic Research in the Russian Federation for a long-term period (2021-2030) (project no. 122030100170-5). Publisher Copyright: © 2022, Pleiades Publishing, Ltd.

PY - 2022/8

Y1 - 2022/8

N2 - 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.

AB - 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.

KW - 7-methylguanine

KW - 8-hydroxy-7-methylguanine

KW - DNA repair

KW - inhibitor

KW - poly(ADP-ribose) polymerase

KW - NAD

KW - Humans

KW - Nucleic Acids

KW - Guanine/analogs & derivatives

UR - http://www.scopus.com/inward/record.url?scp=85135913019&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/ed5403f8-f352-33fa-8b31-c5b1e46de2fb/

U2 - 10.1134/S0006297922080132

DO - 10.1134/S0006297922080132

M3 - Article

C2 - 36171646

AN - SCOPUS:85135913019

VL - 87

SP - 823

EP - 831

JO - Biochemistry (Moscow)

JF - Biochemistry (Moscow)

SN - 0006-2979

IS - 8

ER -