Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1
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...
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| Veröffentlicht in: | Biochemistry (Moscow) 2022-08, Vol.87 (8), p.823-831 |
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| creator | Kurgina, Tatyana A. Shram, Stanislav I. Kutuzov, Mikhail M. Abramova, Tatyana V. Shcherbakova, Tatyana A. Maltseva, Ekaterina A. Poroikov, Vladimir V. Lavrik, Olga I. Švedas, Vytas K. Nilov, Dmitry K. |
| description | 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 IC
50
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. |
| doi_str_mv | 10.1134/S0006297922080132 |
| format | Article |
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50
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.</description><identifier>ISSN: 0006-2979</identifier><identifier>EISSN: 1608-3040</identifier><identifier>DOI: 10.1134/S0006297922080132</identifier><language>eng</language><publisher>Moscow: Pleiades Publishing</publisher><subject>Adenosine diphosphate ; Analysis ; Anisotropy ; Biochemistry ; Biology ; Biomedical and Life Sciences ; Biomedicine ; Bioorganic Chemistry ; Cancer ; Computer applications ; DNA polymerase ; DNA repair ; Enzymatic activity ; Enzymes ; Fluorescence ; Gene expression ; Hydrogen bonds ; Internet resources ; Life Sciences ; Metabolites ; Methylguanine ; Microbiology ; Monosaccharides ; Nucleic acids ; Poly(ADP-ribose) ; Poly(ADP-ribose) polymerase ; Ribose ; Selectivity ; Substrates ; Sugars ; Transfer RNA</subject><ispartof>Biochemistry (Moscow), 2022-08, Vol.87 (8), p.823-831</ispartof><rights>Pleiades Publishing, Ltd. 2022</rights><rights>COPYRIGHT 2022 Springer</rights><rights>Pleiades Publishing, Ltd. 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-d65813837385d3294420768f4cab43eeebbe21dfabe0ca0c0fed941cedce8a893</citedby><cites>FETCH-LOGICAL-c416t-d65813837385d3294420768f4cab43eeebbe21dfabe0ca0c0fed941cedce8a893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1134/S0006297922080132$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1134/S0006297922080132$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids></links><search><creatorcontrib>Kurgina, Tatyana A.</creatorcontrib><creatorcontrib>Shram, Stanislav I.</creatorcontrib><creatorcontrib>Kutuzov, Mikhail M.</creatorcontrib><creatorcontrib>Abramova, Tatyana V.</creatorcontrib><creatorcontrib>Shcherbakova, Tatyana A.</creatorcontrib><creatorcontrib>Maltseva, Ekaterina A.</creatorcontrib><creatorcontrib>Poroikov, Vladimir V.</creatorcontrib><creatorcontrib>Lavrik, Olga I.</creatorcontrib><creatorcontrib>Švedas, Vytas K.</creatorcontrib><creatorcontrib>Nilov, Dmitry K.</creatorcontrib><title>Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1</title><title>Biochemistry (Moscow)</title><addtitle>Biochemistry Moscow</addtitle><description>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 IC
50
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.</description><subject>Adenosine diphosphate</subject><subject>Analysis</subject><subject>Anisotropy</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bioorganic Chemistry</subject><subject>Cancer</subject><subject>Computer applications</subject><subject>DNA polymerase</subject><subject>DNA repair</subject><subject>Enzymatic activity</subject><subject>Enzymes</subject><subject>Fluorescence</subject><subject>Gene expression</subject><subject>Hydrogen bonds</subject><subject>Internet resources</subject><subject>Life Sciences</subject><subject>Metabolites</subject><subject>Methylguanine</subject><subject>Microbiology</subject><subject>Monosaccharides</subject><subject>Nucleic acids</subject><subject>Poly(ADP-ribose)</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Ribose</subject><subject>Selectivity</subject><subject>Substrates</subject><subject>Sugars</subject><subject>Transfer 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8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1</title><author>Kurgina, Tatyana A. ; Shram, Stanislav I. ; Kutuzov, Mikhail M. ; Abramova, Tatyana V. ; Shcherbakova, Tatyana A. ; Maltseva, Ekaterina A. ; Poroikov, Vladimir V. ; Lavrik, Olga I. ; Švedas, Vytas K. ; Nilov, Dmitry K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-d65813837385d3294420768f4cab43eeebbe21dfabe0ca0c0fed941cedce8a893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adenosine diphosphate</topic><topic>Analysis</topic><topic>Anisotropy</topic><topic>Biochemistry</topic><topic>Biology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bioorganic Chemistry</topic><topic>Cancer</topic><topic>Computer applications</topic><topic>DNA polymerase</topic><topic>DNA repair</topic><topic>Enzymatic 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V.</au><au>Lavrik, Olga I.</au><au>Švedas, Vytas K.</au><au>Nilov, Dmitry K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1</atitle><jtitle>Biochemistry (Moscow)</jtitle><stitle>Biochemistry Moscow</stitle><date>2022-08-01</date><risdate>2022</risdate><volume>87</volume><issue>8</issue><spage>823</spage><epage>831</epage><pages>823-831</pages><issn>0006-2979</issn><eissn>1608-3040</eissn><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 IC
50
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.</abstract><cop>Moscow</cop><pub>Pleiades Publishing</pub><doi>10.1134/S0006297922080132</doi><tpages>9</tpages></addata></record> |
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| subjects | Adenosine diphosphate Analysis Anisotropy Biochemistry Biology Biomedical and Life Sciences Biomedicine Bioorganic Chemistry Cancer Computer applications DNA polymerase DNA repair Enzymatic activity Enzymes Fluorescence Gene expression Hydrogen bonds Internet resources Life Sciences Metabolites Methylguanine Microbiology Monosaccharides Nucleic acids Poly(ADP-ribose) Poly(ADP-ribose) polymerase Ribose Selectivity Substrates Sugars Transfer RNA |
| title | Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1 |
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