Catalytically Competent Conformation of the Active Site of Human 8-Oxoguanine-DNA Glycosylase Full article
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Biochemistry (Moscow)
ISSN: 0006-2979 , E-ISSN: 1608-3040 |
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| Output data | Year: 2020, Volume: 85, Number: 2, Pages: 192-204 Pages count : 13 DOI: 10.1134/s0006297920020066 | ||||
| Tags | DNA damage; DNA repair; 8-oxoguanine-DNA N-glycosylase; substrate specificity | ||||
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Abstract:
8-Oxoguanine-DNA N-glycosylase (OGG1) is a eukaryotic DNA repair enzyme responsible for the removal of 8-oxoguanine (oxoG), one of the most abundant oxidative DNA lesions. OGG1 catalyzes two successive reactions - N-gly-cosidic bond hydrolysis (glycosylase activity) and DNA strand cleavage on the 3’-side of the lesion by ß-elimination (lyase activity). The enzyme also exhibits lyase activity with substrates containing apurinic/apyrimidinic (AP) sites (deoxyribose moieties lacking the nucleobase). OGG1 is highly specific for the base opposite the lesion, efficiently excising oxoG and cleaving AP sites located opposite to C, but not opposite to A. The activity is also profoundly decreased by amino acid changes that sterically interfere with oxoG binding in the active site of the enzyme after the lesion is everted from the DNA duplex. Earlier, the molecular dynamics approach was used to study the conformational dynamics of such human OGG1 mutants in complexes with the oxoG:C-containing substrate DNA, and the population density of certain conformers of two OGG1 catalytic residues, Lys249 and Asp268, was suggested to determine the enzyme activity. Here, we report the study of molecular dynamics of human OGG1 bound to the oxoG:A-containing DNA and OGG1 mutants bound to the AP:C-con-taining DNA. We showed that the enzyme low activity is associated with a decrease in the populations of Lys249 and Asp268 properly configured for catalysis. The experimentally measured rate constants for the OGG1 mutants show a good agreement with the models. We conclude that the enzymatic activity of OGG1 is determined majorly by the population density of the catalytically competent conformations of the active site residues Lys249 and Asp268.
Cite:
Popov A.V.
, Yudkina A.V.
, Vorobjev Y.N.
, Zharkov D.O.
Catalytically Competent Conformation of the Active Site of Human 8-Oxoguanine-DNA Glycosylase
Biochemistry (Moscow). 2020. V.85. N2. P.192-204. DOI: 10.1134/s0006297920020066 WOS Scopus OpenAlex
Catalytically Competent Conformation of the Active Site of Human 8-Oxoguanine-DNA Glycosylase
Biochemistry (Moscow). 2020. V.85. N2. P.192-204. DOI: 10.1134/s0006297920020066 WOS Scopus OpenAlex
Dates:
| Submitted: | Apr 15, 2019 |
| Accepted: | Nov 9, 2019 |
| Published print: | Feb 1, 2020 |
| Published online: | Feb 17, 2020 |
Identifiers:
| Web of science: | WOS:000514515900006 |
| Scopus: | 2-s2.0-85079700375 |
| OpenAlex: | W3008685530 |