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Vol 55(2021) N 2 p. 243-253; DOI 10.1134/S0026893321020035  I.V. Alekseeva1, A.S. Bakman1,2, D.A. Iakovlev1, N.A. Kuznetsov1*, O.S. Fedorova1** Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4 1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090 Russia2Department of Natural Sciences, Novosibirsk State University, Novosibirsk, 630090 Russia *nikita.kuznetsov@niboch.nsc.ru **fedorova@niboch.nsc.ru Received - 2020-10-12; Revised - 2020-10-12; Accepted - 2020-10-26 The human N-glycosylases SMUG1 and MBD4 catalyze the removal of uracil residues from DNA resulting from cytosine deamination or replication errors. For polymorphic variants of SMUG1 (G90C, P240H, N244S, N248Y) and the MBD4cat catalytic domain (S470L, G507S, R512W, H557D), the structures of enzyme-substrate complexes were obtained by molecular dynamic simulation. It was experimentally found that the SNP variants of SMUG1, N244S and N248Y, had increased catalytic activity compared to the wild-type enzyme, probably due to the acceleration of the dissociation of the enzyme-product complex and an increase in the enzyme turnover rate. All other SNP variants of SMUG1 (G90C, P240H) and MBD4cat, in which amino acid substitutions disrupted the substrate binding region and/or active site, had significantly lower catalytic activity than the wild-type enzymes. DNA repair, human uracil-DNA glycosylase, MBD4, SMUG1, polymorphic variant, active site, catalysis |
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