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Comparative Analysis of the Activity of the Polymorphic Variants of Human Uracil-DNA-Glycosylases SMUG1 and MBD4

Authors
  • Alekseeva, I. V.1
  • Bakman, A. S.1, 2
  • Iakovlev, D. A.1
  • Kuznetsov, N. A.1
  • Fedorova, O. S.1
  • 1 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090, Russia , Novosibirsk (Russia)
  • 2 Department of Natural Sciences, Novosibirsk State University, Novosibirsk, 630090, Russia , Novosibirsk (Russia)
Type
Published Article
Journal
Molecular Biology
Publisher
Pleiades Publishing
Publication Date
Mar 01, 2021
Volume
55
Issue
2
Pages
241–251
Identifiers
DOI: 10.1134/S0026893321020035
Source
Springer Nature
Keywords
License
Yellow

Abstract

AbstractThe 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.

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