Research output: Contribution to journal › Article › peer-review
Predictive Analysis and Validation of Critical Missense SNPs of the ABH2 Gene Using Structural Bioinformatics. / Davletgildeeva, Anastasiia T.; Tyugashev, Timofey E.; Sagalakova, Viktoriia V. et al.
In: International Journal of Molecular Sciences, Vol. 26, No. 23, 11593, 29.11.2025.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Predictive Analysis and Validation of Critical Missense SNPs of the ABH2 Gene Using Structural Bioinformatics
AU - Davletgildeeva, Anastasiia T.
AU - Tyugashev, Timofey E.
AU - Sagalakova, Viktoriia V.
AU - Zhao, Mingxing
AU - Kuznetsov, Nikita A.
N1 - This work was supported by the Russian Ministry of Science and Higher Education (project no. 125012300658-9).
PY - 2025/11/29
Y1 - 2025/11/29
N2 - Human DNA dioxygenase ABH2 is a key enzyme of the AlkB family of Fe(II)/α-ketoglutarate-dependent oxygenases, which is specialized in removing alkyl groups from damaged DNA bases in the cell nucleus. At the same time, the occurrence of single-nucleotide polymorphisms (SNPs) in the human ABH2 gene can lead to amino acid substitutions that, in turn, may disrupt the normal functioning of the ABH2 enzyme. Currently, databases contain information about more than 2500 nucleotide substitutions in the ABH2 gene. Using a comprehensive bioinformatics approach, in this review, we analyzed over 200 non-synonymous ABH2 SNPs with eleven prediction programs to identify variants capable of negatively affecting its enzymatic activity. The combination of various programs with different evaluation algorithms and scoring approaches allows us to more reliably identify potentially deleterious amino acid substitutions. Moreover, the differences between the programs used allowed for comparison of their tendency to predict amino acid substitutions as deleterious. Structural analysis of the ABH2-substrate complex showed that selected functionally significant SNPs often affect the organization of the active site, reduce the efficiency of substrate binding, and/or disrupt the coordination of Fe2+ and α-ketoglutarate cofactors, leading to changes in catalytic efficiency. The data obtained from the conducted analysis suggest that naturally occurring polymorphisms in the ABH2 gene found in the human population may reduce the repair efficiency of DNA dioxygenase ABH2 and, consequently, modulate susceptibility to oncogenesis and influence the effectiveness of antitumor therapy for carriers of these SNPs.
AB - Human DNA dioxygenase ABH2 is a key enzyme of the AlkB family of Fe(II)/α-ketoglutarate-dependent oxygenases, which is specialized in removing alkyl groups from damaged DNA bases in the cell nucleus. At the same time, the occurrence of single-nucleotide polymorphisms (SNPs) in the human ABH2 gene can lead to amino acid substitutions that, in turn, may disrupt the normal functioning of the ABH2 enzyme. Currently, databases contain information about more than 2500 nucleotide substitutions in the ABH2 gene. Using a comprehensive bioinformatics approach, in this review, we analyzed over 200 non-synonymous ABH2 SNPs with eleven prediction programs to identify variants capable of negatively affecting its enzymatic activity. The combination of various programs with different evaluation algorithms and scoring approaches allows us to more reliably identify potentially deleterious amino acid substitutions. Moreover, the differences between the programs used allowed for comparison of their tendency to predict amino acid substitutions as deleterious. Structural analysis of the ABH2-substrate complex showed that selected functionally significant SNPs often affect the organization of the active site, reduce the efficiency of substrate binding, and/or disrupt the coordination of Fe2+ and α-ketoglutarate cofactors, leading to changes in catalytic efficiency. The data obtained from the conducted analysis suggest that naturally occurring polymorphisms in the ABH2 gene found in the human population may reduce the repair efficiency of DNA dioxygenase ABH2 and, consequently, modulate susceptibility to oncogenesis and influence the effectiveness of antitumor therapy for carriers of these SNPs.
KW - DNA repair
KW - base methylation
KW - demethylation efficiency
KW - enzymatic activity
KW - human DNA dioxygenase ABH2
KW - single-nucleotide polymorphism
UR - https://www.scopus.com/pages/publications/105024643220
UR - https://www.mendeley.com/catalogue/412a1361-7ca4-3aa8-a2f5-b0aa997091a7/
U2 - 10.3390/ijms262311593
DO - 10.3390/ijms262311593
M3 - Article
C2 - 41373746
VL - 26
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 23
M1 - 11593
ER -
ID: 72828112