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Switching Demethylation Activities between AlkB Family RNA/DNA Demethylases through Exchange of Active‐Site Residues
Author(s) -
Zhu Chenxu,
Yi Chengqi
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201310050
Subject(s) - alkb , active site , dna demethylation , dna , demethylation , biology , rna , biochemistry , binding site , enzyme , genetics , dna repair , dna methylation , gene , gene expression
The AlkB family demethylases AlkB, FTO, and ALKBH5 recognize differentially methylated RNA/DNA substrates, which results in their distinct biological roles. Here we identify key active‐site residues that contribute to their substrate specificity. Swapping such active‐site residues between the demethylases leads to partially switched demethylation activities. Combined evidence from X‐ray structures and enzyme kinetics suggests a role of the active‐site residues in substrate recognition. Such a divergent active‐site sequence may aid the design of selective inhibitors that can discriminate these homologue RNA/DNA demethylases.