State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China).
Angew Chem Int Ed Engl. 2014 Apr 1;53(14):3659-62. doi: 10.1002/anie.201310050. Epub 2014 Mar 5.
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.
AlkB 家族去甲基酶 AlkB、FTO 和 ALKBH5 可识别差异甲基化的 RNA/DNA 底物，从而发挥其独特的生物学功能。在此，我们确定了对其底物特异性有贡献的关键活性位点残基。在去甲基酶之间交换这些活性位点残基会导致部分切换的去甲基化活性。来自 X 射线结构和酶动力学的综合证据表明，活性位点残基在底物识别中起作用。这种差异的活性位点序列可能有助于设计选择性抑制剂，以区分这些同源 RNA/DNA 去甲基酶。
