Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, OX1 3TA, United Kingdom.
Chemistry - School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne, NE1 7RU, United Kingdom.
Commun Biol. 2024 Nov 27;7(1):1583. doi: 10.1038/s42003-024-07183-5.
2-Oxoglutarate (2OG) dependent N-methyl lysine demethylases (JmjC-KDMs) regulate eukaryotic transcription. We report studies showing that isolated forms of all human KDM4 and KDM5 JmjC enzymes catalyse demethylation of N-methylated Arg-3 of histone H2a. Unexpectedly, the results reveal that KDM4E and, less efficiently, KDM4D catalyse C-4 hydroxylation of Arg-20 of H2a on peptides, recombinant H2a, and calf histone extracts, including when the Arg-20 guanidino group is N-methylated. Combined with previous observations, our biochemical results highlight the importance of sequence context in determining the relative efficiencies of lysine and arginine demethylation reactions catalysed by KDM4s and KDM5s. At least in some cases changes in sequence can also enable a different JmjC reaction mode, such as C-4 arginine hydroxylation instead of demethylation. Further work is thus required to define the full scope of JmjC catalysed reactions in cells.
2-氧戊二酸（2OG）依赖性 N-甲基赖氨酸去甲基酶（JmjC-KDMs）调节真核转录。我们报告的研究表明，所有人类 KDM4 和 KDM5 JmjC 酶的分离形式都能催化组蛋白 H2a 的 N-甲基精氨酸 3 的去甲基化。出乎意料的是，结果表明 KDM4E 和效率较低的 KDM4D 能在肽、重组 H2a 和小牛组蛋白提取物上催化 H2a 的精氨酸 20 的 C-4 羟化，包括当精氨酸 20 的胍基被 N-甲基化时。结合以前的观察结果，我们的生化结果强调了序列背景在决定 KDM4 和 KDM5 催化的赖氨酸和精氨酸去甲基化反应相对效率中的重要性。至少在某些情况下，序列的变化也可以使不同的 JmjC 反应模式成为可能，例如 C-4 精氨酸羟化而不是去甲基化。因此，需要进一步的工作来确定 JmjC 催化的细胞内反应的全部范围。
