Demethylasen

Demethylasen (English: demethylases) are enzymes that catalyze the removal of methyl groups from substrates. In biology, they regulate gene expression and chromatin state by removing methyl groups from histone proteins or through pathways that reverse DNA methylation. By altering methylation patterns, demethylasen influence development, differentiation and disease processes.

Histone demethylases act on methylated lysines on histone tails, thereby changing chromatin compaction and transcriptional activity. The two major classes in humans are the lysine-specific demethylases (KDMs) and the JmjC-domain-containing demethylases. The KDM1 family (LSD1/KDM1A and LSD2/KDM1B) are FAD-dependent amine oxidases that remove mono- and di-methyl marks but cannot demethylate tri-methyl lysines. JmjC demethylases (KDM2-7) require Fe(II) and α-ketoglutarate and can remove mono-, di- and tri-methyl lysines, with substrate specificities spanning K9, K27, K4, and others.

DNA demethylation involves TET enzymes that oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized forms, which are then processed by base excision repair to replace the modified cytosine with unmethylated cytosine. In addition, AlkB/ABH family demethylases repair methylated bases on DNA and RNA via oxidative demethylation, illustrating a broader class of alkylation demethylases.

Demethylasen use distinct cofactors: FAD for LSD1/2 and Fe(II)/α-KG for JmjC and AlkB family enzymes. Proper regulation of demethylasen is essential for development and cellular differentiation, and abnormal activity is linked to cancer, neurological disorders and metabolic diseases. Well-studied examples include KDM1A (LSD1), KDM4A, KDM5A, KDM6A, and others.