Demethylase

A demethylase is an enzyme that catalyzes the removal of methyl groups from substrates, most notably histones, DNA, RNA, and small molecules. By reversing methylation, demethylases can alter chromatin structure, gene expression, RNA metabolism, and other cellular processes, making them important mediators of development, differentiation, and homeostasis.

Two major classes act on histones. FAD-dependent amine oxidases, such as LSD1 (KDM1A) and related enzymes, remove mono- and di-methyl groups from certain lysine residues on histones but cannot demethylate trimethyl marks. JmjC domain-containing demethylases are Fe(II)/α-ketoglutarate-dependent dioxygenases that hydroxylate methyl groups and release formaldehyde, enabling removal of tri- and di-methyl marks from multiple lysine residues. These enzymes collectively regulate many histone methylation states associated with transcriptional activation or repression.

RNA demethylases include members of the AlkB family, notably FTO and ALKBH5, which erase methyl marks such as N6-methyladenosine (m6A) on RNA molecules. Demethylation of RNA influences RNA stability, splicing, and translation, impacting gene expression programs post-transcriptionally.

DNA demethylation in mammals primarily involves TET enzymes, which oxidize 5-methylcytosine to 5-hydroxymethylcytosine and further to 5-formyl- and 5-carboxylcytosine. These modified bases are processed by base excision repair pathways to restore unmethylated cytosine, thereby effecting DNA demethylation without direct removal of a methyl group in a single step.

Biological significance and medical relevance: demethylases regulate development, cell fate, and epigenetic memory. Their misregulation is linked to cancer, metabolic and neurological disorders, and other diseases. Inhibitors of demethylases, including LSD1 inhibitors, are explored as therapeutic agents.