ALKBH

ALKBH refers to AlkB homologs, a group of non-heme iron(II) and α-ketoglutarate–dependent dioxygenases found across bacteria, archaea, and eukaryotes. They catalyze oxidative demethylation of alkylated nucleic acids, protecting genomes from alkylation damage and, in some lineages, regulating RNA modifications.

In bacteria, the AlkB protein repairs alkylated bases such as 1-methyladenine and 3-methylcytosine in DNA and RNA, helping cells recover from exposure to alkylating agents. In humans, eight members have been described: ALKBH1-8, showing a range of substrate specificities and cellular roles. ALKBH2 and ALKBH3 are primarily involved in repair of alkylated DNA and RNA bases. ALKBH5 and FTO act as RNA demethylases, removing N6-methyladenosine (m6A) marks and influencing RNA metabolism and gene expression. ALKBH8 participates in tRNA modification, while other family members (such as ALKBH1, ALKBH4-7) have more diverse or less well characterized roles in nucleic acid metabolism and regulation of transcription.

Mechanistically, all ALKBH enzymes require Fe2+ and α-ketoglutarate as cofactors. They catalyze oxidative demethylation by hydroxylating the methyl group on the damaged base, forming a unstable hydroxymethyl intermediate that decomposes to restore the unmodified base, with formaldehyde or other byproducts released as part of the reaction.

Biological significance encompasses genome stability, RNA epigenetics, development, and cellular stress responses. Dysregulation of ALKBH activity has been implicated in various diseases, including cancer and metabolic disorders, with FTO and ALKBH5 being among the most studied for their roles in m6A RNA demethylation. Further research continues to define the precise functions of the less characterized ALKBH members.