ALKBH5

ALKBH5 is an enzyme in humans encoded by the ALKBH5 gene and is a member of the AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases. It functions as an RNA demethylase that removes the methyl group from N6-methyladenosine (m6A) in RNA, thereby reversing a common epitranscriptomic mark and influencing RNA metabolism.

Mechanistically, ALKBH5 uses Fe2+ and α-ketoglutarate as cofactors to catalyze an oxidative demethylation reaction on m6A. The reaction involves hydroxylation of the methyl group, generating hm6A as an intermediate and ultimately yielding adenosine with release of formaldehyde, while the co-substrates are converted to succinate and CO2. The enzyme is predominantly localized to the nucleus, though it has also been detected in the cytoplasm under certain conditions, and it can associate with various RNA substrates depending on cellular context.

Biological roles of ALKBH5 arise from its ability to regulate m6A levels on target transcripts. By modulating mRNA stability, splicing, export, and translation, ALKBH5 influences processes such as embryonic development, germ cell differentiation, and the regulation of X-chromosome inactivation through demethylation of the XIST long noncoding RNA. Its activity also affects stem cell biology and responses to cellular stresses.

Expression and regulation of ALKBH5 are widespread, with notable enrichment in reproductive tissues and the brain. Its activity is influenced by cellular cues, including oxygen availability and hormonal signaling, and it interacts with the broader m6A regulatory network that includes writers and readers.

Clinical and research relevance of ALKBH5 has been explored in cancer and fertility contexts, where dysregulation of m6A editing can impact tumor biology and developmental processes.