Revealing the catalytic mechanism of the Fe(II)/2-oxoglutarate-dependent human epigenetic modifying enzyme ALKBH5.

ABSTRACT: ALKBH5 is one of only two known human non-heme Fe(II)/2-oxoglutarate-dependent oxygenases that catalyze the demethylation of N⁶-methyladenine (m⁶A) in single-stranded mRNA, underscoring its role in diverse cancers. Unlike its homolog, the fat mass and obesity-associated protein (FTO), which oxidizes m⁶A to a stable N⁶-hydroxymethyladenine (hm⁶A) intermediate, ALKBH5 demethylates m⁶A, yielding adenine and formaldehyde as products. Here, we integrate molecular dynamics simulations and quantum mechanics/molecular mechanics methods to elucidate ALKBH5's complete catalytic mechanism. Two post-hydroxylation pathways were evaluated: a proton transfer pathway and a Schiff base formation pathway, with the former emerging as the favor

SUBMITTER: Cherilakkudy FH 

PROVIDER: S-EPMC12439684 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature