An α-ketoglutarate conformational switch controls iron accessibility, activation, and substrate selection of the human FTO protein.

ABSTRACT: The fat mass and obesity-associated fatso (FTO) protein is a member of the Alkb family of dioxygenases and catalyzes oxidative demethylation of N⁶-methyladenosine (m⁶A), N¹-methyladenosine (m¹A), 3-methylthymine (m³T), and 3-methyluracil (m³U) in single-stranded nucleic acids. It is well established that the catalytic activity of FTO proceeds via two coupled reactions. The first reaction involves decarboxylation of alpha-ketoglutarate (αKG) and formation of an oxyferryl species. In the second reaction, the oxyferryl intermediate oxidizes the methylated nucleic acid to reestablish Fe(II) and the canonical base. However, it remains unclear how binding of the nucleic acid activates the αKG decarboxylation reaction and why FTO d

SUBMITTER: Burns D 

PROVIDER: S-EPMC11194561 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature