Fe2+-dependent dioxygenase

Fe2+-dependent dioxygenase refers to a superfamily of enzymes that require ferrous iron (Fe2+) as a cofactor and molecular oxygen to catalyze a wide range of oxidative reactions including hydroxylation, demethylation, ring formation, desaturation, and more[1][2][3][4][5][6][7]. These enzymes almost always also require 2-oxoglutarate (α-ketoglutarate) as a co-substrate, resulting in the production of succinate and CO₂ with each catalytic turnover[1][5][7]. Structurally, they share a distinctive double-stranded β-helix fold and coordinate Fe2+ with a highly conserved 2-His-1-carboxylate facial triad motif[4][5][6]. Biologically, Fe2+-dependent dioxygenases perform central roles in many pathways: they regulate the hypoxia response by hydroxylating and promoting degradation of HIF-α, demethylate histones and DNA to control epigenetics, ensure proper collagen maturation (lysyl and prolyl hydroxylases), participate in repair of alkylated nucleic acids, and synthesize or modify a spectrum of metabolites and signaling molecules[2][3][5][7]. Their dysfunction or inhibition is implicated in a variety of diseases, including cancer (e.g., via epigenetic dysregulation), anemia, fibrosis, metabolic syndromes, and rare genetic disorders (e.g., Refsum disease)[1][2][3][5][7]. Multiple drugs, particularly HIF prolyl hydroxylase inhibitors, are either approved or in clinical trials for therapeutic modulation of this enzyme class, but safety concerns persist due to the broad physiological roles and potential for off-target effects[1][2][3][5].

Other names

2-oxoglutarate-dependent dioxygenase2OG-oxygenase2-OGDDFe(II)/2OG-dependent oxygenase2OGX2OG oxygenase

Inhibition of prolyl hydroxylases, stabilizing HIF-α for therapeutic effects in anemia; Inhibition or modulation of lysyl hydroxylases affecting collagen maturation; Inhibition of histone demethylases, influencing gene expression/epigenetics; Modulation of DNA repair enzymes, impacting DNA alkylation damage response.