2OGdependent

2-oxoglutarate-dependent dioxygenases (2OGDDs) are a large family of non-heme iron(II)-dependent enzymes that catalyze oxidation reactions using molecular oxygen and 2-oxoglutarate (2OG) as co-substrates. In typical reactions, 2OG is decarboxylated to succinate and CO2, while the resulting high-valent iron-oxo species hydroxylates or otherwise oxidizes the substrate. The family is widespread across bacteria, archaea, plants, and animals and participates in processes ranging from metabolism and collagen maturation to epigenetic regulation and DNA repair.

Mechanistically, Fe(II) in the active site is coordinated by a conserved 2-His-1-carboxylate facial triad. 2OG binds to iron, and molecular oxygen is activated to generate Fe(IV)=O. This species abstracts a hydrogen atom from the substrate and delivers a hydroxyl group, completing the oxidation and converting 2OG to succinate. Some 2OGDDs can catalyze alternative reactions such as demethylation, desaturation, or halogenation, depending on enzyme context and available co-substrates.

Biological roles include collagen biosynthesis, where prolyl 4-hydroxylases modify proline residues; regulation of the hypoxic response by HIF prolyl hydroxylases; epigenetic modulation through JmjC-domain histone demethylases and TET family DNA demethylases; and DNA/RNA repair and modification by AlkB family enzymes. In plants and microbes, 2OGDDs influence development, metabolism, and stress responses.

Physiological and pathological relevance arises from sensitivity to cellular levels of 2OG and to oncometabolites such as succinate, fumarate, and 2-hydroxyglutarate, which can inhibit 2OGDD activity and disrupt signaling and epigenetic regulation. Because of their central roles, 2OGDDs are targets in cancer therapy research and are explored for biocatalysis and biotechnological applications.