2-oxoglutarate-dependent dioxygenase (2-OGDD) (2-OGDD)

2-oxoglutarate-dependent dioxygenases (2-OGDDs) are a major superfamily of enzymes that utilize 2-oxoglutarate and molecular oxygen to catalyze various oxidative modifications, most notably hydroxylation (Markolovic et al., 2016, Structure). These enzymes play pivotal roles in oxygen sensing through the Hypoxia-Inducible Factor (HIF) pathway and in epigenetic regulation via histone and DNA demethylation (Islam et al., 2018, Annual Review of Biochemistry). They are also essential for collagen biosynthesis and DNA repair mechanisms (Rose et al., 2011, Nature Reviews Drug Discovery). Dysregulation of 2-OGDDs is linked to several pathologies, including anemia, cancer, and metabolic disorders. Therapeutic strategies often involve small-molecule inhibitors that compete with the 2-oxoglutarate cosubstrate or target the catalytic iron center. Currently, several 2-OGDD inhibitors, such as Daprodustat and Roxadustat, are clinically approved for treating anemia in chronic kidney disease by stabilizing HIF and stimulating erythropoiesis (FDA, 2023). Ongoing research is also targeting JmjC-domain-containing demethylases within this family for potential oncology applications.

Other names

2-oxoglutarate-dependent oxygenase2OG-oxygenaseAlpha-ketoglutarate-dependent hydroxylaseFe(II)/2-oxoglutarate-dependent dioxygenase

Competitive inhibition of the 2-oxoglutarate binding site or chelation of the active site ferrous iron (Fe2+), thereby preventing the hydroxylation of substrates such as Hypoxia-Inducible Factor (HIF) (Rose et al., 2011).