Fe(II) and 2-oxoglutarate-dependent dioxygenase (2OGDD) (2OGDD)

Fe(II) and 2-oxoglutarate-dependent dioxygenases (2OGDDs) constitute a large and diverse superfamily of enzymes that catalyze a wide range of oxidative reactions, typically involving the hydroxylation of a substrate coupled with the oxidative decarboxylation of 2-oxoglutarate (α-ketoglutarate) to succinate and CO2 (Islam et al., 2018). These enzymes require ferrous iron [Fe(II)] as a cofactor and molecular oxygen as a co-substrate to function (Hausinger, 2004). In humans, the 2OGDD superfamily includes over 60 members that play critical roles in diverse biological processes such as collagen biosynthesis, hypoxia signaling via prolyl hydroxylases, fatty acid metabolism, and epigenetic regulation through histone and DNA/RNA demethylation (Markolovic et al., 2016). Due to their central roles in cellular homeostasis and gene expression, 2OGDDs are implicated in various pathologies, including cancer, anemia, and metabolic diseases (Rose et al., 2011). Therapeutic strategies often focus on small-molecule inhibitors that compete with the 2-oxoglutarate co-substrate or chelate the active-site iron. Several 2OGDD inhibitors, particularly those targeting hypoxia-inducible factor prolyl hydroxylases (HIF-PHDs), such as Roxadustat and Daprodustat, have been approved for the treatment of anemia associated with chronic kidney disease (Gupta & Wish, 2022).

Other names

α-ketoglutarate-dependent dioxygenase2-oxoglutarate-dependent oxygenaseα-KG-dependent hydroxylaseFe(II)/2-OG-dependent dioxygenase

Competitive inhibition of the 2-oxoglutarate (2OG) binding site or chelation of the catalytic Fe(II) ion within the active site.