2-oxoglutarate-dependent dioxygenase (2OGDD)

2-oxoglutarate-dependent dioxygenases (2OGDDs) constitute a large and diverse superfamily of enzymes that catalyze a wide range of oxidative reactions, including hydroxylations, desaturations, and ring closures. These enzymes are characterized by their requirement for ferrous iron [Fe(II)] as a cofactor and 2-oxoglutarate (2OG) as a co-substrate, with ascorbate (Vitamin C) typically serving as a necessary reducing agent to maintain the iron in its active state (Loenarz & Schofield, 2011). They play pivotal roles in fundamental biological processes such as the cellular response to hypoxia via prolyl hydroxylases (PHDs), collagen stabilization through prolyl and lysyl hydroxylases, and epigenetic regulation via histone demethylases (KDMs) and TET DNA hydroxylases (Rose et al., 2011). In clinical medicine, 2OGDDs are significant therapeutic targets; for instance, PHD inhibitors like Roxadustat are used to treat anemia by stabilizing hypoxia-inducible factors (HIFs) to stimulate erythropoietin production (FDA, 2023). Furthermore, the dysregulation of 2OGDDs is implicated in various cancers and fibrotic diseases, making them focal points for the development of novel small-molecule inhibitors aimed at modulating epigenetic marks or metabolic pathways (Gupta & Yeh, 2017). Despite their therapeutic potential, the high structural conservation of the 2OG-binding pocket across the superfamily presents a significant challenge for developing highly selective inhibitors, raising concerns about off-target effects and systemic toxicity (Markolovic et al., 2016).

Other names

α-ketoglutarate-dependent hydroxylaseFe(II)/2-oxoglutarate-dependent dioxygenase2-oxoglutarate-dependent oxygenase2-oxoglutarate-dependent dioxygenase superfamilyAscorbate-dependent 2-oxoglutarate-dependent dioxygenase

Competitive inhibition of the 2-oxoglutarate binding site or chelation of the active site ferrous iron (Fe2+), thereby preventing the oxidative decarboxylation of 2-oxoglutarate and subsequent substrate hydroxylation (Rose et al., 2011).