Alpha-ketoglutarate-dependent dioxygenase (2-OGDD)

Alpha-ketoglutarate-dependent dioxygenases (2-OGDDs) are a vast superfamily of enzymes that catalyze oxidative reactions using alpha-ketoglutarate (alpha-KG) and molecular oxygen as co-substrates, with ferrous iron [Fe(II)] as a mandatory cofactor (Hausinger, 2004, PMID: 15585535). In humans, this family includes more than 60 members that regulate essential physiological processes such as the cellular response to hypoxia via prolyl hydroxylase domain (PHD) enzymes, epigenetic modifications through JmjC-domain-containing histone demethylases, and the structural integrity of the extracellular matrix via collagen prolyl hydroxylases (Markolovic et al., 2016, PMID: 26797129). Dysregulation of these enzymes is implicated in various pathologies, including chronic kidney disease-associated anemia, where PHD activity prevents the stabilization of hypoxia-inducible factors (HIF), and various cancers where altered alpha-KG levels or enzyme mutations disrupt normal epigenetic signaling (Islam et al., 2018, PMID: 29702044). Pharmacological targeting of 2-OGDDs primarily involves small molecules that act as alpha-KG mimetics or iron chelators to inhibit enzyme activity. Clinically approved drugs like Roxadustat and Daprodustat target PHD enzymes to treat anemia by inducing endogenous erythropoietin production (FDA, 2023). However, the high structural homology within the catalytic domains of this superfamily poses significant challenges for achieving the isoform selectivity required to avoid off-target toxicities (Rose et al., 2011, PMID: 21473587).

Other names

2-oxoglutarate-dependent dioxygenasealpha-KG-dependent hydroxylaseFe(II)/2-oxoglutarate-dependent oxygenaseAlpha-ketoglutarate-dependent hydroxylase

Competitive inhibition of the alpha-ketoglutarate binding site and chelation of the catalytic ferrous iron [Fe(II)] within the enzyme active site (Markolovic et al., 2016, PMID: 26797129).