Iron(II) and 2-oxoglutarate-dependent dioxygenases (2-OGDDs)

Iron(II) and 2-oxoglutarate-dependent dioxygenases (2-OGDDs) represent a vast superfamily of enzymes that utilize ferrous iron as a cofactor and 2-oxoglutarate (alpha-ketoglutarate) as a co-substrate to catalyze various oxidative reactions, most notably hydroxylation (Martinez and Hausinger, 2015; PMID: 26130111). In humans, this family includes over 60 members that regulate critical physiological processes such as the cellular response to low oxygen via HIF prolyl hydroxylases (PHDs) and the maintenance of the epigenome through TET DNA demethylases and JmjC histone demethylases (Markolovic et al., 2016; PMID: 27179578). Because of their central role in oxygen sensing and gene regulation, 2-OGDDs have become significant therapeutic targets. Specifically, inhibitors of HIF-PHDs have been developed and approved for treating anemia associated with chronic kidney disease by stimulating endogenous erythropoietin production. Beyond anemia, the superfamily is actively researched for its potential in oncology, where modulating the activity of epigenetic 2-OGDDs could reverse aberrant DNA or histone methylation patterns in cancer cells.

Other names

2-oxoglutarate-dependent oxygenasesAlpha-ketoglutarate-dependent hydroxylasesFe(II)/2OG dioxygenases2OG-dependent dioxygenasesNon-heme iron dioxygenases

Competitive inhibition of the 2-oxoglutarate binding site within the catalytic domain, preventing the hydroxylation of substrates such as Hypoxia-Inducible Factor (HIF) alpha subunits, thereby stabilizing HIF and activating erythropoiesis or modulating gene expression (Islam et al., 2018; PMID: 29441751).