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

Iron(II) and 2-oxoglutarate-dependent dioxygenases (2-OGDDs) constitute a vast superfamily of enzymes that catalyze a diverse array of oxidative reactions, most notably the hydroxylation of protein residues, nucleic acids, and small molecules (Martinez & Hausinger, 2015, JBC). These enzymes are characterized by a conserved double-stranded beta-helix (DSBH) fold and require ferrous iron [Fe(II)] as a cofactor and 2-oxoglutarate (alpha-ketoglutarate) as a co-substrate (Markolovic et al., 2016, Biol Chem). They play pivotal roles in fundamental biological processes, including the cellular response to hypoxia via the Prolyl Hydroxylase Domain (PHD) enzymes, collagen biosynthesis, and the regulation of the epigenetic landscape through JmjC-domain histone demethylases and TET DNA hydroxylases (Islam et al., 2018, Essays Biochem). Dysregulation of 2-OGDD activity is implicated in various diseases; for instance, the accumulation of the oncometabolite (R)-2-hydroxyglutarate in IDH-mutant cancers competitively inhibits these enzymes, leading to hypermethylation and impaired differentiation (Losman & Kaelin, 2013, Genes Dev). In the context of chronic kidney disease, the failure of PHD enzymes to stabilize Hypoxia-Inducible Factor (HIF) contributes to the development of renal anemia (Maxwell & Eckardt, 2016, Nat Rev Nephrol). Therapeutically, 2-OGDDs are targeted by small-molecule inhibitors that typically compete with the 2-oxoglutarate binding site or chelate the active-site iron. Several PHD inhibitors, such as Roxadustat and Daprodustat, have been approved for clinical use to stimulate erythropoiesis by stabilizing HIF-2alpha. Ongoing research also explores the potential of JmjC-domain inhibitors as epigenetic therapies for various malignancies.

Other names

Fe(II)/alpha-ketoglutarate-dependent dioxygenases2-oxoglutarate-dependent dioxygenasesalpha-KG-dependent dioxygenases2OGDDs2-oxoglutarate-dependent hydroxylases

Competitive inhibition of the 2-oxoglutarate binding site or chelation of the active-site ferrous iron, leading to the stabilization of substrates (e.g., HIF-alpha) or prevention of epigenetic modifications.