2-oxoglutarate-dependent dioxygenases (2-OGDD) (2-OGDD)

Prolyl and lysyl hydroxylases and other ascorbate-dependent enzymes, scientifically classified as 2-oxoglutarate-dependent dioxygenases (2-OGDDs), constitute a diverse superfamily of enzymes that catalyze the oxidation of various biological substrates using ferrous iron, 2-oxoglutarate, and molecular oxygen (Hausinger, 2004, PMID: 15230343). These enzymes are critical for the post-translational modification of collagen, where prolyl 4-hydroxylase and lysyl hydroxylase (PLOD) ensure the stability and cross-linking of the extracellular matrix; a deficiency in the essential cofactor ascorbate leads to the clinical manifestation of scurvy (Myllyharju, 2003, PMID: 12678434). Another therapeutically significant group within this family is the hypoxia-inducible factor prolyl hydroxylases (PHDs), which act as cellular oxygen sensors by targeting the HIF-1alpha subunit for proteasomal degradation under normal oxygen levels. The development of small-molecule inhibitors for PHDs, such as roxadustat and daprodustat, has provided a novel oral treatment for anemia in patients with chronic kidney disease by stabilizing HIF and stimulating endogenous erythropoietin production (Sanghani & Haase, 2019, PMID: 31138568). Furthermore, the 2-OGDD family includes epigenetic regulators like Jumonji-C domain-containing histone demethylases and TET DNA hydroxylases, which are currently being explored as potential targets in oncology and fibrotic diseases (Markolovic et al., 2016, PMID: 27131014). Safety concerns associated with targeting this class include the risk of thromboembolic events and the potential for promoting tumor angiogenesis due to sustained HIF activation.

Other names

2-oxoglutarate-dependent dioxygenasesFe(II)/2-oxoglutarate-dependent hydroxylasesalpha-ketoglutarate-dependent dioxygenasesAscorbate-dependent hydroxylasesProlyl and lysyl hydroxylases

Inhibition of prolyl hydroxylase domain (PHD) enzymes to stabilize hypoxia-inducible factor (HIF) and stimulate erythropoiesis; cofactor supplementation to support collagen synthesis.