2-oxoglutarate-dependent prolyl and lysyl hydroxylases (2-OGDDs)

2-oxoglutarate-dependent prolyl and lysyl hydroxylases are a superfamily of enzymes that catalyze the hydroxylation of specific proline or lysine residues in proteins, utilizing 2-oxoglutarate (alpha-ketoglutarate) and molecular oxygen as co-substrates (PMID: 30612074). This class includes the Prolyl Hydroxylase Domain (PHD) enzymes, which act as cellular oxygen sensors by hydroxylating Hypoxia-Inducible Factor (HIF) for proteasomal degradation under normoxic conditions (UniProt: Q9GZT9). It also encompasses lysyl hydroxylases (PLODs), which are critical for the post-translational modification and cross-linking of collagen in the extracellular matrix (UniProt: Q02809). Therapeutically, PHD inhibitors like Roxadustat and Daprodustat have been developed to treat anemia associated with chronic kidney disease by stabilizing HIF and stimulating endogenous erythropoietin production (FDA: Jesduvroq label). Conversely, dysregulation of these enzymes is implicated in various pathologies, including cancer progression, where HIF stabilization promotes angiogenesis, and fibrotic diseases characterized by excessive collagen deposition (PMID: 33536613). These enzymes require iron (FeII) and ascorbate as essential cofactors for their catalytic activity. The inhibition of these enzymes provides a non-erythropoietin-stimulating agent (ESA) approach to managing anemia. Furthermore, research into PLOD inhibitors is ongoing for the treatment of fibrotic disorders and metastatic cancer.

Other names

2-oxoglutarate-dependent dioxygenasesalpha-ketoglutarate-dependent hydroxylasesProlyl hydroxylasesLysyl hydroxylasesHIF prolyl hydroxylasesProcollagen-lysine 5-dioxygenases

Competitive inhibition of the 2-oxoglutarate binding site, preventing the hydroxylation of target residues (e.g., HIF-alpha), which leads to protein stabilization and downstream gene activation (PMID: 30612074).