Ascorbate-dependent hydroxylases (2-OGDDs)

Ascorbate-dependent hydroxylases are a diverse group of enzymes, primarily belonging to the Fe(II)/2-oxoglutarate-dependent dioxygenase superfamily, that require Vitamin C (ascorbate) as a cofactor to maintain their catalytic activity (PMID: 30634371). These enzymes play critical roles in various physiological processes, including the post-translational modification of collagen, the regulation of the hypoxia-inducible factor (HIF) pathway, and the synthesis of neurotransmitters like norepinephrine (PMID: 29033370). In these reactions, ascorbate serves as a reducing agent to keep the enzyme's active-site iron in the ferrous (Fe2+) state, which is essential for the activation of molecular oxygen (PMID: 11207051). Deficiencies in ascorbate lead to impaired enzyme function, most notably resulting in scurvy due to defective collagen cross-linking (StatPearls: Vitamin C Deficiency). Beyond collagen, these enzymes are involved in epigenetic regulation through the demethylation of DNA and histones, influencing gene expression patterns (PMID: 24074455). Therapeutically, specific members of this family, such as HIF prolyl hydroxylases, are targeted by small-molecule inhibitors like roxadustat to treat conditions like anemia associated with chronic kidney disease by stabilizing HIF and stimulating erythropoietin production (PMID: 31340116). Other members, such as dopamine beta-hydroxylase, are targeted in the management of cardiovascular conditions and certain neurological disorders (PMID: 26160351). The broad distribution and varied functions of these enzymes make them significant subjects for drug development, though selectivity remains a major challenge.

Other names

2-oxoglutarate-dependent dioxygenasesFe(II)/2-oxoglutarate-dependent hydroxylasesVitamin C-dependent enzymesAscorbate-requiring hydroxylases2-OGDD superfamily

Ascorbate acts as a specific electron donor to maintain the prosthetic iron atom in the reduced ferrous (Fe2+) state, preventing its inactivation by oxidation to the ferric (Fe3+) state during the catalytic cycle (PMID: 11207051). Therapeutic inhibitors of these enzymes, such as HIF-PHD inhibitors, typically act as 2-oxoglutarate mimetics that compete for the cofactor binding site, thereby stabilizing HIF-alpha subunits and inducing erythropoiesis (PMID: 31340116).