Ascorbate-dependent hydroxylases and dioxygenases (2-OGDDs)

Ascorbate-dependent hydroxylases and dioxygenases are a diverse group of enzymes that utilize ascorbic acid (Vitamin C) as a crucial cofactor or reducing agent to maintain their metal centers in an active state (Kuiper & Vissers, 2014). This group primarily includes the iron-containing 2-oxoglutarate-dependent dioxygenases (2-OGDDs), such as prolyl hydroxylases (PHDs) and lysyl hydroxylases, as well as copper-dependent monooxygenases like dopamine beta-hydroxylase (DBH) (Prigge et al., 1997; Monfort & Wutz, 2013). These enzymes are involved in essential biological processes, including the post-translational modification of collagen, the regulation of the hypoxia-inducible factor (HIF) pathway, the synthesis of catecholamines, and the epigenetic modification of DNA and histones (Gorres & Raines, 2010; Haase, 2017). Dysregulation of these enzymes is associated with a variety of conditions, including anemia, scurvy, cardiovascular diseases, and cancer (Kuiper & Vissers, 2014). Pharmacological modulation of this class is a significant area of drug development, most notably with the approval of PHD inhibitors like roxadustat and daprodustat for treating anemia in chronic kidney disease, which work by stabilizing HIF to stimulate endogenous erythropoietin production (Haase, 2017; Markolovic et al., 2015).

Other names

Vitamin C-dependent hydroxylases2-oxoglutarate-dependent dioxygenasesFe(II)/2-oxoglutarate-dependent oxygenasesCopper-dependent monooxygenasesAlpha-ketoglutarate-dependent hydroxylases

These enzymes catalyze the hydroxylation or oxygenation of substrates using molecular oxygen and a metal cofactor (Fe or Cu). Ascorbate (Vitamin C) acts as a specific electron donor to maintain the metal center in its active reduced state (e.g., Fe2+ or Cu+), preventing the accumulation of inactive oxidized forms (Kuiper & Vissers, 2014). Therapeutic inhibitors, such as PHD inhibitors, typically act as 2-oxoglutarate mimetics that competitively bind to the active site, thereby stabilizing hypoxia-inducible factors (HIF) and promoting erythropoiesis (Haase, 2017).