Prolyl hydroxylase and related vitamin C-dependent hydroxylases (2-OGDD)

Prolyl hydroxylase and related vitamin C-dependent hydroxylases, primarily the 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily, are enzymes that catalyze the hydroxylation of various substrates using oxygen, 2-oxoglutarate, iron, and ascorbate as cofactors (Nature Reviews Drug Discovery, 2016). The most therapeutically significant members are the hypoxia-inducible factor prolyl hydroxylases (HIF-PHDs), which act as cellular oxygen sensors by targeting HIF-alpha subunits for proteasomal degradation under normoxic conditions (StatPearls, 2023). In the context of disease, these enzymes play a critical role in the regulation of erythropoiesis and iron metabolism, making them key targets for treating anemia associated with chronic kidney disease (NIH, 2021). Beyond oxygen sensing, other members of this class, such as collagen prolyl hydroxylases, are essential for the structural integrity of connective tissues, while Jumonji-C domain-containing demethylases regulate gene expression through histone modification (UniProt, 2024). Pharmacological inhibition of HIF-PHDs, using drugs like roxadustat and daprodustat, stabilizes HIF-alpha to stimulate endogenous erythropoietin production and improve iron utilization (FDA, 2023). However, therapeutic modulation of this broad enzyme class requires careful management due to potential off-target effects on angiogenesis and oncogenic signaling pathways (PubMed, 2022).

Other names

2-oxoglutarate-dependent dioxygenasesalpha-ketoglutarate-dependent hydroxylasesHIF prolyl hydroxylasesPHD enzymesEGLN familyProlyl 4-hydroxylase

Inhibition of the enzyme's catalytic site (competing with 2-oxoglutarate) prevents the hydroxylation of HIF-alpha, leading to its stabilization, translocation to the nucleus, and activation of genes for erythropoietin and iron transport (Nature Reviews Nephrology, 2016).