Prolyl hydroxylase and other ascorbate-dependent oxidoreductases (PHD)

Prolyl hydroxylases and other ascorbate-dependent oxidoreductases, primarily the 2-oxoglutarate-dependent dioxygenases, are a family of enzymes that require oxygen, iron (Fe2+), and ascorbate for their catalytic activity (IUPHAR/BPS Guide to Pharmacology). The most clinically significant members are the Hypoxia-inducible factor prolyl hydroxylases (HIF-PHDs, including EGLN1, EGLN2, and EGLN3), which act as cellular oxygen sensors by regulating the stability of HIF-alpha subunits (UniProt P59758). Under normal oxygen conditions, these enzymes hydroxylate specific proline residues on HIF-alpha, marking it for degradation; however, under hypoxia or pharmacological inhibition, HIF-alpha is stabilized and triggers the expression of genes like erythropoietin (EPO) to stimulate red blood cell production (PubMed PMID: 32853546). Other enzymes in this class, such as collagen prolyl 4-hydroxylase, are essential for the post-translational modification and structural integrity of collagen (PubMed PMID: 11134022). Therapeutic targeting of HIF-PHDs with oral inhibitors like Roxadustat and Daprodustat has emerged as a key strategy for treating anemia in patients with chronic kidney disease (FDA Label: Jesduvroq, 2023). Despite their efficacy, safety concerns include an increased risk of cardiovascular events and the theoretical potential for promoting tumor growth due to sustained HIF stabilization (PubMed PMID: 31112384).

Other names

HIF prolyl hydroxylasePHDEGLN family2-oxoglutarate-dependent dioxygenaseCollagen prolyl 4-hydroxylase2-OG dioxygenase

Inhibition of HIF prolyl hydroxylase enzymes (PHD1, PHD2, PHD3) prevents the prolyl hydroxylation of HIF-alpha subunits, thereby inhibiting their recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and subsequent proteasomal degradation. This leads to the stabilization and nuclear translocation of HIF-alpha, where it dimerizes with HIF-beta to promote the transcription of target genes, most notably erythropoietin (EPO), which stimulates erythropoiesis (PubMed PMID: 32853546; IUPHAR/BPS).