Prolyl hydroxylase domain-containing protein 2 (PHD2) (PHD2)

Prolyl hydroxylase domain-containing protein 2 (PHD2), encoded by the EGLN1 gene, is the primary oxygen sensor in mammalian cells (UniProt: P59796). It belongs to a family of iron-dependent and 2-oxoglutarate-dependent dioxygenases that catalyze the post-translational hydroxylation of proline residues on the Hypoxia-Inducible Factor (HIF) alpha subunits (PubMed: 11292861). Under normoxic conditions, PHD2-mediated hydroxylation marks HIF-α for rapid degradation via the ubiquitin-proteasome pathway (PubMed: 11336703). However, under hypoxic conditions or in the presence of pharmacological inhibitors, PHD2 activity is reduced, leading to the stabilization and accumulation of HIF-α. This accumulation triggers a coordinated transcriptional response that includes the upregulation of erythropoietin (EPO), vascular endothelial growth factor (VEGF), and proteins involved in iron metabolism (PubMed: 22565144). Consequently, PHD2 has emerged as a major therapeutic target for treating anemia associated with chronic kidney disease (CKD), as its inhibition mimics the physiological response to hypoxia and stimulates endogenous erythropoiesis (StatPearls: NBK585047).

Other names

EGLN1Egl nine homolog 1HPH-2HIF-PH2Hypoxia-inducible factor prolyl hydroxylase 2

Inhibition of PHD2 prevents the prolyl hydroxylation of Hypoxia-Inducible Factor alpha (HIF-α) subunits, which normally targets them for von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation (PubMed: 11292861). Stabilization of HIF-α allows it to dimerize with HIF-β and activate the transcription of target genes, most notably erythropoietin (EPO), thereby stimulating red blood cell production (PubMed: 30635230).