Prolyl hydroxylase domain-containing protein (PHD) family (PHD)

The prolyl hydroxylase domain-containing protein (PHD) family, primarily consisting of PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3), functions as the central oxygen-sensing apparatus in human cells [1, 2, 3]. These enzymes are iron-dependent and 2-oxoglutarate-dependent dioxygenases that catalyze the hydroxylation of hypoxia-inducible factor (HIF) alpha subunits [4]. Under normal oxygen levels, this hydroxylation allows the von Hippel-Lindau (VHL) protein to recognize HIF-alpha for ubiquitination and subsequent proteasomal degradation [1, 4]. PHD2 is the dominant isoform responsible for regulating HIF-alpha stability under normoxic conditions [1]. When oxygen is scarce or the enzymes are inhibited, HIF-alpha stabilizes and translocates to the nucleus to activate genes involved in erythropoiesis, glycolysis, and angiogenesis [5]. Therapeutically, small-molecule inhibitors of the PHD family, known as HIF-PHIs, are used to treat anemia associated with chronic kidney disease by boosting endogenous erythropoietin production [6, 7]. Beyond anemia, the PHD family is investigated for its roles in myocardial ischemia, peripheral artery disease, and various cancers where oxygen signaling is dysregulated [4, 7]. However, long-term stabilization of HIF raises safety concerns regarding potential tumor growth promotion and cardiovascular complications such as thromboembolism [6, 7].

Other names

EGLN familyHIF prolyl hydroxylaseHPHEgg-laying defective nine proteinHypoxia-inducible factor prolyl hydroxylaseEGLN1EGLN2EGLN3

Inhibition of prolyl hydroxylase enzymes prevents the hydroxylation of hypoxia-inducible factor (HIF) alpha subunits, leading to their stabilization and translocation to the nucleus [4]. This induces the transcription of target genes such as erythropoietin (EPO) and iron metabolism regulators (e.g., ferroportin, transferrin), thereby stimulating red blood cell production and improving iron utilization [5, 7].