Prolyl hydroxylase domain-containing protein 1, Prolyl hydroxylase domain-containing protein 2, Prolyl hydroxylase domain-containing protein 3 (PHD1, PHD2, PHD3)

Prolyl hydroxylase domain-containing proteins 1, 2, and 3 (PHD1, PHD2, PHD3) are non-heme, Fe^2+- and α-ketoglutarate-dependent dioxygenase enzymes that function as cellular oxygen sensors. They catalyze the hydroxylation of conserved proline residues within the oxygen-dependent degradation domain of hypoxia-inducible factor alpha subunits (HIF-α), marking these for recognition by the von Hippel-Lindau (pVHL) protein and subsequent ubiquitin-mediated proteasomal degradation under normoxic conditions. Under hypoxic conditions, PHD activity is inhibited, leading to HIF-α stabilization, nuclear translocation, and induction of genes involved in erythropoiesis, angiogenesis, glycolysis, and cellular adaptation to low oxygen environments. PHD2 is the dominant isoform in most tissues for HIF regulation, but all isoforms have both overlapping and specialized roles, and they are mechanistically central to the therapeutic manipulation of hypoxia pathways, such as in the treatment of anemia and ischemic disease.

Other names

PHD1EGLN2PHD2EGLN1HIF-PH2Egl nine homolog 1PHD3EGLN3SM-20HIF prolyl-hydroxylase

Inhibition of PHDs stabilizes HIF-α by preventing its prolyl hydroxylation and subsequent degradation, leading to activation of hypoxia-responsive genes.