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

Prolyl hydroxylase domain-containing proteins (PHD1, PHD2, PHD3) are evolutionary conserved enzymes that act as cellular oxygen sensors. They do so by catalyzing the oxygen- and iron-dependent hydroxylation of specific proline residues in the alpha subunits of hypoxia-inducible factors (HIF1α, HIF2α), marking them for proteasomal degradation under normoxic conditions. Each isoform has a non-redundant role and tissue-specific expression: PHD2 is the most ubiquitously expressed and functionally important, while PHD1 and PHD3 are more restricted. Mutations or dysregulation of these proteins is linked to cancer progression, erythrocytosis, and other hypoxia-related disorders. Targeting these enzymes with small molecule inhibitors represents an established therapeutic strategy for anemia and is under active investigation for other hypoxia-associated diseases.

Other names

EGLN1 (PHD2)EGLN2 (PHD1)EGLN3 (PHD3)HIF prolyl hydroxylaseHIF-PHD

Inhibition of prolyl hydroxylase activity stabilizes HIF-α subunits, activates HIF pathway, and upregulates adaptive genes, including erythropoietin