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

Prolyl hydroxylase domain-containing proteins 1, 2, and 3 (PHD1, PHD2, PHD3) are iron and 2-oxoglutarate-dependent dioxygenases that catalyze the hydroxylation of specific proline residues on hypoxia-inducible factor α-subunits (HIF-α). This post-translational modification allows for the recognition and degradation of HIF-α via the proteasome under normoxic conditions, thus regulating the cellular hypoxic response[1][2][3][4][5]. Among them, PHD2 is considered the main oxygen sensor and regulator of HIF stability in most tissues[2][4]. Inhibition of these enzymes stabilizes HIF, mimicking hypoxia and permitting therapeutic applications such as treatment of renal anemia[5]. However, targeting PHDs carries risks related to HIF pathway activation, including the potential for tumor progression and vascular complications[5].

Other names

EGLN2HIF-prolyl hydroxylase 1EGLN1HIF-prolyl hydroxylase 2HPH2EGLN3HIF-prolyl hydroxylase 3SM-20

Inhibition of PHD enzymes prevents HIF-α hydroxylation, leading to HIF stabilization and increased transcription of HIF target genes, including erythropoietin Mimics hypoxic response, promoting erythropoiesis and adaptive responses to low oxygen