Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2) (HIF-PH2)

Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), also known as PHD2 or EGLN1, is a key oxygen-sensing enzyme that regulates the stability of hypoxia-inducible factors (HIFs) [1, 4]. Under normal oxygen levels, HIF-PH2 hydroxylates specific proline residues on the HIF-alpha subunit, leading to its recognition by the von Hippel-Lindau (VHL) protein and subsequent proteasomal degradation [1, 3]. In conditions of hypoxia or through pharmacological inhibition, HIF-PH2 activity is reduced, allowing HIF-alpha to accumulate and translocate to the nucleus where it promotes the expression of genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF) [3, 4]. This pathway is therapeutically exploited to treat anemia in patients with chronic kidney disease (CKD) by stimulating endogenous erythropoietin production [2, 3]. Drugs targeting HIF-PH2, such as Roxadustat and Daprodustat, act as small-molecule inhibitors that mimic the hypoxic response [2]. While effective for anemia, the broad transcriptional influence of HIF stabilization necessitates careful monitoring for potential side effects like hypertension or the promotion of tumor angiogenesis [2, 3].

Other names

Egl nine homolog 1PHD2Prolyl hydroxylase domain-containing protein 2HPH-2HPH2EGLN1

Competitive inhibition of the 2-oxoglutarate binding site of HIF-PH2, which prevents the hydroxylation and subsequent degradation of HIF-alpha subunits, thereby increasing the transcription of erythropoietin and other hypoxia-responsive genes [2, 3].