Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1)

Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) is an oxygen-sensitive enzyme belonging to the family of prolyl hydroxylase domain proteins (PHDs) that hydroxylate specific proline residues on hypoxia-inducible factor alpha (HIF-α) subunits, primarily targeting HIF-1α[1][2][5]. This hydroxylation reaction marks HIF-α for recognition by the von Hippel-Lindau (VHL) ubiquitin ligase complex, leading to proteasomal degradation under normoxic (oxygen-rich) conditions. In hypoxia, PHD1 activity is reduced due to its dependence on oxygen as a co-substrate, enabling HIF-α accumulation, nuclear translocation, and activation of genes critical for the cellular response to low oxygen[1][4][7]. PHD1 is considered a druggable enzyme target in diseases like anemia of chronic kidney disease, inflammation, and certain cancers, where manipulating the HIF pathway may have therapeutic benefits[4][2][5]. Several small-molecule inhibitors of PHD enzymes have been developed and approved for clinical use, most targeting the broader PHD family rather than PHD1 specifically. Importantly, inhibition of PHD enzymes is associated with safety concerns due to their wide-ranging roles in gene expression, vascularization, and metabolism[4].

Other names

Prolyl hydroxylase domain-containing protein 1EGLN2 (Egl nine homolog 2)HPH3 (HIF-prolyl hydroxylase 3)HIF-P4H1

Inhibition of prolyl hydroxylase activity, resulting in stabilization of HIF-α, leading to increased expression of hypoxia-responsive genes (including erythropoietin and vascular endothelial growth factor)[4]. Competitive binding to the 2-oxoglutarate site or Fe(II) site, blocking the enzyme’s hydroxylase function[3][6].