Hypoxia-inducible factor prolyl hydroxylase 3 (PHD3) (PHD3)

Hypoxia-inducible factor prolyl hydroxylase 3 (PHD3), also known as EGLN3, is a key oxygen-sensing enzyme belonging to the 2-oxoglutarate-dependent dioxygenase family [3, 7]. It regulates the cellular response to oxygen levels by catalyzing the post-translational 4-hydroxylation of specific proline residues on the alpha subunit of hypoxia-inducible factor (HIF), showing a particular preference for the HIF-2α isoform [1, 5]. Under normal oxygen conditions, this modification targets HIF-α for polyubiquitination by the von Hippel-Lindau (VHL) E3 ligase and subsequent degradation by the proteasome [1, 15]. In disease states, PHD3 is notably upregulated in certain malignancies like clear cell renal cell carcinoma and is a primary therapeutic target for the treatment of anemia associated with chronic kidney disease [4, 5]. Small molecule inhibitors of the PHD family, such as roxadustat and daprodustat, stabilize HIF-α to stimulate the production of endogenous erythropoietin and improve iron metabolism [2, 8, 9]. Beyond its role in HIF regulation, PHD3 is also involved in modulating apoptosis, the cell cycle, and metabolic pathways independent of oxygen-sensing machinery [1, 3, 7].

Other names

EGLN3Egl nine homolog 3Prolyl hydroxylase domain-containing protein 3HIF-PH3HPH-1HPH-3SM-20HIF prolyl hydroxylase 3

Inhibition of the enzymatic activity of PHD3 prevents the prolyl hydroxylation of HIF-alpha subunits (specifically HIF-2 alpha), thereby preventing their recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase and subsequent proteasomal degradation [1, 14, 15]. This leads to the stabilization and accumulation of HIF-alpha, which promotes the transcription of genes involved in erythropoiesis, such as erythropoietin, and proteins that facilitate iron absorption and transport [4, 8, 17].