Egl nine homolog 3 (EGLN3) (EGLN3)

Egl nine homolog 3 (EGLN3), also known as Prolyl hydroxylase domain-containing protein 3 (PHD3), is a critical oxygen-sensing enzyme that regulates the stability of Hypoxia-Inducible Factor (HIF) alpha subunits (UniProt Q9H6Z9). Under normoxic conditions, EGLN3 uses molecular oxygen and 2-oxoglutarate to hydroxylate specific proline residues on HIF-alpha, marking it for polyubiquitination by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and subsequent degradation (PubMed: 11292861). When oxygen levels drop (hypoxia), EGLN3 activity is diminished, allowing HIF-alpha to accumulate, translocate to the nucleus, and activate the transcription of genes essential for erythropoiesis, angiogenesis, and metabolic adaptation (PubMed: 21407211). Beyond its role in hypoxia, EGLN3 is involved in regulating apoptosis and cell cycle progression, particularly in neuronal and muscle tissues (PubMed: 18568040). Pharmacologically, EGLN3 is targeted by pan-PHD inhibitors such as Roxadustat and Daprodustat, which are used to treat anemia associated with chronic kidney disease by stimulating endogenous erythropoietin production (PubMed: 31340090). However, the therapeutic stabilization of HIF raises safety concerns regarding the potential for promoting tumor growth or increasing the risk of cardiovascular complications like thrombosis (PubMed: 27699533).

Other names

PHD3Prolyl hydroxylase domain-containing protein 3HIF-PH3HIF-prolyl hydroxylase 3HPH-1HPH-3

Inhibition of prolyl hydroxylase activity to prevent the hydroxylation and subsequent proteasomal degradation of Hypoxia-Inducible Factor (HIF) alpha subunits, thereby promoting the expression of erythropoietin and other hypoxia-responsive genes.