Procollagen-proline dioxygenase (P4H) (P4H)

Procollagen-proline dioxygenase (P4H) and the related Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase superfamily represent a diverse group of enzymes that catalyze oxidative reactions essential for various biological processes [UniProt, PubMed]. P4H is primarily responsible for the 4-hydroxylation of proline residues in procollagen, a modification vital for the structural integrity and thermal stability of the collagen triple helix [PubMed, PMC2883323]. Other critical members of this family include the Hypoxia-Inducible Factor (HIF) prolyl hydroxylases (PHDs), which act as oxygen sensors by regulating the stability of HIF-alpha subunits in response to cellular oxygen levels [Nature Reviews Nephrology]. In clinical practice, these enzymes are significant therapeutic targets; P4H inhibitors are investigated for treating fibrotic disorders, while HIF-PHD inhibitors like Roxadustat and Daprodustat are approved for treating anemia associated with chronic kidney disease [FDA, EMA]. The primary mechanism of drug interaction involves small molecules acting as 2-OG mimetics that occupy the active site, thereby preventing the hydroxylation of target substrates [PubMed]. Selectivity remains a major challenge in drug development due to the highly conserved nature of the catalytic domain across the superfamily [Critical Reviews in Biochemistry and Molecular Biology].

Other names

Prolyl 4-hydroxylase2-oxoglutarate-dependent dioxygenaseFe(II)/2-oxoglutarate-dependent dioxygenaseHIF prolyl hydroxylaseAlpha-ketoglutarate-dependent hydroxylase

Inhibition of enzymatic activity by competing with the co-substrate 2-oxoglutarate or by chelating the essential Fe(II) cofactor in the catalytic site.