Procollagen prolyl and lysyl hydroxylases (P4H/PLOD)

Procollagen prolyl and lysyl hydroxylases are a group of iron- and 2-oxoglutarate-dependent dioxygenases essential for the post-translational modification of collagen [UniProt]. Prolyl 4-hydroxylase (P4H) catalyzes the formation of 4-hydroxyproline, which is critical for the thermal stability of the collagen triple helix, while lysyl hydroxylase (PLOD) produces hydroxylysine residues necessary for stable intermolecular cross-linking [StatPearls]. Dysregulation of these enzymes is a hallmark of various fibrotic diseases, where excessive collagen deposition leads to organ dysfunction, and in cancer, where they facilitate extracellular matrix remodeling and metastasis [PubMed]. Therapeutic strategies often focus on small-molecule inhibitors that compete with the 2-oxoglutarate cofactor or chelate the active-site iron to reduce collagen stability and accumulation [PubMed]. However, targeting these enzymes presents challenges regarding selectivity and the potential for systemic side effects, such as impaired wound healing or interference with other oxygen-sensing pathways like the HIF system [PubMed].

Other names

Collagen hydroxylasesProcollagen-proline 4-dioxygenaseProcollagen-lysine 5-dioxygenaseP4HPLODProlyl 4-hydroxylaseLysyl hydroxylase

Inhibition of procollagen hydroxylation by competing with the 2-oxoglutarate cofactor or chelating the active-site Fe2+ ion, which prevents the formation of stable collagen triple helices and cross-links [StatPearls, PubMed].