Procollagen hydroxylase (P4H)

Procollagen hydroxylases are a group of 2-oxoglutarate-dependent dioxygenases essential for the post-translational modification of collagen. This group primarily includes prolyl 4-hydroxylase (P4H), prolyl 3-hydroxylase (P3H), and lysyl hydroxylase (LH/PLOD), which catalyze the hydroxylation of specific proline and lysine residues within the collagen polypeptide chains (Myllyharju, 2003). These modifications are crucial for the stability of the collagen triple helix and the subsequent formation of covalent cross-links that provide tensile strength to the extracellular matrix (Gorres & Raines, 2010). The enzymes require ferrous iron, molecular oxygen, 2-oxoglutarate, and ascorbic acid as essential cofactors for their catalytic activity (UniProt). Dysregulation of these enzymes is strongly linked to fibrotic disorders, such as pulmonary and hepatic fibrosis, where excessive collagen deposition leads to organ dysfunction (Rappu et al., 2019). In oncology, these enzymes are often upregulated, promoting a stiffened tumor stroma that facilitates cancer cell invasion and metastasis (Yamauchi & Sricholpech, 2012). Therapeutic strategies focus on small-molecule inhibitors that compete with the 2-oxoglutarate cofactor or iron to reduce collagen stability and accumulation in pathological states.

Other names

Collagen synthesis dioxygenasesProcollagen-proline, 2-oxoglutarate 4-dioxygenaseProcollagen-lysine, 2-oxoglutarate 5-dioxygenaseCollagen prolyl 4-hydroxylaseLysyl hydroxylasePLOD2-oxoglutarate-dependent collagen hydroxylases

Competitive inhibition of the 2-oxoglutarate binding site or chelation of the active-site ferrous iron (Fe2+), thereby preventing the hydroxylation of prolyl or lysyl residues required for collagen stability.