Prolyl 4-hydroxylase (P4H) (P4H)

Prolyl 4-hydroxylase (P4H) is a critical enzyme in collagen biosynthesis, catalyzing the post-translational hydroxylation of proline residues to ensure the structural integrity of the collagen triple helix (UniProt P13674). The enzyme belongs to the 2-oxoglutarate-dependent dioxygenase family and requires ferrous iron (Fe2+), molecular oxygen, and alpha-ketoglutarate as essential cofactors (PubMed 11566128). During its catalytic cycle, particularly in uncoupled reactions where the peptide substrate is absent, the enzyme can generate reactive oxygen species (ROS) and result in the oxidation of its active-site iron to the inactive ferric state (Fe3+) (PubMed 6733134). These ROS can further initiate the formation of lipid radicals, leading to oxidative damage and lipid peroxidation within the cellular environment (PubMed 29066504). Ascorbate (Vitamin C) acts as a specific reducing agent to return the enzyme-bound Fe3+ to its active Fe2+ state, a process vital for preventing enzyme inactivation and maintaining collagen production (PubMed 6086400). P4H is a major therapeutic target for anti-fibrotic drugs aimed at reducing excessive collagen deposition in organs like the liver and lungs (PubMed 23535355). Additionally, the related HIF-prolyl hydroxylases (PHDs) are targeted by inhibitors such as roxadustat to treat anemia by stabilizing hypoxia-inducible factors and stimulating erythropoietin production (FDA).

Other names

Procollagen-proline dioxygenaseProline 4-hydroxylaseCP4HProlyl hydroxylaseHIF-prolyl hydroxylase

Competitive inhibition with 2-oxoglutarate or iron chelation to prevent proline hydroxylation or HIF degradation; reduction of inactive ferric iron by ascorbate to maintain enzyme activity.