Procollagen-proline 4-dioxygenase (P4H) (P4H)

Procollagen-proline 4-dioxygenase, commonly referred to as prolyl 4-hydroxylase (P4H), is a key enzyme in the biosynthesis of collagen, the most abundant protein in the human body [2, 4]. It catalyzes the post-translational hydroxylation of proline residues in procollagen to 4-hydroxyproline, a modification that is strictly required for the stability of the collagen triple helix at body temperature [4, 8]. The enzyme is a tetrameric complex consisting of two catalytic alpha subunits and two beta subunits, the latter being identical to protein disulfide-isomerase (PDI), which aids in the folding and retention of the enzyme in the endoplasmic reticulum [4, 11]. Because excessive collagen deposition is the primary driver of fibrotic diseases such as liver cirrhosis, pulmonary fibrosis, and systemic sclerosis, P4H is a major therapeutic target for anti-fibrotic drug development [2, 9]. Additionally, P4H activity is upregulated in various cancers, where it contributes to the stiffening of the extracellular matrix, promoting tumor invasion and metastasis [2, 3]. Therapeutic strategies involve the use of iron chelators and competitive inhibitors of the cofactor alpha-ketoglutarate to disrupt collagen maturation, though clinical application is challenged by the need for tissue specificity and the risk of impairing normal wound healing [2, 9].

Other names

Prolyl 4-hydroxylaseCP4HProtocollagen hydroxylaseProline 2-oxoglutarate 4-dioxygenaseProtocollagen prolyl hydroxylase

Inhibition of the catalytic alpha subunit of prolyl 4-hydroxylase to prevent the formation of 4-hydroxyproline, thereby destabilizing the collagen triple helix and reducing collagen accumulation.