CP4H

CP4H, or collagen prolyl 4‑hydroxylase, is a key enzyme in the post‑translational modification of collagen. It catalyzes the hydroxylation of specific proline residues in the Y‑position of the Gly‑X‑Y repeat found in procollagen chains, a reaction essential for the stability of the triple‑helical structure of mature collagen. The hydroxylation requires molecular oxygen, α‑ketoglutarate, Fe²⁺, and ascorbate as a co‑factor, and it produces succinate and CO₂ as by‑products.

The functional enzyme is a heterotetramer composed of two α subunits, which contain the catalytic domain, and two β subunits, identified as protein disulfide isomerase (PDI). In humans, two α isoforms, α(I) and α(II), are encoded by the genes P4HA1 and P4HA2, respectively, and they can combine with the β subunit to form distinct holoenzymes with tissue‑specific expression patterns. The β subunit also serves as a chaperone, facilitating proper folding of the α subunits and assisting in procollagen processing within the endoplasmic reticulum.

Mutations or dysregulation of CP4H activity are linked to connective‑tissue disorders. Deficient hydroxylation leads to unstable collagen and is implicated in conditions such as osteogenesis imperfecta and certain forms of Ehlers‑Danlos syndrome. Conversely, overexpression has been observed in fibrotic diseases and in the tumor microenvironment, where it promotes extracellular matrix deposition and tumor progression.

CP4H is a target for therapeutic intervention; small‑molecule inhibitors, such as ethyl‑3,4‑dihydroxybenzoate, are under investigation for antifibrotic and anticancer applications. The enzyme remains a focal point in studies of collagen biosynthesis, tissue repair, and related pathological processes.