prolyl3hydroxylases

Prolyl 3-hydroxylases (P3Hs) are a family of enzymes that play a critical role in the post-translational modification of collagen and other extracellular matrix proteins. These enzymes belong to the broader class of 2-oxoglutarate-dependent dioxygenases, which utilize iron and molecular oxygen to catalyze hydroxylation reactions. Specifically, P3Hs add a hydroxyl group to the β-carbon of proline residues within the characteristic Gly-X-Y repeat motifs found in collagen triple helices, where X and Y are often proline or hydroxyproline.

The three known isoforms of P3Hs in humans—P3H1 (LEPRE1), P3H2 (B3GLCT), and P3H3 (ASPH)—each exhibit distinct tissue-specific expression patterns and substrate specificities. P3H1 is primarily involved in collagen modification, while P3H2 and P3H3 have broader roles, including the hydroxylation of non-collagenous proteins like agrin and perlecan. These modifications are essential for proper protein folding, stability, and function, particularly in tissues under mechanical stress.

Mutations in P3H1 are associated with Ehlers-Danlos syndrome (EDS) type VI, a connective tissue disorder characterized by joint hypermobility, skin fragility, and ocular fragility. This condition arises from impaired collagen hydroxylation, leading to defective triple helix formation and weakened extracellular matrices. Research into P3Hs has also highlighted their potential involvement in other diseases, including cancer, where altered hydroxylation may influence tumor progression and metastasis.

The enzymatic activity of P3Hs is regulated by cofactors such as ascorbate (vitamin C), which donates electrons to the iron center, and 2-oxoglutarate, which serves as the oxygen atom donor. Dysregulation of these enzymes or their cofactors can disrupt tissue integrity and contribute to pathological conditions. Ongoing studies continue to explore the broader physiological roles of P3Hs and their therapeutic implications in diseases linked to extracellular matrix dysfunction.