Prolyl hydroxylase and lysyl hydroxylase (None standardized for the pair; individually, prolyl hydroxylase is often abbreviated as P4H or PHD (for HIF-prolyl hydroxylases), and lysyl hydroxylase as LH or PLOD (for procollagen-lysine,2-oxoglutarate,5-dioxygenase))

Prolyl hydroxylases and lysyl hydroxylases are iron- and 2-oxoglutarate-dependent dioxygenase enzymes responsible for critical post-translational modifications of collagen and related proteins. Prolyl hydroxylases catalyze the hydroxylation of proline residues to hydroxyproline, conferring thermal stability to the collagen triple helix—a modification essential for connective tissue integrity. Lysyl hydroxylases perform hydroxylation of lysine residues and further catalyze glycosylation steps, supporting collagen maturation and supramolecular organization in the extracellular matrix. These enzymes also play roles in oxygen-sensing pathways; specifically, HIF-prolyl hydroxylases (PHDs) regulate hypoxia-inducible factor stability and transcriptional responses to oxygen levels. Dysregulation of these enzymes is implicated in various diseases, including cancer, fibrosis, cardiovascular and neurodegenerative disorders, and genetic connective tissue diseases. Both are recognized drug targets, with inhibitors in clinical and experimental use targeting fibrosis, anemia, and cancer metastasis.

Other names

Prolyl 4-hydroxylase (P4H or CP4H)Hypoxia-inducible factor prolyl hydroxylase (PHD)Lysyl hydroxylase (LH, LH1, LH2, LH3; PLOD1, PLOD2, PLOD3)Collagen prolyl hydroxylaseCollagen lysyl hydroxylase

Small molecule inhibitors block the Fe2+- and 2-oxoglutarate-dependent active site to prevent hydroxylation of proline or lysine residues. Iron chelation reduces enzyme activity. In the case of HIF-PHDs, inhibition stabilizes HIF-α, activating hypoxia-response genes.