Collagen prolyl and lysyl hydroxylase enzymes (C-P4H/P3H/LH)

The collagen prolyl and lysyl hydroxylase enzymes are a group of iron- and 2-oxoglutarate-dependent dioxygenases located in the lumen of the endoplasmic reticulum [1.1.2, 1.3.1]. This group includes collagen prolyl 4-hydroxylases (C-P4Hs), prolyl 3-hydroxylases (P3Hs), and lysyl hydroxylases (LHs, also known as PLODs) [1.3.1, 1.4.4]. These enzymes catalyze the post-translational hydroxylation of specific proline and lysine residues in procollagen chains, which is a critical step for the structural integrity and functional maturation of collagen [1.3.2, 1.4.4]. Specifically, C-P4Hs and P3Hs form hydroxyproline residues that are essential for the thermal stability of the collagen triple helix, while LHs generate hydroxylysine residues that facilitate subsequent glycosylation and the formation of covalent cross-links [1.3.1, 1.4.1]. Dysregulation or overexpression of these enzymes is a hallmark of various pathological conditions, including fibrotic diseases of the liver, lungs, and kidneys, as well as cancer, where they promote extracellular matrix remodeling, stiffness, and metastasis [1.1.2, 1.4.5]. Mutations in the genes encoding these enzymes lead to severe connective tissue disorders such as Ehlers-Danlos syndrome type VIA, osteogenesis imperfecta, and Bruck syndrome [1.4.1, 1.4.2]. As such, these enzymes are significant therapeutic targets; pharmacological inhibitors, including 2-oxoglutarate mimetics and iron chelators, are being investigated for their potential to reduce excessive collagen accumulation and disrupt the tumor microenvironment [1.2.1, 1.5.3]. However, therapeutic development faces challenges such as ensuring selectivity over other 2-oxoglutarate-dependent dioxygenases, like the hypoxia-inducible factor (HIF) prolyl hydroxylases, and avoiding systemic toxicity related to impaired wound healing [1.1.4, 1.3.2].

Other names

Procollagen-proline dioxygenaseProcollagen-lysine 5-dioxygenaseProlyl hydroxylaseLysyl hydroxylasePLODP4HP3HLeprecanCartilage-associated protein complex enzymes

Competitive inhibition of 2-oxoglutarate binding at the catalytic site, chelation of the essential Fe2+ cofactor, and inhibition of procollagen hydroxylation to prevent triple helix stabilization and cross-linking.