Collagen prolyl and lysyl hydroxylases (C-P4H/LH)

Collagen prolyl and lysyl hydroxylases are a group of enzymes responsible for the essential post-translational modifications of collagen molecules within the endoplasmic reticulum. These enzymes, which include prolyl 4-hydroxylases (C-P4H), prolyl 3-hydroxylases (C-P3H), and lysyl hydroxylases (LH or PLOD), catalyze the hydroxylation of specific proline and lysine residues in nascent procollagen chains (NIH, 2018). This process is critical for the thermal stability of the collagen triple helix and the formation of covalent cross-links that provide structural integrity to the extracellular matrix (ECM) (ResearchGate, 2021). Dysregulation of these enzymes is a hallmark of various pathological conditions, including fibrotic diseases (such as liver and pulmonary fibrosis) and cancer, where they contribute to ECM stiffening, tumor invasion, and metastasis (NIH, 2018; MDPI, 2020). Consequently, they are considered promising therapeutic targets, with several small-molecule inhibitors like lufironil and minoxidil being explored for their anti-fibrotic and anti-tumor properties (NIH, 1996; IJS RT Journal, 2021). However, achieving selectivity over other 2-oxoglutarate-dependent dioxygenases remains a significant challenge in drug development (ACS, 2018).

Other names

Procollagen-proline dioxygenaseProcollagen-lysine 5-dioxygenaseProcollagen-proline 4-hydroxylaseProcollagen-proline 3-hydroxylasePLODP4HCollagen hydroxylases

Competitive inhibition with respect to the co-substrate 2-oxoglutarate (alpha-ketoglutarate) or chelation of the essential iron (Fe2+) cofactor at the enzyme active site.