Prolyl 4-hydroxylase and lysyl hydroxylase (P4H/LH)

Prolyl 4-hydroxylase (P4H) and lysyl hydroxylase (LH) are essential enzymes that catalyze the post-translational modification of procollagen chains within the endoplasmic reticulum (UniProtKB - P4HA1, PLOD1). P4H is a tetrameric enzyme responsible for the formation of 4-hydroxyproline, a modification that is strictly required for the thermal stability of the collagen triple helix at physiological temperatures (Myllyharju, 2003). LH, also known as procollagen-lysine 5-dioxygenase (PLOD), hydroxylates lysine residues to hydroxylysine, which serves as the foundation for subsequent glycosylation and the formation of covalent cross-links that provide tensile strength to collagen fibers (Yamauchi & Sricholpech, 2012). Both enzymes belong to the 2-oxoglutarate-dependent dioxygenase superfamily and require ferrous iron, ascorbate (vitamin C), and molecular oxygen as cofactors. Pathologically, the upregulation of these enzymes is a key driver of excessive extracellular matrix (ECM) deposition in fibrotic diseases of the liver, lungs, and kidneys, and is also implicated in promoting cancer metastasis by increasing ECM stiffness (Gjaltema & Bank, 2017). Pharmacological inhibition of these enzymes, such as with minoxidil for LH or various 2-oxoglutarate analogues for P4H, aims to reduce pathological collagen accumulation and disrupt the structural integrity of the fibrotic or tumor microenvironment (Murad et al., 1992). Note that this entry is flagged as incorrect because it combines two distinct enzyme families into a single target definition.

Other names

Collagen hydroxylasesProcollagen-proline 4-dioxygenaseProcollagen-lysine 5-dioxygenaseP4HPLODProcollagen hydroxylases

Inhibition of the hydroxylation of proline and lysine residues in procollagen, which prevents the formation of stable collagen triple helices and covalent cross-links, thereby reducing the accumulation of the extracellular matrix.