Prolyl hydroxylase and lysyl hydroxylase enzymes (PHD/LH)

Prolyl hydroxylase and lysyl hydroxylase enzymes are a group of 2-oxoglutarate-dependent dioxygenases essential for the post-translational modification of proteins, most notably collagen and the hypoxia-inducible factor (HIF) (Gorres & Raines, 2010, Critical Reviews in Biochemistry and Molecular Biology). Prolyl hydroxylases (PHDs) catalyze the addition of hydroxyl groups to proline residues; collagen PHDs (P4H) are critical for the thermal stability of the collagen triple helix, while HIF-PHDs (EGLN family) regulate the oxygen-dependent degradation of HIF-alpha subunits (Kivirikko & Pihlajaniemi, 1998, Advances in Enzymology and Related Areas of Molecular Biology). Lysyl hydroxylases (LHs or PLODs) catalyze the hydroxylation of lysine residues in collagen, providing sites for glycosylation and subsequent cross-linking that ensures structural integrity of the extracellular matrix (Yamauchi & Sricholpech, 2012, Essays in Biochemistry). In clinical medicine, HIF-PHD inhibitors like roxadustat and daprodustat are used to treat anemia associated with chronic kidney disease by stabilizing HIF and stimulating endogenous erythropoietin production (Maxwell & Eckardt, 2016, Nature Reviews Nephrology). Conversely, dysregulation of these enzymes is linked to various pathologies, including fibrotic diseases, Ehlers-Danlos syndrome type VI, and cancer metastasis, making them significant targets for therapeutic intervention (Gjaltema & Bank, 2017, Molecules). Therapeutic challenges include maintaining tissue specificity and avoiding off-target effects on the diverse members of the 2-oxoglutarate-dependent dioxygenase superfamily (Haase, 2013, Kidney International).

Other names

Collagen prolyl 4-hydroxylaseProcollagen-lysine,2-oxoglutarate 5-dioxygenasePLODEGLNHIF prolyl hydroxylaseP4HProcollagen-proline dioxygenase

These enzymes are inhibited by molecules that compete with the co-substrate 2-oxoglutarate, bind to the active site ferrous iron (Fe2+), or mimic the peptide substrate, thereby blocking the hydroxylation of specific proline or lysine residues (Haase, 2013, Kidney International; Myllyharju, 2003, Matrix Biology).