Prolyl and lysyl hydroxylases (PHD/PLOD)

Prolyl and lysyl hydroxylases are a group of 2-oxoglutarate-dependent dioxygenases that play essential roles in the post-translational modification of proteins, most notably collagen (Gorres & Raines, 2010). Prolyl hydroxylases (PHDs) catalyze the 4-hydroxylation of proline residues, which is required for the thermal stability of the collagen triple helix, and also act as cellular oxygen sensors by hydroxylating Hypoxia-Inducible Factor (HIF) alpha subunits to trigger their degradation under normoxic conditions (Maxwell & Eckardt, 2016). Lysyl hydroxylases (PLODs) catalyze the hydroxylation of lysine residues in collagen, providing the sites for glycosylation and the formation of stable covalent cross-links that are vital for the structural integrity of the extracellular matrix (Yamauchi & Sricholpech, 2012). Dysregulation of these enzymes is associated with various diseases, including anemia, where HIF-PHD inhibitors are used to stimulate erythropoiesis, and fibrotic disorders or cancer, where excessive collagen modification promotes disease progression (Gilkes et al., 2013). Therapeutic agents targeting these enzymes include approved HIF-PHD inhibitors like Roxadustat and Daprodustat for renal anemia, while inhibitors of collagen-modifying hydroxylases are being explored for anti-fibrotic and anti-cancer therapy.

Other names

Procollagen-proline dioxygenaseProcollagen-lysine dioxygenaseProlyl 4-hydroxylase (P4H)Lysyl hydroxylase (LH)HIF-prolyl hydroxylaseEGLNPLOD2-oxoglutarate-dependent dioxygenase

Inhibition of 2-oxoglutarate-dependent dioxygenase activity by competing with the co-substrate 2-oxoglutarate or chelating the active site ferrous iron (Fe2+), thereby preventing the hydroxylation of specific proline or lysine residues on target proteins such as collagen or HIF-1α (Maxwell & Eckardt, 2016; Gorres & Raines, 2010).