Peptidyl-proline 4-hydroxylase (P4H)

Peptidyl-proline 4-hydroxylase (P4H) is a critical enzyme responsible for the post-translational modification of collagen, the most abundant protein in the human body. It catalyzes the hydroxylation of proline residues to 4-hydroxyproline, a modification essential for the thermal stability and structural integrity of the collagen triple helix [3, 5]. The enzyme typically exists as a tetramer composed of two catalytic alpha subunits (P4HA1, P4HA2, or P4HA3) and two beta subunits (P4HB, also known as protein disulfide-isomerase) [1, 2]. In pathological states, overactivity of P4H leads to excessive collagen deposition, a hallmark of fibrotic diseases such as liver cirrhosis and pulmonary fibrosis [1, 4]. Furthermore, P4H is frequently upregulated in various cancers, where it promotes tumor stiffening, invasion, and metastasis by remodeling the extracellular matrix [2, 6]. Therapeutic strategies targeting P4H primarily involve small-molecule inhibitors that compete with the co-substrate 2-oxoglutarate or chelate the active-site iron, aiming to reduce collagen stability and accumulation [7, 8]. While several inhibitors have been explored in clinical and preclinical settings for fibrosis and oncology, achieving selectivity over related hydroxylases remains a significant challenge [1, 4].

Other names

Prolyl 4-hydroxylaseCollagen prolyl 4-hydroxylaseProcollagen-proline 4-dioxygenaseC-P4HCP4HP4HA1P4HA2P4HA3P4HB

Competitive inhibition of the 2-oxoglutarate binding site or chelation of the active-site iron, preventing the hydroxylation of proline residues in protocollagen and thereby destabilizing the collagen triple helix.