Prolyl 4-hydroxylase, transmembrane (P4H-TM)

Prolyl 4-hydroxylase, transmembrane (P4H-TM) is an endoplasmic reticulum membrane-localized enzyme of the 2-oxoglutarate-dependent dioxygenase superfamily, characterized by a unique EF-hand calcium-binding domain inserted in the catalytic core[1]. P4H-TM catalyzes the post-translational hydroxylation of specific proline residues, mainly in hypoxia-inducible factor (HIF) α proteins, regulating their stability and degradation under normal oxygen levels (normoxia)[2][3]. Through HIFα hydroxylation, it contributes to cellular adaptation to hypoxia and oxygen sensing. Pathogenic variants in the P4HTM gene result in HIDEA syndrome—a multisystem neurodevelopmental disorder including epilepsy, hypotonia, hypoventilation, intellectual disability, dysautonomia, and eye abnormalities[3]. P4H-TM's exact physiological substrate(s) and broader roles are under investigation, but it is confirmed as an important therapeutic enzyme target for hypoxia-related pathologies. Experimental inhibition, for instance by N-oxalylglycine, blocks HIFα hydroxylation, thereby affecting hypoxia signaling. Loss-of-function mutations have profound neurological consequences, marking P4H-TM as both a vital regulator and a potential therapeutic vulnerability[1][2][3].

Other names

P4HTMPH4HIF-PH4HIF-prolyl hydroxylase 4HPH-4PHD4FLJ20262EGLN4Hypoxia-inducible factor prolyl hydroxylase 4Prolyl hydroxylase domain-containing 4HIDEATransmembrane prolyl 4-hydroxylase

Inhibitors block prolyl hydroxylation of HIFα, leading to stabilization of HIF proteins and modulation of the hypoxia response. Disruption of the enzyme's activity affects degradation of HIFα via hydroxylation/proteasomal targeting[1][2]