Peptidyl-glycine alpha-hydroxylating monooxygenase (PHM) (PHM)

Peptidyl-glycine alpha-hydroxylating monooxygenase (PHM) is a copper-dependent enzyme that serves as the first catalytic domain of the bifunctional Peptidyl-glycine alpha-amidating monooxygenase (PAM) protein. It is responsible for the rate-limiting step in the C-terminal amidation of over half of all known neuropeptides and peptide hormones, a modification that is typically required for their full biological activity [PubMed: 21111018]. The enzyme utilizes molecular oxygen and ascorbate to hydroxylate the alpha-carbon of a C-terminal glycine residue on pro-peptide substrates. This process is vital for the maturation of key signaling molecules such as oxytocin, vasopressin, and calcitonin, which regulate diverse physiological functions from lactation to calcium homeostasis. In clinical contexts, PHM activity is a potential target for treating diseases characterized by peptide overproduction, such as certain neuroendocrine tumors, or for modulating cardiovascular and neurological signaling [PubMed: 16337115]. Inhibitors like disulfiram or substrate analogs can block this amidation process, leading to the accumulation of inactive glycine-extended precursors. Because of its broad substrate specificity, therapeutic targeting of PHM requires careful consideration of systemic endocrine effects [PubMed: 25637143].

Other names

Peptidylglycine 2-hydroxylasePeptidyl-alpha-hydroxyglycine synthasePAMPeptidylglycine alpha-hydroxylating monooxygenasePHM domain

PHM catalyzes the stereospecific hydroxylation of the alpha-carbon of C-terminal glycine-extended peptides using two copper centers, molecular oxygen, and ascorbate as a reducing agent [UniProt: P19021].