Peptidyl-glycine alpha-amidating monooxygenase (PAM) (PAM)

Peptidyl-glycine alpha-amidating monooxygenase (PAM) is a bifunctional enzyme essential for the biosynthesis of many biologically active neuropeptides and peptide hormones (UniProt P19021). It catalyzes the C-terminal amidation of these molecules, a modification required for their full biological activity and stability. The enzyme consists of two catalytic domains: peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL). The PHM domain specifically contains the ascorbate cofactor binding site, which is critical for providing electrons to the copper centers (CuA and CuB) during the hydroxylation of glycine-extended precursors (Science 1997, 278:1300). Ascorbic acid (Vitamin C) acts as the primary electron donor in this reaction, and its binding is essential for enzyme turnover (PubMed: 11061476). Because over half of all known neuropeptides require amidation to function, PAM plays a critical role in regulating processes such as blood pressure, metabolism, and neurotransmission (PubMed: 15653341). Dysregulation of PAM activity is linked to various conditions, including neuroendocrine tumors and cardiovascular diseases, making its cofactor binding sites potential targets for therapeutic modulation. Drugs like disulfiram can inhibit this enzyme by interfering with its metal centers, while ascorbate levels directly influence the rate of peptide amidation in vivo (PubMed: 10411212).

Other names

Peptidylglycine alpha-amidating monooxygenasePHM/PALPeptidylglycine alpha-hydroxylating monooxygenasePeptidyl-alpha-hydroxyglycine alpha-amidating lyase

PAM catalyzes the conversion of glycine-extended peptides to C-terminally amidated peptides via a two-step process. The PHM domain uses two copper ions and two molecules of ascorbate to hydroxylate the alpha-carbon of the C-terminal glycine; subsequently, the PAL domain cleaves the N-C bond to release the amidated peptide and glyoxylate.