Peptidylglycine alpha-amidating monooxygenase as a therapeutic target or biomarker for human diseases

Peptides play a key role in controlling many physiological and neurobiological pathways. Many bioactive peptides require a C-terminal alpha-amide for full activity. The bifunctional enzyme catalysing alpha-amidation, peptidylglycine alpha-amidating monooxygenase (PAM), is the sole enzyme responsible for amidated peptide biosynthesis, from Chlamydomonas reinhardtii to Homo sapiens. Many neuronal and endocrine functions are dependent upon amidated peptides; additional amidated peptides are growth promoters in tumours. The amidation reaction occurs in two steps, glycine alpha-hydroxylation followed by dealkylation to generate the alpha-amide product. Currently, most potentially useful inhibitors target the first reaction, which is rate-limiting. PAM is a membrane-bound enzyme that visits the cell surface during peptide secretion. PAM is then used again in the biosynthetic pathway, meaning that cell-impermeable inhibitors or inactivators could have therapeutic value for the treatment of cancer or psychiatric abnormalities. To date, inhibitor design has not fully exploited the structures and mechanistic details of PAM.