Abstract
Peptides play a key role in controlling many physiological and
neurobiological pathways. Many bioactive peptides require a C-terminal
α-amide for full activity. The bifunctional enzyme catalyzing
α-amidation, peptidylglycine α-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 tumors. The amidation reaction occurs
in two steps, glycine α-hydroxylation followed by dealkylation to
generate the α-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.