Peptidylglycine alpha-amidating mono-oxygenase: neuropeptide amidation as a target for drug design.
1. Peptidylglycine alpha-amidating mono-oxygenase (PAM) is a bifunctional key enzyme in the bioactivation of neuropeptides. Its biosynthesis, distribution, functional role, and pharmacological manipulation are discussed. 2. PAM biosynthesis from a single gene precursor is characterized by alternative splicing and endoproteolytic events, which control intracellular transport, targeting, and enzyme activity. 3. The enzyme is mainly stored in secretory vesicles of many neuronal and endocrine cells with high abundance in the pituitary gland. Its functional role has been studied using enzyme inhibitors. Thus selective, peripheral PAM inhibition reduces substance P along with an anti-inflammatory action. 4. PAM-related pathologies are characterized by an increased relative abundance of alpha-amidated neuropeptides. To attenuate such hormone overproduction, novel, specific, and disease-targeted PAM inhibitors may be developed based on enzyme polymorphism.
Bolkenius
F N
FN
Synthélabo Biomoléculaire 16, Strasbourg, France.
Ganzhorn
A J
AJ
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D009097:Multienzyme Complexes; D009479:Neuropeptides / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009479:Neuropeptides; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase