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J Mol Endocrinol. 2016 May;56(4):T63-76. doi: 10.1530/JME-15-0266. Epub 2015 Dec 14.

60 YEARS OF POMC: From POMC and α-MSH to PAM, molecular oxygen, copper, and vitamin C.

Author information

1
Departments of Molecular Biology and BiophysicsUniversity of Connecticut Health Center, Farmington, Connecticut, USA.
2
Department of NeuroscienceUniversity of Connecticut Health Center, Farmington, Connecticut, USA mains@uchc.edu eipper@uchc.edu.
3
Departments of Molecular Biology and BiophysicsUniversity of Connecticut Health Center, Farmington, Connecticut, USA Department of NeuroscienceUniversity of Connecticut Health Center, Farmington, Connecticut, USA mains@uchc.edu eipper@uchc.edu.

Abstract

A critical role for peptide C-terminal amidation was apparent when the first bioactive peptides were identified. The conversion of POMC into adrenocorticotropic hormone and then into α-melanocyte-stimulating hormone, an amidated peptide, provided a model system for identifying the amidating enzyme. Peptidylglycine α-amidating monooxygenase (PAM), the only enzyme that catalyzes this modification, is essential; mice lacking PAM survive only until mid-gestation. Purification and cloning led to the discovery that the amidation of peptidylglycine substrates proceeds in two steps: peptidylglycine α-hydroxylating monooxygenase catalyzes the copper- and ascorbate-dependent α-hydroxylation of the peptidylglycine substrate; peptidyl-α-hydroxyglycine α-amidating lyase cleaves the N-C bond, producing amidated product and glyoxylate. Both enzymes are contained in the luminal domain of PAM, a type 1 integral membrane protein. The structures of both catalytic cores have been determined, revealing how they interact with metals, molecular oxygen, and substrate to catalyze both reactions. Although not essential for activity, the intrinsically disordered cytosolic domain is essential for PAM trafficking. A phylogenetic survey led to the identification of bifunctional membrane PAM in Chlamydomonas, a unicellular eukaryote. Accumulating evidence points to a role for PAM in copper homeostasis and in retrograde signaling from the lumen of the secretory pathway to the nucleus. The discovery of PAM in cilia, cellular antennae that sense and respond to environmental stimuli, suggests that much remains to be learned about this ancient protein.

KEYWORDS:

amidation; cilia; copper; energy homeostasis; monooxygenase; obesity; peptides; sensory; signaling

PMID:
26667899
PMCID:
PMC4899100
DOI:
10.1530/JME-15-0266
[Indexed for MEDLINE]
Free PMC Article

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