Striking Oxygen Sensitivity of the Peptidylglycine α-Amidating Monooxygenase (PAM) in Neuroendocrine Cells

J Biol Chem. 2015 Oct 9;290(41):24891-901. doi: 10.1074/jbc.M115.667246. Epub 2015 Aug 19.


Interactions between biological pathways and molecular oxygen require robust mechanisms for detecting and responding to changes in cellular oxygen availability, to support oxygen homeostasis. Peptidylglycine α-amidating monooxygenase (PAM) catalyzes a two-step reaction resulting in the C-terminal amidation of peptides, a process important for their stability and biological activity. Here we show that in human, mouse, and insect cells, peptide amidation is exquisitely sensitive to hypoxia. Different amidation events on chromogranin A, and on peptides processed from proopiomelanocortin, manifest similar striking sensitivity to hypoxia in a range of neuroendocrine cells, being progressively inhibited from mild (7% O2) to severe (1% O2) hypoxia. In developing Drosophila melanogaster larvae, FMRF amidation in thoracic ventral (Tv) neurons is strikingly suppressed by hypoxia. Our findings have thus defined a novel monooxygenase-based oxygen sensing mechanism that has the capacity to signal changes in oxygen availability to peptidergic pathways.

Keywords: copper monooxygenase; hypoxia; hypoxia-inducible factor (HIF); peptide hormone; secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Hypoxia / drug effects
  • Cell Line
  • Chromogranin A / pharmacology
  • Drosophila melanogaster / enzymology
  • Humans
  • Mice
  • Mixed Function Oxygenases / chemistry
  • Mixed Function Oxygenases / metabolism*
  • Molecular Sequence Data
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / metabolism*
  • Neuroendocrine Cells / drug effects
  • Neuroendocrine Cells / metabolism*
  • Oxygen / metabolism*


  • Amides
  • Chromogranin A
  • Multienzyme Complexes
  • Mixed Function Oxygenases
  • peptidylglycine monooxygenase
  • Oxygen