Abstract
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.
Highlights
Peptidylglycine ␣-Amidating Monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important post-translational modification
We show that C-terminal amidation of a range of peptides by the copper-dependent enzyme, PAM is strikingly sensitive to hypoxia in cells
Because PAM is essential during development [14, 15], and ␣-amidation is important for the bioactivity of peptide hormones and other molecules, our findings point to an important interface of these processes with cellular hypoxia
Summary
Peptidylglycine ␣-Amidating Monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important post-translational modification. Conclusion: PAM-dependent amidation has the potential to signal oxygen levels in the same range as the hypoxia-inducible factor (HIF) system. Given that the human genome encodes multiple types of oxygenase for which molecular oxygen is an obligatory co-substrate, these findings have generated interest in the possibility that one or more of these enzymes might have the potential to signal oxygen levels in cells. The HIF system is responsible for regulating many cellular processes, other responses to hypoxia, those occurring very rapidly, appear to be independent of HIF-mediated transcription [9, 10] This has led to interest in defining other oxygen-sensitive pathways, which might be dependent on oxygenases whose activity on relevant substrates is effectively restricted at moderate cellular oxygen concentrations
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