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Peptidylglycine α-amidating monooxygenase as a therapeutic target or biomarker
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  • David Merkler,
  • Aidan Hawley,
  • Betty Eipper,
  • Richard Mains
David Merkler
University of South Florida
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Aidan Hawley
University of South Florida
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Betty Eipper
UConn Health Center
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Richard Mains
UConn Health Center
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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.

Peer review status:UNDER REVIEW

23 Jun 2021Submitted to British Journal of Pharmacology
23 Jun 2021Assigned to Editor
23 Jun 2021Submission Checks Completed
28 Jul 2021Reviewer(s) Assigned