New insights into copper monooxygenases and peptide amidation: Structure, mechanism and function

S. T. Prigge, R. E. Mains, B. A. Eipper, L. M. Amzel

Research output: Contribution to journalReview article

Abstract

Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-Cα bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine α-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine α-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the stereospecific hydroxylation of the glycine α-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-α-hydroxyglycine α-amidating lyase (PAL; EC 4.3.2.5) generates α-amidated peptide product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates. The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis. Since PHM is homologous in sequence and mechanism to dopamine β-monooxygenase (DBM; EC 1.14.17.1), the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM.

Original languageEnglish (US)
Pages (from-to)1236-1259
Number of pages24
JournalCellular and Molecular Life Sciences
Volume57
Issue number8-9
DOIs
StatePublished - Jan 1 2000

Keywords

  • Amidation
  • Ascorbate
  • Copper
  • Dopamine β-monooxygenase
  • Electron transfer
  • Oxygen chemistry
  • Peptide hormones
  • Peptidylglycine α-amidating monooxygenase
  • Structure

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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