New insights into copper monooxygenases and peptide amidation: Structure, mechanism and function
Open accessAbstract
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-C alpha bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the stereospecific hydroxylation of the glycine alpha-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL; EC 4.3.2.5), generates alpha-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 beta-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.
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Physiologically high vitamin C levels (2-10 mM) are found in neurons and endocrine cells, particularly the adrenal and pituitary gland, apparently related to the synthesis of hormones and neuro-mediators.
“Physiologically high levels (2–10 mM) are found in neurons and endocrine cells (particularly, the adrenal and pituitary gland), which is apparently related to the synthesis of hormones and neuro-mediators described below [4,6,8,72,73].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
The hydroxylation active site of PAM is composed of two copper ions and the corresponding reaction is ascorbate-dependent.
“The former active site is composed of two copper ions and the corresponding reaction is ascorbate-dependent.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
The α-amidation reaction catalyzed by PAM is crucial for the production of a number of hormones/neurotransmitters (e.g., calcitonin, oxytocin, vasopressin, GLP-1, substance P, neuropeptide Y).
“The reaction is crucial for the production of a number of hormones/neurotransmitters (e.g., calcitonin, oxytocin, vasopressin, GLP-1, substance P, neuropeptide Y)”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
Ascorbate likely enables conversion between a cupric and cuprous state and is reduced stoichiometrically to an ascorbyl radical in PAM.
“Ascorbate likely enables conversion between a cupric and cuprous state and is reduced stoichiometrically to an ascorbyl radical.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
PAM catalyzes two-step carboxyterminal amidation of peptides.
“PAM is a bifunctional enzyme catalyzing two-step carboxyterminal amidation of peptides.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
There are two monooxygenases dependent on vitamin C: dopamine-β-hydroxylase and peptidyl-glycine α-amidating monooxygenase (PAM).
“There are two monooxygenases dependent on vitamin C: dopamine-β-hydroxylase and peptidyl-glycine α-amidating monooxygenase (PAM).”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
PAM is the only known human enzyme able to catalyze α-amidation of peptides.
“It is the only known human enzyme able to catalyze α-amidation of peptides [72,147,148,149].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
Ascorbic acid is involved in the reduction of copper in dopamine-β-hydroxylase.
“Ascorbic acid seems to be involved in the reduction of copper.”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
Other reductants can replace ascorbic acid in PAM but are less potent.
“Other reductants can replace ascorbic acid but are less potent [4,72,147,148,149].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [72]
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Vitamin C. Biosynthesis, recycling and degradation in mammals
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The neuropeptide complement of the marine annelid Platynereis dumerilii
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Zelfand, E. (2020) · Integrative Medicine · Cited by 8 · see citing works
- Authors
- Prigge, S. T., Mains, R. E., Eipper, B. A., & Amzel* **, L. M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2000-08
- Volume
- 57
- Issue
- 8
- Pages
- 1236-1259
- ISSN
- 1420-682X (ISSN-L)
- PMC
- PMC11146793
- OpenAlex
- W2017750045
- Cited by
- 460
- References
- 154
- Citations by year
- 2026: 12 · 2025: 7 · 2024: 13 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 22 · 2019: 14 · 2018: 19 · 2017: 11 · 2016: 16 · 2015: 14 · 2014: 20 · 2013: 19 · 2012: 26
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cellular and Molecular Life Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA.00266)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-32948, DK32949)
- Topics
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- copper monooxygenase, peptide amidation, peptidylglycine alpha-amidating monooxygenase, peptidylglycine alpha-hydroxylating monooxygenase, dopamine beta-monooxygenase, oxidative cleavage, electron transfer, enzyme mechanism, enzyme structure, substrate specificity, hormone biosynthesis, glyoxylic acid
- MeSH terms
- Amino Acid Sequence, Animals, Copper, Dopamine beta-Hydroxylase, Humans, Mixed Function Oxygenases, Molecular Sequence Data, Multienzyme Complexes, Protein Conformation, Substrate Specificity, Sequence Alignment, Sequence Homology, Amino Acid, Amidine-Lyases, Rats
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