Peptidylglycine α‐amidating monooxygenase: A multifunctional protein with catalytic, processing, and routing domains
Open accessAbstract
Peptide α‐amidation is a widespread, often essential posttranslational modification shared by many bioactive peptides and accomplished by the products of a single gene encoding a multifunctional protein, peptidylglycine α‐amidating monooxygenase (PAM). PAM has two catalytic domains that work sequentially to produce the final α‐amidated product peptide. Tissue‐specific alternative splicing can generate forms of PAM retaining or lacking a domain required for the posttranslational separation of the two catalytic activities by endoproteases found in neuroendocrine tissue. Tissue‐specific alternative splicing also governs the presence of a transmembrane domain and generation of integral membrane or soluble forms of PAM. The COOH‐terminal domain of the integral membrane PAM proteins contains routing information essential for the retrieval of PAM from the surface of endocrine and nonendocrine cells. Tissue‐specific endoproteolytic processing can generate soluble PAM proteins from integral membrane precursors. Soluble PAM proteins are rapidly secreted from stably transfected nonneuroendo‐crine cells but are stored in the regulated secretory granules characteristic of neurons and endocrine cells.
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PAM catalyzes two-step carboxyterminal amidation of peptides.
“PAM is a bifunctional enzyme catalyzing two-step carboxyterminal amidation of peptides.”
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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 [147]
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 [147]
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 [147]
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 [147]
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Self-citationProteomic analysis of rat atrial secretory granules: a platform for testable hypotheses.
Muth, E., Driscoll, W., Smalstig, A., Goping, G., & Mueller, G. (2004) · Biochimica et Biophysica Acta · doi:10.1016/j.bbapap.2004.03.007 · Cited by 44
A functionally atypical amidating enzyme from the human parasite Schistosoma mansoni
Mair, G., Niciu, M., Stewart, M. T., Brennan, G., Omar, H., Halton, D., Mains, R., Eipper, B., Maule, A., & Day, T. (2004) · The FASEB Journal · doi:10.1096/fj.03-0429com · Cited by 44 · see citing works
“PHM requires copper, O2, and ascorbate, and is the rate-limiting step in amidation (17, 19, 20).”
BackgroundSelf-citationBaek, J. H., & Lee, S. (2010) · Toxicon · doi:10.1016/j.toxicon.2009.10.023 · Cited by 43
Chen, L.-H., Johnson, R. C., & Milgram, S. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.50.33524 · Cited by 43
Self-citationPoulsen, L. L. C., Plá, I., Sánchez, A., Grøndahl, M. L., Marko‐Varga, G., Andersen, C. Y., Englund, A. L. M., & Malm, J. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110522 · Cited by 47 · see citing works
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Post-translational N-Glycosylation of a Truncated Form of a Peptide Processing Enzyme
Kolhekar, A. S., Quon, A. S. W., Berard, C. A., Mains, R. E., & Eipper, B. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.36.23012 · Cited by 44 · see citing works
Self-citationTandem mass spectrometry of amidated peptides.
Mouls, L., Subra, G., Aubagnac, J., Martínez, J., & Enjalbal, C. (2006) · Journal of Mass Spectrometry · doi:10.1002/jms.1118 · Cited by 39
Attenborough, R., Hayward, D. C., Kitahara, M. V., Miller, D. J., & Ball, E. E. (2012) · Molecular Biology and Evolution · doi:10.1093/molbev/mss114 · Cited by 36 · see citing works
“…PAMa NP_000910 Glauder et al. (1990) Monodelphis domestica PAM XP_001380068 Mus musculus PAM NP_038654 Rattus norvegicus PAMa NP_037132 Reviewed in Eipper et al. (1993) Xenopus laevis PAM-Aa NP_001079520 Mizuno et al. (1987), Iwasaki et al. (1991) PAM-Ba NP_001081254 Ohsuye et al. (1988), Suzuki…”
BackgroundA Venom-derived Neurotoxin, CsTx-1, from the Spider Cupiennius salei Exhibits Cytolytic Activities*
Kuhn-Nentwig, L., Fedorova, I. M., Lüscher, B., Kopp, L. S., Trachsel, C., Schaller, J., Vu, X. L., Seebeck, T., Streitberger, K., Nentwig, W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.339051 · Cited by 37
“Three different posttranslational processing steps are involved in the maturation process of CsTx-1; 1) cleavage of the signal peptide, 2) limited proteolysis of the acidic propeptide at the processing quadruplet motif (PQM: 44EQAR47) according to the EtoR rule (26), and 3) additionally, a C-terminal amidation taking…”
BackgroundSaldise, L., Martínez, A., Montuenga, L. M., Treston, A., Springall, D., Polak, J., & Vázquez, J. (1996) · Journal of Histochemistry and Cytochemistry · doi:10.1177/44.1.8543779 · Cited by 37
The Dual α-Amidation System in Scorpion Venom Glands
Delgado-Prudencio, G., Possani, L., Becerril, B., & Ortiz, E. (2019) · Toxins · doi:10.3390/toxins11070425 · Cited by 36
“These isoforms include configurations with and without internal proteolytic sites, resulting in both independent PHM and PAL, and the bifunctional PAM [27,33].”
BackgroundNeuropeptide Gene Families in Caenorhabditis elegans
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Mass spectrometric evidence for neuropeptide-amidating enzymes in
Bael, S. V., Watteyne, J., Boonen, K., Haes, W. D., Menschaert, G., Ringstad, N., Horvitz, H. R., Schoofs, L., Husson, S. J., & Temmerman, L. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000731 · Cited by 43 · see citing works
Beinfeld, M., Funkelstein, L., Foulon, T., Cadel, S., Kitagawa, K., Toneff, T., Reinheckel, T., Peters, C., & Hook, V. (2009) · Peptides · doi:10.1016/j.peptides.2009.06.030 · Cited by 34
Neuropeptides and photic behavior in Cnidaria
Plickert, G., & Schneider, B. (2004) · Hydrobiologia · doi:10.1007/s10750-004-2689-x · Cited by 30 · see citing works
“C-terminal amidation is the rate-limiting step in peptide biosynthesis (Eipper et al., 1993) and is likely essential for receptor binding and activation (review by Kulathila et al.”
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Secretory Granule Membrane Protein Recycles through Multivesicular Bodies
Bäck, N., Rajagopal, C., Mains, R. E., & Eipper, B. A. (2010) · Traffic · doi:10.1111/j.1600-0854.2010.01066.x · Cited by 32 · see citing works
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Chioti, V. T., Clark, K. A., Ganley, J. G., Han, E. J., & Seyedsayamdost, M. R. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c11740 · Cited by 34 · see citing works
Industrial Fermentation of Vitamin C
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Baptista-Saidemberg, N. B., Saidemberg, D., de Souza, B. M., Cesar-Tognoli, L. M. M., Ferreira, V., Mendes, M., Cabrera, M. P. D. S., Ruggiero, J., & Palma, M. (2010) · Toxicon · doi:10.1016/j.toxicon.2010.06.011 · Cited by 32
Meskini, R. E., Galano, G. J., Marx, R., Mains, R., & Eipper, B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008062200 · Cited by 32 · see citing works
Self-citation
- Authors
- Eipper, B. A., Milgram, S. L., Jean Husten, E., Yun, H., & Mains, R. E.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Eipper, Betty A.
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 1993-04
- Volume
- 2
- Issue
- 4
- Pages
- 489-497
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC2142366
- OpenAlex
- W2029240910
- Cited by
- 270
- References
- 0
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 10 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 9 · 2013: 8 · 2012: 13
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Public Health Service (DK-32949, DK-32948, DA-00266, DA-00098, DA-00097, GM-15293)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- peptidylglycine alpha-amidating monooxygenase, post-translational modification, alternative splicing, transmembrane domain, integral membrane proteins, endoproteolytic processing, neuroendocrine cells, multifunctional enzyme
- MeSH terms
- Animals, Binding Sites, Enzyme Precursors, Humans, Mixed Function Oxygenases, Multienzyme Complexes, Neurosecretory Systems, Molecular Structure, Alternative Splicing, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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