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Information on EC 1.14.17.3 - peptidylglycine monooxygenase and Organism(s) Mus musculus and UniProt Accession P97467
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1.14.17.3 peptidylglycine monooxygenaseIUBMB Comments
A copper protein. The enzyme binds two copper ions with distinct roles during catalysis. Peptidylglycines with a neutral amino acid residue in the penultimate position are the best substrates for the enzyme. The product is unstable and dismutates to glyoxylate and the corresponding desglycine peptide amide, a reaction catalysed by EC 4.3.2.5 peptidylamidoglycolate lyase. In mammals, the two activities are part of a bifunctional protein. Involved in the final step of biosynthesis of alpha-melanotropin and related biologically active peptides.
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Word Map
- 1.14.17.3
-
glycine-extended
- neuropeptides
-
beta-monooxygenase
-
peptidyl-alpha-hydroxyglycine
-
prohormone
- alpha-hydroxyglycine
- peptidylamidoglycolate
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endoproteolytic
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neurointermediate
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corticotrope
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ascorbate-dependent
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exafs
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4.3.2.5
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4-phenyl-3-butenoic
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noncoupled
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side-on
- dbetam
- medicine
- analysis
- synthesis
- pharmacology
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
peptidylglycine alpha-hydroxylating monooxygenase, bifunctional pam, peptidylglycine monooxygenase, peptidyl-glycine alpha-amidating monooxygenase, alpha-ae, phmcc, peptidylglycine alpha-amidating mono-oxygenase, pam-b, peptidylglycine alpha-monooxygenase, peptidylglycine-alpha-amidating monooxygenase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
PAM
PAM-A
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-
-
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PAM-B
-
-
-
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peptide alpha-amidating enzyme
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-
-
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peptide alpha-amide synthase
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-
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peptide-alpha-amide synthetase
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-
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peptidyl alpha-amidating enzyme
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-
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peptidylglycine 2-hydroxylase
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-
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peptidylglycine alpha-amidating monooxygenase
peptidylglycine alpha-hydroxylase
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-
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synthase, peptide alpha-amide
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-
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PAM
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-
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peptidylglycine alpha-amidating monooxygenase
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peptidylglycine alpha-amidating monooxygenase
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peptidylglycine alpha-amidating monooxygenase
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two catalytic domains: peptidylglycine alpha-hydroxylating monooxygenase and peptidyl-alpha-hydroxyglycine alpha-amidating lyase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
[peptide]-glycine + 2 ascorbate + O2 = [peptide]-(2S)-2-hydroxyglycine + 2 monodehydroascorbate + H2O
bifunctional enzyme showing peptidylglycine alpha-hydroxylating monooxygenase, EC 1.14.17.3, and peptidylamidoglycolate lyase, PAL, EC 4.3.2.5, activities, the enzyme possesses 2 catalytic domains
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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-
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oxidation
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-
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reduction
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SYSTEMATIC NAME
IUBMB Comments
[peptide]-glycine,ascorbate:oxygen oxidoreductase (2-hydroxylating)
A copper protein. The enzyme binds two copper ions with distinct roles during catalysis. Peptidylglycines with a neutral amino acid residue in the penultimate position are the best substrates for the enzyme. The product is unstable and dismutates to glyoxylate and the corresponding desglycine peptide amide, a reaction catalysed by EC 4.3.2.5 peptidylamidoglycolate lyase. In mammals, the two activities are part of a bifunctional protein. Involved in the final step of biosynthesis of alpha-melanotropin and related biologically active peptides.
CAS REGISTRY NUMBER
COMMENTARY
90597-47-0
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
D-Tyr-Val-Gly + ascorbate + O2
D-Tyr-Val-2-hydroxyglycine + dehydroascorbate + H2O
-
-
-
-
?
peptidylglycine + ascorbate + O2
peptidyl(2-hydroxyglycine) + dehydroascorbate + H2O
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-
-
-
?
peptidylglycine + ascorbate + O2
peptidyl(2-hydroxyglycine) + dehydroascorbate + H2O
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peptidylglycine alpha-hydroxylating monooxygenase reaction
the carbinol is the substrate for the peptidylamidoglycolate lyase reaction, EC 4.3.2.5, forming glyoxylate and amidated peptide
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?
additional information
?
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C-terminally amidation of a range of peptides by the copper-dependent enzyme, peptidylglycine alpha-amidating monooxygenase, PAM
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-
?
additional information
?
-
-
enzyme is involved in peptide posttranslational activation
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-
?
additional information
?
-
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PAM is the only enzyme capable of amidating peptides, amidated peptides are numerous
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
peptidylglycine + ascorbate + O2
peptidyl(2-hydroxyglycine) + dehydroascorbate + H2O
-
-
-
-
?
peptidylglycine + ascorbate + O2
peptidyl(2-hydroxyglycine) + dehydroascorbate + H2O
-
peptidylglycine alpha-hydroxylating monooxygenase reaction
the carbinol is the substrate for the peptidylamidoglycolate lyase reaction, EC 4.3.2.5, forming glyoxylate and amidated peptide
-
?
additional information
?
-
C-terminally amidation of a range of peptides by the copper-dependent enzyme, peptidylglycine alpha-amidating monooxygenase, PAM
-
-
?
additional information
?
-
-
enzyme is involved in peptide posttranslational activation
-
-
?
additional information
?
-
-
PAM is the only enzyme capable of amidating peptides, amidated peptides are numerous
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
copper
copper
-
dependent on, copper-deficiency decreases the enzyme activity, tissue copper status, overview
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, hypoxia inhibits amidation of constitutively secreted POMC 18-kDa fragment
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
3 - 8
activity range, wild-type and mutant enzymes, pH profiles, overview
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
peptidylglycine monooxygenase from the HL-1 cell line shows a 5fold higher specific activity compared to the enzyme from rat atrium
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peptidylglycine alpha-amidating monooxygenase activity in copper-deficient lactating dams is reduced to 15% compared to controls. Pups fed by copper-deficient dams showed an earlier decrease of peptidylglycine alpha-amidating monooxygenase activity throughout lactation
additional information
-
enzyme expression level in different tissues in copper adequate and deficient status, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
the enzyme is localized to the perinuclear region in a complex reticular pattern resembling that of the Golgi complex
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
mutating the His residues His364, His366, and His367 to Ala in the His-rich cluster (His-Gly-His-His) in the linker region connecting the enzyme's two catalytic domains affects enzyme trafficking. H3A mutation eliminates the ability of internalized PAM-1 to return to secretory granules
physiological function
physiological function
additional information
the protease-resistant catalytic core of PHM (PHMcc) is followed by a well conserved cluster of three His residues. This His cluster is included in the final exon encoding PHMcc and is followed by a poorly conserved, protease-sensitive region encoded by a short exon present in each of the major splice variants of PAM. The non-catalytic linker region between PHM and PAL includes a 315-nt exon in PAM-1. Exon 16 plays an important role in PAM-1 trafficking and in the ability of PAM-1 to participate in transmembrane signaling
physiological function
decreasing luminal pH is thought to play a role in the entry of newly synthesized and endocytosed membrane proteins into secretory granules. Secretory granule membrane proteins are retrieved and reused or degraded after exocytosis. The two catalytic domains of peptidylglycine alpha-amidating monooxygenase (PAM) catalyze the sequential reactions that convert peptidyl-Gly substrates into amidated products. A conserved His-rich cluster (His-Gly-His-His) in the linker region connecting its two catalytic domains senses pH and is involved in enzyme trafficking
physiological function
PAM is a bifunctional enzyme, its copper-dependent peptidylglycine alpha-hydroxylating monooxygenase, PHM, domain converts peptidylglycine substrates to peptidyl-alpha-hydroxyglycine intermediates that are subsequently converted into amidated products plus glyoxylate by the zinc-dependent peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. The reaction catalyzed by PHM results in the stereospecific incorporation of one atom of molecular oxygen into the substrate in a reaction that involves two single electron transfer steps. PAM-mediated C-terminal amidation occurs across a range of biologically active endocrine and nervous system peptides and in many cases has been shown to be required for normal biological activity in vivo. Peptidylglycine alpha-amidating monooxygenase (PAM) is solely responsible for catalysis of amidation, a biologically important posttranslational modification. Peptide substrate amidation is strikingly sensitive to the exposure of cells to moderate hypoxia, physiological effects of hypoxia may be PAM-dependent. Because PAM-dependent amidation is irreversible, bi-directional responses that rapidly upregulate and downregulate levels of amidation can only be observed on rapidly turned-over PAM substrates
physiological function
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regulation of the hypothalamic-pituitary-thyroid axis and body temperature are selected for evaluation
physiological function
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essential for the synthesis of all amidated neuropeptides, mice lacking peptidylglycine alpha-amidating monooxygenase do not survive gestation
physiological function
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the enzyme is a regulator of copper homeostasis in neuroendocrine cells
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). AMD_MOUSE
979
1
108963
Swiss-Prot
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
the protease-resistant catalytic core of PHM (PHMcc) is followed by a well conserved cluster of three His residues. This His cluster is included in the final exon encoding PHMcc and is followed by a poorly conserved, protease-sensitive region encoded by a short exon present in each of the major splice variants of PAM. The non-catalytic linker region between PHM and PAL includes a 315-nt exon in PAM-1. Exon 16 plays an important role in PAM-1 trafficking and in the ability of PAM-1 to participate in transmembrane signaling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H364A/H366A/H367A
site-directed mutagenesis. mutant PAM-1/H3A shows affected trafficking through the endogenous membranes. The PAM-1/H3A mutant exhibits the same pH optimum as the wild-type of pH 4.5, but shows slightly lower activity from pH 5.5-7.0. Mutant PAM-1/H3A and wild-type PAM-1 are processed differently when expressed in AtT-20 corticotrope tumor cells. Proteolytic processing of PAM-1 and PAM-1/H3A in AtT-20 cells is similar. Newly synthesized PAM-1/H3A disappears more quickly than newly synthesized PAM-1 in the cells. The H3A mutation eliminates the ability of internalized PAM-1 to return to secretory granules. Alkalinizing agents show differential effects on PAM-1 and PAM-1/H3A. Phenotype comparisons of wild-type and mutant enzymes and enzyme expressing cells, overview
additional information
siRNA knockdown of PAM is accompanied by a loss of 18 kDa JP-NH2 immunoactivity with gamma3-MSH immunoactivity remaining unaffected
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
oxygen sensitivity of the peptidylglycine alpha-amidating monooxygenase (PAM) in neuroendocrine cells
745332
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant GST-tagged wild-type and mutant enzymes from Escherichia coli strain BL21 by glutathione affinity chromatography, tag cleavage by HRV3C protease overnight, and followed by anion echange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene PAM, splice variant PAM-1, recombinant expression of GST-tagged wild-type and mutant PAM-1/H3A enzymes in stable AtT-20 and HEK293 cells cell lines, and recombinant expression of GST-tagged wild-type and mutant PAM-1/H3A enzymes Escherichia coli strain BL21
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
enzyme PAM-dependent amidation has the potential to signal oxygen levels in the same range as the hypoxia-inducible factor (HIF) system
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Prohaska, J.R.; Gybina, A.A.; Broderius, M.; Brokate, B.
Peptidylglycine-alpha-amidating monooxygenase activity and protein are lower in copper-deficient rats and suckling copper-deficient mice
Arch. Biochem. Biophys.
434
212-220
2005
Mus musculus, Rattus norvegicus
Prohaska, J.R.; Broderius, M.
Plasma peptidylglycine alpha-amidating monooxygenase (PAM) and ceruloplasmin are affected by age and copper status in rats and mice
Comp. Biochem. Physiol. B
143
360-366
2006
Mus musculus, Rattus norvegicus
Driscoll, W.J.; Hill, D.; Smalstig, A.; Mueller, G.P.
Murine atrial HL-1 cells express highly active peptidylglycine alpha-amidating enzyme
Peptides
27
1547-1553
2006
Mus musculus
Bousquet-Moore, D.; Ma, X.M.; Nillni, E.A.; Czyzyk, T.A.; Pintar, J.E.; Eipper, B.A.; Mains, R.E.
Reversal of physiological deficits caused by diminished levels of peptidylglycine alpha-amidating monooxygenase by dietary copper
Endocrinology
150
1739-1747
2009
Mus musculus
Bousquet-Moore, D.; Prohaska, J.R.; Nillni, E.A.; Czyzyk, T.; Wetsel, W.C.; Mains, R.E.; Eipper, B.A.
Interactions of peptide amidation and copper: Novel biomarkers and mechanisms of neural dysfunction
Neurobiol. Dis.
37
130-140
2010
Mus musculus
Bousquet-Moore, D.; Mains, R.E.; Eipper, B.A.
Peptidylgycine alpha-amidating monooxygenase and copper: a gene-nutrient interaction critical to nervous system function
J. Neurosci. Res.
88
2535-2545
2010
Mus musculus
Otoikhian, A.; Barry, A.N.; Mayfield, M.; Nilges, M.; Huang, Y.; Lutsenko, S.; Blackburn, N.J.
Lumenal loop M672-P707 of the Menkes protein (ATP7A) transfers copper to peptidylglycine monooxygenase
J. Am. Chem. Soc.
134
10458-10468
2012
Mus musculus
Gaier, E.D.; Miller, M.B.; Ralle, M.; Aryal, D.; Wetsel, W.C.; Mains, R.E.; Eipper, B.A.
Peptidylglycine alpha-amidating monooxygenase heterozygosity alters brain copper handling with region specificity
J. Neurochem.
127
605-619
2013
Mus musculus
Vishwanatha, K.; Baeck, N.; Mains, R.E.; Eipper, B.A.
A histidine-rich linker region in peptidylglycine alpha-amidating monooxygenase has the properties of a pH sensor
J. Biol. Chem.
289
12404-12420
2014
Mus musculus (P97467)
Simpson, P.D.; Eipper, B.A.; Katz, M.J.; Gandara, L.; Wappner, P.; Fischer, R.; Hodson, E.J.; Ratcliffe, P.J.; Masson, N.
Striking oxygen sensitivity of the peptidylglycine alpha-amidating monooxygenase (PAM) in neuroendocrine cells
J. Biol. Chem.
290
24891-24901
2015
Drosophila melanogaster (O01404), Homo sapiens (P19021), Mus musculus (P97467)
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