EzCatDB: M00214
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DB codeM00214
CATH domainDomain 12.60.120.310 : Jelly RollsCatalytic domain
Domain 22.60.120.230 : Jelly RollsCatalytic domain
Domain 32.120.10.- : Neuraminidase
Domain 4-.-.-.-
E.C.1.14.17.3,4.3.2.5
CSA1opm
MACiEM0135

CATH domainRelated DB codes (homologues)
2.60.120.230 : Jelly RollsD00462

Enzyme Name
UniProtKBKEGG

P14925
Protein namePeptidyl-glycine alpha-amidating monooxygenasepeptidylglycine monooxygenase
   (EC 1.14.17.3)

peptidylglycine 2-hydroxylase
   (EC 1.14.17.3)

peptidyl alpha-amidating enzyme
   (EC 1.14.17.3)

peptide-alpha-amide synthetase
   (EC 1.14.17.3)

synthase, peptide alpha-amide
   (EC 1.14.17.3)

peptide alpha-amidating enzyme
   (EC 1.14.17.3)

peptide alpha-amide synthase
   (EC 1.14.17.3)

peptidylglycine alpha-hydroxylase
   (EC 1.14.17.3)

peptidylglycine alpha-amidating monooxygenase
   (EC 1.14.17.3)

PAM-A
   (EC 1.14.17.3)

PAM-B
   (EC 1.14.17.3)

PAM
   (EC 1.14.17.3)

peptidylamidoglycolate lyase
   (EC 4.3.2.5)

alpha-hydroxyglycine amidating dealkylase
   (EC 4.3.2.5)

peptidyl-alpha-hydroxyglycine alpha-amidating lyase
   (EC 4.3.2.5)

HGAD
   (EC 4.3.2.5)

PGL
   (EC 4.3.2.5)

PAL
   (EC 4.3.2.5)

peptidylamidoglycolate peptidylamide-lyase
   (EC 4.3.2.5)

SynonymsPAM
IncludesPeptidylglycine alpha-hydroxylating monooxygenase
(PHM)
   EC 1.14.17.3
Peptidyl-alpha-hydroxyglycine alpha-amidating lyase
   EC 4.3.2.5
Peptidylamidoglycolate lyase
(PAL)
RefSeqNP_037132.2 (Protein)
NM_013000.2 (DNA/RNA sequence)
PfamPF01082 (Cu2_monooxygen)
PF01436 (NHL)
[Graphical view]


UniProtKB:Accession NumberP14925
Entry nameAMD_RAT
ActivityPeptidylglycine + ascorbate + O(2) = peptidyl(2-hydroxyglycine) + dehydroascorbate + H(2)O.,Peptidylamidoglycolate = peptidyl amide + glyoxylate.
SubunitMonomer. Interacts with RASSF9.
Subcellular locationCytoplasmic vesicle, secretory vesicle membrane, Single-pass membrane protein. Note=Secretory granules.
CofactorZinc, for the lyase reaction.,Binds 2 copper ions per subunit, For the monoxygenase reaction.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00070C00038C02303C00072C00007C03303C03303C05422C00001C02179C00048
E.C.1.14.17.34.3.2.51.14.17.31.14.17.31.14.17.34.3.2.51.14.17.31.14.17.31.14.17.34.3.2.54.3.2.5
CompoundCopperZincPeptidylglycineAscorbateO2PeptidylamidoglycolatePeptidylamidoglycolateDehydroascorbateH2OPeptidyl amideGlyoxylate
Typeheavy metalheavy metalpeptide/proteincarbohydrate,aromatic ring (with hetero atoms other than nitrogen atoms)otherscarbohydrate,peptide/proteincarbohydrate,peptide/proteincarbohydrateH2Oamide group,peptide/proteincarbohydrate,carboxyl group
ChEBI28694
30052
29105

29073
27140
26689
15379


27956
15377

16891
PubChem23978
32051

54670067
977


440667
962
22247451

760
                   
1opmA01Bound:_CUUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1phmA01Bound:_CUUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
3phmA01Bound:_CUUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1sdwA01Bound:_CUUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnboundUnbound
1opmA02Analogue:_CUUnboundBound:IYG 801UnboundUnboundUnboundUnboundUnboundBound:HOH 803UnboundUnbound
1phmA02Bound:_CU 358UnboundUnboundUnboundUnboundUnboundUnboundUnboundBound:HOH 360UnboundUnbound
3phmA02Analogue:_CUUnboundUnboundUnboundUnboundUnboundUnboundUnboundBound:HOH 705UnboundUnbound
1sdwA02Bound:_CUUnboundBound:IYT 701UnboundBound:OXYUnboundUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P14925 & literature [16], [24] & [26]
pdbCatalytic residuesCofactor-binding residues
          
1opmA01HIS 108;GLN 170;HIS 172
HIS 107;HIS 108;HIS 172(Copper-1 binding)
1phmA01HIS 108;GLN 170;HIS 172
HIS 107;HIS 108;HIS 172(Copper-1 binding)
3phmA01HIS 108;GLN 170;HIS 172
HIS 107;HIS 108;HIS 172(Copper-1 binding)
1sdwA01HIS 108;GLN 170;HIS 172
HIS 107;HIS 108;HIS 172(Copper-1 binding)
1opmA02HIS 242
HIS 242;HIS 244;MET 314(Copper-2 binding)
1phmA02HIS 242
HIS 242;HIS 244;MET 314(Copper-2 binding)
3phmA02HIS 242
HIS 242;HIS 244;MET 314(Copper-2 binding)
1sdwA02HIS 242
HIS 242;HIS 244;MET 314(Copper-2 binding)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[8]Scheme 1
[10]Scheme 1, p.1303-1304
[13]Fig.6, p.15095
[16]Fig.8, p.979-981
[17]Fig.10, p.8014-8015
[18]Fig.10, Fig.11, Fig.12, p.1247-1252
[19]Fig.2, p.341-342, p.351-352
[24]Scheme 2, p.13280-13281
[26]Fig.5, p.7141
[27]Scheme 2, p.1818
[28]FIGURE 7, p.5744-5745
[29]Scheme 1, Scheme 2, Scheme 3, p.4997-5000
[30]Fig.2, Fig.3, p.394-398
[31]Fig.4, p.865-866

references
[1]
PubMed ID2792366
JournalFEBS Lett
Year1989
Volume255
Pages116-20
AuthorsSouthan C, Kruse LI
TitleSequence similarity between dopamine beta-hydroxylase and peptide alpha-amidating enzyme: evidence for a conserved catalytic domain.
[2]
PubMed ID2265607
JournalEMBO J
Year1990
Volume9
Pages4259-65
AuthorsSuzuki K, Shimoi H, Iwasaki Y, Kawahara T, Matsuura Y, Nishikawa Y
TitleElucidation of amidating reaction mechanism by frog amidating enzyme, peptidylglycine alpha-hydroxylating monooxygenase, expressed in insect cell culture.
[3]
PubMed ID2059626
JournalBiochemistry
Year1991
Volume30
Pages6189-94
AuthorsKatopodis AG, Ping DS, Smith CE, May SW
TitleFunctional and structural characterization of peptidylamidoglycolate lyase, the enzyme catalyzing the second step in peptide amidation.
[4]
PubMed ID1894599
JournalJ Biol Chem
Year1991
Volume266
Pages17004-10
AuthorsHusten EJ, Eipper BA
TitleThe membrane-bound bifunctional peptidylglycine alpha-amidating monooxygenase protein. Exploration of its domain structure through limited proteolysis.
[5]
PubMed ID8518727
JournalProtein Sci
Year1993
Volume2
Pages489-97
AuthorsEipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE
TitlePeptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains.
[6]
PubMed ID8198547
JournalBiochem J
Year1994
Volume300
Pages31-6
AuthorsLi C, Oldham CD, May SW
TitleNN-dimethyl-1,4-phenylenediamine as an alternative reductant for peptidylglycine alpha-amidating mono-oxygenase catalysis.
[7]
PubMed ID7893699
JournalBiochemistry
Year1995
Volume34
Pages2857-65
AuthorsEipper BA, Quon AS, Mains RE, Boswell JS, Blackburn NJ
TitleThe catalytic core of peptidylglycine alpha-hydroxylating monooxygenase: investigation by site-directed mutagenesis, Cu X-ray absorption spectroscopy, and electron paramagnetic resonance.
[8]
PubMed ID8823157
JournalBiochemistry
Year1996
Volume35
Pages12241-50
AuthorsBoswell JS, Reedy BJ, Kulathila R, Merkler D, Blackburn NJ
TitleStructural investigations on the coordination environment of the active-site copper centers of recombinant bifunctional peptidylglycine alpha-amidating enzyme.
[9]
PubMed ID9283080
JournalBiochemistry
Year1997
Volume36
Pages10901-9
AuthorsKolhekar AS, Keutmann HT, Mains RE, Quon AS, Eipper BA
TitlePeptidylglycine alpha-hydroxylating monooxygenase: active site residues, disulfide linkages, and a two-domain model of the catalytic core.
[10]
CommentsX-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 45-354
Medline ID98028752
PubMed ID9360928
JournalScience
Year1997
Volume278
Pages1300-5
AuthorsPrigge ST, Kolhekar AS, Eipper BA, Mains RE, Amzel LM
TitleAmidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase.
Related PDB1phm
Related UniProtKBP14925
[11]
PubMed ID9609721
JournalBiochemistry
Year1998
Volume37
Pages8244-52
AuthorsFrancisco WA, Merkler DJ, Blackburn NJ, Klinman JP
TitleKinetic mechanism and intrinsic isotope effects for the peptidylglycine alpha-amidating enzyme reaction.
[12]
PubMed ID9868369
JournalTrends Biochem Sci
Year1998
Volume23
Pages474-5
AuthorsSlack FJ, Ruvkun G
TitleA novel repeat domain that is often associated with RING finger and B-box motifs.
[13]
PubMed ID10563791
JournalBiochemistry
Year1999
Volume38
Pages15086-96
AuthorsJaron S, Blackburn NJ
TitleDoes superoxide channel between the copper centers in peptidylglycine monooxygenase? A new mechanism based on carbon monoxide reactivity.
[14]
PubMed ID10079066
JournalBiochemistry
Year1999
Volume38
Pages3235-45
AuthorsWilcox BJ, Ritenour-Rodgers KJ, Asser AS, Baumgart LE, Baumgart MA, Boger DL, DeBlassio JL, deLong MA, Glufke U, Henz ME, King L 3rd, Merkler KA, Patterson JE, Robleski JJ, Vederas JC, Merkler DJ
TitleN-acylglycine amidation: implications for the biosynthesis of fatty acid primary amides.
[15]
PubMed ID10574929
JournalJ Biol Chem
Year1999
Volume274
Pages34646-56
AuthorsCaldwell BD, Darlington DN, Penzes P, Johnson RC, Eipper BA, Mains RE
TitleThe novel kinase peptidylglycine alpha-amidating monooxygenase cytosolic interactor protein 2 interacts with the cytosolic routing determinants of the peptide processing enzyme peptidylglycine alpha-amidating monooxygenase.
[16]
CommentsX-ray crystallography
PubMed ID10504734
JournalNat Struct Biol
Year1999
Volume6
Pages976-83
AuthorsPrigge ST, Kolhekar AS, Eipper BA, Mains RE, Amzel LM
TitleSubstrate-mediated electron transfer in peptidylglycine alpha-hydroxylating monooxygenase.
Related PDB1opm,3phm
[17]
PubMed ID10891082
JournalBiochemistry
Year2000
Volume39
Pages8007-16
AuthorsDriscoll WJ, Konig S, Fales HM, Pannell LK, Eipper BA, Mueller GP
TitlePeptidylglycine-alpha-hydroxylating monooxygenase generates two hydroxylated products from its mechanism-based suicide substrate, 4-phenyl-3-butenoic acid.
[18]
PubMed ID11028916
JournalCell Mol Life Sci
Year2000
Volume57
Pages1236-59
AuthorsPrigge ST, Mains RE, Eipper BA, Amzel LM
TitleNew insights into copper monooxygenases and peptide amidation: structure, mechanism and function.
[19]
PubMed ID10907745
JournalJ Biol Inorg Chem
Year2000
Volume5
Pages341-53
AuthorsBlackburn NJ, Rhames FC, Ralle M, Jaron S
TitleMajor changes in copper coordination accompany reduction of peptidylglycine monooxygenase: implications for electron transfer and the catalytic mechanism.
[20]
PubMed ID11389601
JournalBiochemistry
Year2001
Volume40
Pages6867-75
AuthorsJaron S, Blackburn NJ
TitleCharacterization of a half-apo derivative of peptidylglycine monooxygenase. Insight into the reactivity of each active site copper.
[21]
PubMed ID11395514
JournalJ Biol Chem
Year2001
Volume276
Pages29854-63
AuthorsBell-Parikh LC, Eipper BA, Mains RE
TitleResponse of an integral granule membrane protein to changes in pH.
[22]
PubMed ID11472020
JournalJ Biol Inorg Chem
Year2001
Volume6
Pages567-77
AuthorsRhames FC, Murthy NN, Karlin KD, Blackburn NJ
TitleIsocyanide binding to the copper(I) centers of the catalytic core of peptidylglycine monooxygenase (PHMcc).
[23]
PubMed ID11251076
JournalMol Biol Cell
Year2001
Volume12
Pages629-44
AuthorsAlam MR, Steveson TC, Johnson RC, Back N, Abraham B, Mains RE, Eipper BA
TitleSignaling mediated by the cytosolic domain of peptidylglycine alpha-amidating monooxygenase.
[24]
PubMed ID12403629
JournalBiochemistry
Year2002
Volume41
Pages13274-82
AuthorsJaron S, Mains RE, Eipper BA, Blackburn NJ
TitleThe catalytic role of the copper ligand H172 of peptidylglycine alpha-hydroxylating monooxygenase (PHM): a spectroscopic study of the H172A mutant.
[25]
CommentsDISULFIDE BONDS IN CATALYTIC DOMAIN.
Medline ID22257256
PubMed ID12369828
JournalBiochemistry
Year2002
Volume41
Pages12384-94
AuthorsKolhekar AS, Bell J, Shiozaki EN, Jin L, Keutmann HT, Hand TA, Mains RE, Eipper BA
TitleEssential features of the catalytic core of peptidyl-alpha-hydroxyglycine alpha-amidating lyase.
Related UniProtKBP14925
[26]
PubMed ID12795609
JournalBiochemistry
Year2003
Volume42
Pages7133-42
AuthorsBell J, El Meskini R, D'Amato D, Mains RE, Eipper BA
TitleMechanistic investigation of peptidylglycine alpha-hydroxylating monooxygenase via intrinsic tryptophan fluorescence and mutagenesis.
[27]
PubMed ID12590568
JournalBiochemistry
Year2003
Volume42
Pages1813-9
AuthorsFrancisco WA, Blackburn NJ, Klinman JP
TitleOxygen and hydrogen isotope effects in an active site tyrosine to phenylalanine mutant of peptidylglycine alpha-hydroxylating monooxygenase: mechanistic implications.
[28]
PubMed ID15134448
JournalBiochemistry
Year2004
Volume43
Pages5735-47
AuthorsChen P, Bell J, Eipper BA, Solomon EI
TitleOxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Spectroscopic definition of the resting sites and the putative CuIIM-OOH intermediate.
[29]
PubMed ID15080705
JournalJ Am Chem Soc
Year2004
Volume126
Pages4991-5000
AuthorsChen P, Solomon EI
TitleOxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Reaction mechanism and role of the noncoupled nature of the active site.
[30]
PubMed ID14975510
JournalMed Hypotheses
Year2004
Volume62
Pages392-400
AuthorsOwen TC, Merkler DJ
TitleA new proposal for the mechanism of glycine hydroxylation as catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM).
[31]
PubMed ID15131304
JournalScience
Year2004
Volume304
Pages864-7
AuthorsPrigge ST, Eipper BA, Mains RE, Amzel LM
TitleDioxygen binds end-on to mononuclear copper in a precatalytic enzyme complex.
Related PDB1sdw

comments
Although this enzyme has got two enzyme domains, one for redox reactions (1.14.17.3) and the other for lyase reaction (4.3.2.5), the structure of the domain for lyase reaction has not been determined yet.
According to the literature [19], this enzyme has got two copper sites, CuH or histidine site (copper-1) and CuM or methionine site (copper-2).
According to the literature [19], this enzyme catalyzes several distinct redox reactions:
(A) Reduction of Cu(II) to Cu(I) of the active-site (CuH and CuM) by dehydrogenation of Ascorbate:
(B) Electron transfer from CuH to CuM:
(C) Oxygenation of peptidylglycine by dioxygen (O2) at CuM, producing peptidyl-hydroxylglycine and water (H2O):

createdupdated
2005-04-252009-03-16


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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