DB code: M00214

CATH domain 2.60.120.310 : Jelly Rolls Catalytic domain
2.60.120.230 : Jelly Rolls Catalytic domain
2.120.10.- : Neuraminidase
-.-.-.- :
E.C. 1.14.17.3 4.3.2.5
CSA 1opm
M-CSA 1opm
MACiE M0135

CATH domain Related DB codes (homologues)
2.60.120.230 : Jelly Rolls D00462

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Includes RefSeq Pfam
P14925 Peptidyl-glycine alpha-amidating monooxygenase
PAM
Peptidylglycine alpha-hydroxylating monooxygenase
(PHM)
EC 1.14.17.3
Peptidyl-alpha-hydroxyglycine alpha-amidating lyase
EC 4.3.2.5
Peptidylamidoglycolate lyase
(PAL)
NP_037132.2 (Protein)
NM_013000.2 (DNA/RNA sequence)
PF01082 (Cu2_monooxygen)
PF01436 (NHL)
[Graphical View]

KEGG enzyme name
peptidylglycine 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 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P14925 AMD_RAT Peptidylglycine + ascorbate + O(2) = peptidyl(2-hydroxyglycine) + dehydroascorbate + H(2)O. Peptidylamidoglycolate = peptidyl amide + glyoxylate. Monomer. Interacts with RASSF9. Cytoplasmic vesicle, secretory vesicle membrane, Single-pass membrane protein. Note=Secretory granules. Zinc, for the lyase reaction. Binds 2 copper ions per subunit, For the monoxygenase reaction.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00070 C00038 C02303 C00072 C00007 C03303 C03303 C05422 C00001 C02179 C00048
E.C. 1.14.17.3
4.3.2.5
1.14.17.3
1.14.17.3
1.14.17.3
4.3.2.5
1.14.17.3
1.14.17.3
1.14.17.3
4.3.2.5
4.3.2.5
Compound Copper Zinc Peptidylglycine Ascorbate O2 Peptidylamidoglycolate Peptidylamidoglycolate Dehydroascorbate H2O Peptidyl amide Glyoxylate
Type heavy metal heavy metal peptide/protein carbohydrate,aromatic ring (with hetero atoms other than nitrogen atoms) others carbohydrate,peptide/protein carbohydrate,peptide/protein carbohydrate H2O amide group,peptide/protein carbohydrate,carboxyl group
ChEBI 28694
 30052
 28694
 30052
 		29105
 29105
 		29073
 29073
 		15379
 26689
 27140
 15379
 26689
 27140
 		27956
 27956
 		15377
 15377
 		16891
 16891
PubChem 23978
 23978
 		32051
 32051
 		54670067
 54670067
 		977
 977
 		440667
 440667
 		22247451
 962
 22247451
 962
 		760
 760
1opmA01 Bound:_CU Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1phmA01 Bound:_CU Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3phmA01 Bound:_CU Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1sdwA01 Bound:_CU Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1opmA02 Analogue:_CU Unbound Bound:IYG_801 Unbound Unbound Unbound Unbound Unbound Bound:HOH_803 Unbound Unbound
1phmA02 Bound:_CU_358 Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:HOH_360 Unbound Unbound
3phmA02 Analogue:_CU Unbound Unbound Unbound Unbound Unbound Unbound Unbound Bound:HOH_705 Unbound Unbound
1sdwA02 Bound:_CU Unbound Bound:IYT_701 Unbound Bound:OXY Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P14925 & literature [16], [24] & [26]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1opmA01 HIS 108;GLN 170;HIS 172 HIS 107;HIS 108;HIS 172(Copper-1 binding)
1phmA01 HIS 108;GLN 170;HIS 172 HIS 107;HIS 108;HIS 172(Copper-1 binding)
3phmA01 HIS 108;GLN 170;HIS 172 HIS 107;HIS 108;HIS 172(Copper-1 binding)
1sdwA01 HIS 108;GLN 170;HIS 172 HIS 107;HIS 108;HIS 172(Copper-1 binding)
1opmA02 HIS 242 HIS 242;HIS 244;MET 314(Copper-2 binding)
1phmA02 HIS 242 HIS 242;HIS 244;MET 314(Copper-2 binding)
3phmA02 HIS 242 HIS 242;HIS 244;MET 314(Copper-2 binding)
1sdwA02 HIS 242 HIS 242;HIS 244;MET 314(Copper-2 binding)

References for Catalytic Mechanism
References Sections No. 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]
Resource
Comments
Medline ID
PubMed ID 2792366
Journal FEBS Lett
Year 1989
Volume 255
Pages 116-20
Authors Southan C, Kruse LI
Title Sequence similarity between dopamine beta-hydroxylase and peptide alpha-amidating enzyme: evidence for a conserved catalytic domain.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 2265607
Journal EMBO J
Year 1990
Volume 9
Pages 4259-65
Authors Suzuki K, Shimoi H, Iwasaki Y, Kawahara T, Matsuura Y, Nishikawa Y
Title Elucidation of amidating reaction mechanism by frog amidating enzyme, peptidylglycine alpha-hydroxylating monooxygenase, expressed in insect cell culture.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 2059626
Journal Biochemistry
Year 1991
Volume 30
Pages 6189-94
Authors Katopodis AG, Ping DS, Smith CE, May SW
Title Functional and structural characterization of peptidylamidoglycolate lyase, the enzyme catalyzing the second step in peptide amidation.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 1894599
Journal J Biol Chem
Year 1991
Volume 266
Pages 17004-10
Authors Husten EJ, Eipper BA
Title The membrane-bound bifunctional peptidylglycine alpha-amidating monooxygenase protein. Exploration of its domain structure through limited proteolysis.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 8518727
Journal Protein Sci
Year 1993
Volume 2
Pages 489-97
Authors Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE
Title Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 8198547
Journal Biochem J
Year 1994
Volume 300
Pages 31-6
Authors Li C, Oldham CD, May SW
Title NN-dimethyl-1,4-phenylenediamine as an alternative reductant for peptidylglycine alpha-amidating mono-oxygenase catalysis.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 7893699
Journal Biochemistry
Year 1995
Volume 34
Pages 2857-65
Authors Eipper BA, Quon AS, Mains RE, Boswell JS, Blackburn NJ
Title The catalytic core of peptidylglycine alpha-hydroxylating monooxygenase: investigation by site-directed mutagenesis, Cu X-ray absorption spectroscopy, and electron paramagnetic resonance.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 8823157
Journal Biochemistry
Year 1996
Volume 35
Pages 12241-50
Authors Boswell JS, Reedy BJ, Kulathila R, Merkler D, Blackburn NJ
Title Structural investigations on the coordination environment of the active-site copper centers of recombinant bifunctional peptidylglycine alpha-amidating enzyme.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9283080
Journal Biochemistry
Year 1997
Volume 36
Pages 10901-9
Authors Kolhekar AS, Keutmann HT, Mains RE, Quon AS, Eipper BA
Title Peptidylglycine alpha-hydroxylating monooxygenase: active site residues, disulfide linkages, and a two-domain model of the catalytic core.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 45-354
Medline ID 98028752
PubMed ID 9360928
Journal Science
Year 1997
Volume 278
Pages 1300-5
Authors Prigge ST, Kolhekar AS, Eipper BA, Mains RE, Amzel LM
Title Amidation of bioactive peptides: the structure of peptidylglycine alpha-hydroxylating monooxygenase.
Related PDB 1phm
Related UniProtKB P14925
[11]
Resource
Comments
Medline ID
PubMed ID 9609721
Journal Biochemistry
Year 1998
Volume 37
Pages 8244-52
Authors Francisco WA, Merkler DJ, Blackburn NJ, Klinman JP
Title Kinetic mechanism and intrinsic isotope effects for the peptidylglycine alpha-amidating enzyme reaction.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 9868369
Journal Trends Biochem Sci
Year 1998
Volume 23
Pages 474-5
Authors Slack FJ, Ruvkun G
Title A novel repeat domain that is often associated with RING finger and B-box motifs.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 10563791
Journal Biochemistry
Year 1999
Volume 38
Pages 15086-96
Authors Jaron S, Blackburn NJ
Title Does superoxide channel between the copper centers in peptidylglycine monooxygenase? A new mechanism based on carbon monoxide reactivity.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 10079066
Journal Biochemistry
Year 1999
Volume 38
Pages 3235-45
Authors Wilcox 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
Title N-acylglycine amidation: implications for the biosynthesis of fatty acid primary amides.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 10574929
Journal J Biol Chem
Year 1999
Volume 274
Pages 34646-56
Authors Caldwell BD, Darlington DN, Penzes P, Johnson RC, Eipper BA, Mains RE
Title The 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.
Related PDB
Related UniProtKB
[16]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 10504734
Journal Nat Struct Biol
Year 1999
Volume 6
Pages 976-83
Authors Prigge ST, Kolhekar AS, Eipper BA, Mains RE, Amzel LM
Title Substrate-mediated electron transfer in peptidylglycine alpha-hydroxylating monooxygenase.
Related PDB 1opm 3phm
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 10891082
Journal Biochemistry
Year 2000
Volume 39
Pages 8007-16
Authors Driscoll WJ, Konig S, Fales HM, Pannell LK, Eipper BA, Mueller GP
Title Peptidylglycine-alpha-hydroxylating monooxygenase generates two hydroxylated products from its mechanism-based suicide substrate, 4-phenyl-3-butenoic acid.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 11028916
Journal Cell Mol Life Sci
Year 2000
Volume 57
Pages 1236-59
Authors Prigge ST, Mains RE, Eipper BA, Amzel LM
Title New insights into copper monooxygenases and peptide amidation: structure, mechanism and function.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 10907745
Journal J Biol Inorg Chem
Year 2000
Volume 5
Pages 341-53
Authors Blackburn NJ, Rhames FC, Ralle M, Jaron S
Title Major changes in copper coordination accompany reduction of peptidylglycine monooxygenase: implications for electron transfer and the catalytic mechanism.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 11389601
Journal Biochemistry
Year 2001
Volume 40
Pages 6867-75
Authors Jaron S, Blackburn NJ
Title Characterization of a half-apo derivative of peptidylglycine monooxygenase. Insight into the reactivity of each active site copper.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 11395514
Journal J Biol Chem
Year 2001
Volume 276
Pages 29854-63
Authors Bell-Parikh LC, Eipper BA, Mains RE
Title Response of an integral granule membrane protein to changes in pH.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11472020
Journal J Biol Inorg Chem
Year 2001
Volume 6
Pages 567-77
Authors Rhames FC, Murthy NN, Karlin KD, Blackburn NJ
Title Isocyanide binding to the copper(I) centers of the catalytic core of peptidylglycine monooxygenase (PHMcc).
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 11251076
Journal Mol Biol Cell
Year 2001
Volume 12
Pages 629-44
Authors Alam MR, Steveson TC, Johnson RC, Back N, Abraham B, Mains RE, Eipper BA
Title Signaling mediated by the cytosolic domain of peptidylglycine alpha-amidating monooxygenase.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 12403629
Journal Biochemistry
Year 2002
Volume 41
Pages 13274-82
Authors Jaron S, Mains RE, Eipper BA, Blackburn NJ
Title The catalytic role of the copper ligand H172 of peptidylglycine alpha-hydroxylating monooxygenase (PHM): a spectroscopic study of the H172A mutant.
Related PDB
Related UniProtKB
[25]
Resource
Comments DISULFIDE BONDS IN CATALYTIC DOMAIN.
Medline ID 22257256
PubMed ID 12369828
Journal Biochemistry
Year 2002
Volume 41
Pages 12384-94
Authors Kolhekar AS, Bell J, Shiozaki EN, Jin L, Keutmann HT, Hand TA, Mains RE, Eipper BA
Title Essential features of the catalytic core of peptidyl-alpha-hydroxyglycine alpha-amidating lyase.
Related PDB
Related UniProtKB P14925
[26]
Resource
Comments
Medline ID
PubMed ID 12795609
Journal Biochemistry
Year 2003
Volume 42
Pages 7133-42
Authors Bell J, El Meskini R, D'Amato D, Mains RE, Eipper BA
Title Mechanistic investigation of peptidylglycine alpha-hydroxylating monooxygenase via intrinsic tryptophan fluorescence and mutagenesis.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 12590568
Journal Biochemistry
Year 2003
Volume 42
Pages 1813-9
Authors Francisco WA, Blackburn NJ, Klinman JP
Title Oxygen and hydrogen isotope effects in an active site tyrosine to phenylalanine mutant of peptidylglycine alpha-hydroxylating monooxygenase: mechanistic implications.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 15134448
Journal Biochemistry
Year 2004
Volume 43
Pages 5735-47
Authors Chen P, Bell J, Eipper BA, Solomon EI
Title Oxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Spectroscopic definition of the resting sites and the putative CuIIM-OOH intermediate.
Related PDB
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 15080705
Journal J Am Chem Soc
Year 2004
Volume 126
Pages 4991-5000
Authors Chen P, Solomon EI
Title Oxygen activation by the noncoupled binuclear copper site in peptidylglycine alpha-hydroxylating monooxygenase. Reaction mechanism and role of the noncoupled nature of the active site.
Related PDB
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 14975510
Journal Med Hypotheses
Year 2004
Volume 62
Pages 392-400
Authors Owen TC, Merkler DJ
Title A new proposal for the mechanism of glycine hydroxylation as catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM).
Related PDB
Related UniProtKB
[31]
Resource
Comments
Medline ID
PubMed ID 15131304
Journal Science
Year 2004
Volume 304
Pages 864-7
Authors Prigge ST, Eipper BA, Mains RE, Amzel LM
Title Dioxygen binds end-on to mononuclear copper in a precatalytic enzyme complex.
Related PDB 1sdw
Related UniProtKB

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):

Created Updated
2005-04-25 2009-03-16