EzCatDB: D00192

DB codeD00192
RLCP classification1.13.11400.1261
CATH domainDomain 13.40.630.10Catalytic domain
Domain 23.30.70.360
E.C.3.4.17.11
CSA1cg2

CATH domainRelated DB codes (homologues)
3.40.630.10D00512,S00406,S00407,D00193,D00467

Enzyme Name
Swiss-protKEGG

P06621
Protein nameCarboxypeptidase G2 (CPDG2) (EC 3.4.17.11) (Folate hydrolase G2) (Pteroylmonoglutamic acid hydrolase G2) (Glutamate carboxypeptidase)AltName: INN=Glucarpidase;glutamate carboxypeptidase
carboxypeptidase G
carboxypeptidase G1
carboxypeptidase G2
glutamyl carboxypeptidase
N-pteroyl-L-glutamate hydrolase
SynonymsNone


Swiss-prot:Accession NumberP06621
Entry nameCBPG_PSES6
ActivityRelease of C-terminal glutamate residues from a wide range of N-acylating moieties, including peptidyl, aminoacyl, benzoyl, benzyloxycarbonyl, folyl and pteroyl groups.
SubunitHomodimer.
Subcellular location
CofactorBinds 2 zinc ions per subunit.


CofactorsSubstratesProducts
KEGG-idC00038C00001C00012C00504C00012C00921C00025
CompoundZincH2OPeptideFolic acidPeptideDihydropteroateL-Glutamate
Typeheavy metalH2Opeptide/proteinamino acids,amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl grouppeptide/proteinamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carboxyl groupamino acids,carboxyl group
1cg2A01Bound:2x_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2B01Bound:2x_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2C01Bound:2x_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2D01Bound:2x_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2A02Bound:_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2B02Bound:_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2C02Bound:_ZN
UnboundUnboundUnboundUnboundUnbound
1cg2D02Bound:_ZN
UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P06621 & literature [3]
pdbCatalytic residuesCofactor-binding residues
1cg2A01GLU 175
GLU 176;HIS 385(Zinc-1 binding);HIS 112;GLU 200(Zinc-2 binding);ASP 141(Zinc-1 and -2 binding)
1cg2B01GLU 175
GLU 176;HIS 385(Zinc-1 binding);HIS 112;GLU 200(Zinc-2 binding);ASP 141(Zinc-1 and -2 binding)
1cg2C01GLU 175
GLU 176;HIS 385(Zinc-1 binding);HIS 112;GLU 200(Zinc-2 binding);ASP 141(Zinc-1 and -2 binding)
1cg2D01GLU 175
GLU 176;HIS 385(Zinc-1 binding);HIS 112;GLU 200(Zinc-2 binding);ASP 141(Zinc-1 and -2 binding)
1cg2A02

1cg2B02

1cg2C02

1cg2D02


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]p.342-344

references
[1]
PubMed ID2067015
JournalJ Mol Biol
Year1991
Volume220
Pages17-8
AuthorsLloyd LF, Collyer CA, Sherwood RF
TitleCrystallization and preliminary crystallographic analysis of carboxypeptidase G2 from Pseudomonas sp. strain RS-16.
[2]
PubMed ID9187245
JournalBiochim Biophys Acta
Year1997
Volume1339
Pages247-52
AuthorsRawlings ND, Barrett AJ
TitleStructure of membrane glutamate carboxypeptidase.
[3]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS)
Medline ID97238930
PubMed ID9083113
JournalStructure
Year1997
Volume5
Pages337-47
AuthorsRowsell S, Pauptit RA, Tucker AD, Melton RG, Blow DM, Brick P
TitleCrystal structure of carboxypeptidase G2, a bacterial enzyme with applications in cancer therapy.
Related PDB1cg2
Related Swiss-protP06621
[4]
PubMed ID9666335
JournalCurr Opin Struct Biol
Year1998
Volume8
Pages380-7
AuthorsMurzin AG
TitleHow far divergent evolution goes in proteins.
[5]
PubMed ID10360747
JournalBioorg Med Chem Lett
Year1999
Volume9
Pages1415-8
AuthorsRodriguez CE, Lu H, Dinh TT, Mlodnosky KL, Dastgah A, Lam VQ, Nichols CB, Berkman CE
TitleCompetitive inhibition of a glutamate carboxypeptidase by phosphonamidothionate derivatives of glutamic acid.
[6]
PubMed ID10090777
JournalJ Med Chem
Year1999
Volume42
Pages951-6
AuthorsKhan TH, Eno-Amooquaye EA, Searle F, Browne PJ, Osborn HM, Burke PJ
TitleNovel inhibitors of carboxypeptidase G2 (CPG2): potential use in antibody-directed enzyme prodrug therapy.
[7]
PubMed ID9882712
JournalMol Pharmacol
Year1999
Volume55
Pages179-85
AuthorsSpeno HS, Luthi-Carter R, Macias WL, Valentine SL, Joshi AR, Coyle JT
TitleSite-directed mutagenesis of predicted active site residues in glutamate carboxypeptidase II.
[8]
PubMed ID10595564
JournalProtein Sci
Year1999
Volume8
Pages2546-9
AuthorsMahadevan D, Saldanha JW
TitleThe extracellular regions of PSMA and the transferrin receptor contain an aminopeptidase domain: implications for drug design.
[9]
PubMed ID10531064
JournalScience
Year1999
Volume286
Pages779-82
AuthorsLawrence CM, Ray S, Babyonyshev M, Galluser R, Borhani DW, Harrison SC
TitleCrystal structure of the ectodomain of human transferrin receptor.
[10]
PubMed ID10715144
JournalJ Med Chem
Year2000
Volume43
Pages772-4
AuthorsNan F, Bzdega T, Pshenichkin S, Wroblewski JT, Wroblewska B, Neale JH, Kozikowski AP
TitleDual function glutamate-related ligands: discovery of a novel, potent inhibitor of glutamate carboxypeptidase II possessing mGluR3 agonist activity.
[11]
PubMed ID10739875
JournalPharmacol Ther
Year2000
Volume85
Pages207-15
AuthorsGalivan J, Ryan TJ, Chave K, Rhee M, Yao R, Yin D
TitleGlutamyl hydrolase. pharmacological role and enzymatic characterization.
[12]
PubMed ID11249132
JournalBioorg Med Chem
Year2001
Volume9
Pages395-402
AuthorsLu H, Berkman CE
TitleStereoselective inhibition of glutamate carboxypeptidase by chiral phosphonothioic acids.
[13]
PubMed ID11375762
JournalCurr Med Chem
Year2001
Volume8
Pages949-57
AuthorsJackson PF, Slusher BS
TitleDesign of NAALADase inhibitors: a novel neuroprotective strategy.
[14]
PubMed ID11708918
JournalJ Med Chem
Year2001
Volume44
Pages4170-5
AuthorsJackson PF, Tays KL, Maclin KM, Ko YS, Li W, Vitharana D, Tsukamoto T, Stoermer D, Lu XC, Wozniak K, Slusher BS
TitleDesign and pharmacological activity of phosphinic acid based NAALADase inhibitors.
[15]
PubMed ID11462970
JournalJ Med Chem
Year2001
Volume44
Pages298-301
AuthorsKozikowski AP, Nan F, Conti P, Zhang J, Ramadan E, Bzdega T, Wroblewska B, Neale JH, Pshenichkin S, Wroblewski JT
TitleDesign of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase).
[16]
PubMed ID12127534
JournalBioorg Med Chem Lett
Year2002
Volume12
Pages2189-92
AuthorsTsukamoto T, Flanary JM, Rojas C, Slusher BS, Valiaeva N, Coward JK
TitlePhosphonate and phosphinate analogues of N-acylated gamma-glutamylglutamate. potent inhibitors of glutamate carboxypeptidase II.
[17]
PubMed ID11856302
JournalEur J Biochem
Year2002
Volume269
Pages443-50
AuthorsHakansson K, Miller CG
TitleStructure of peptidase T from Salmonella typhimurium.
[18]
PubMed ID12213057
JournalJ Med Chem
Year2002
Volume45
Pages4140-52
AuthorsRong SB, Zhang J, Neale JH, Wroblewski JT, Wang S, Kozikowski AP
TitleMolecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors.
[19]
PubMed ID11921443
JournalProteomics
Year2002
Volume2
Pages271-9
AuthorsSpencer DI, Robson L, Purdy D, Whitelegg NR, Michael NP, Bhatia J, Sharma SK, Rees AR, Minton NP, Begent RH, Chester KA
TitleA strategy for mapping and neutralizing conformational immunogenic sites on protein therapeutics.
[20]
PubMed ID12885660
JournalBiophys J
Year2003
Volume85
Pages1165-75
AuthorsOcchipinti E, Martelli PL, Spinozzi F, Corsi F, Formantici C, Molteni L, Amenitsch H, Mariani P, Tortora P, Casadio R
Title3D structure of Sulfolobus solfataricus carboxypeptidase developed by molecular modeling is confirmed by site-directed mutagenesis and small angle X-ray scattering.
[21]
PubMed ID15027864
JournalJ Med Chem
Year2004
Volume47
Pages1729-38
AuthorsKozikowski AP, Zhang J, Nan F, Petukhov PA, Grajkowska E, Wroblewski JT, Yamamoto T, Bzdega T, Wroblewska B, Neale JH
TitleSynthesis of urea-based inhibitors as active site probes of glutamate carboxypeptidase II: efficacy as analgesic agents.

comments
This enzyme belongs to the peptidase family-M20A.
According to the literature [3], this enzyme must have a similar mechanism to that of bacterial leucine aminopeptidase (S00406 in this database). The catalytic reaction proceeds as follows (see [3]);
(1) Glu175 acts as a general base, which activate the bridging water between the two catalytic zinc ions.
(2) The activated bridging water molecule acts as a nucleophile to hydrolyze the scissile peptide bond.

createdupdated
2004-08-192009-02-26


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 2010)
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)

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