EzCatDB: D00467

DB codeD00467
RLCP classification1.13.11110.262
CATH domainDomain 13.30.70.340
Domain 23.40.630.10Catalytic domain
E.C.3.4.17.1
CSA1cbx,5cpa
MACiEM0171

CATH domainRelated DB codes (homologues)
3.30.70.340D00512,D00193
3.40.630.10D00512,S00406,S00407,D00192,D00193

Enzyme Name
Swiss-protKEGG

O97389P09954P00730
Protein name
Carboxypeptidase A1Carboxypeptidase A1carboxypeptidase A
carboxypolypeptidase
pancreatic carboxypeptidase A
tissue carboxypeptidase A
SynonymsCarboxypeptidase A
EC 3.4.17.1
EC 3.4.17.1
EC 3.4.17.1


Swiss-prot:Accession NumberO97389P09954P00730
Entry nameO97389_HELAMCBPA1_PIGCBPA1_BOVIN
Activity
Release of a C-terminal amino acid, but little or no action with -Asp, -Glu, -Arg, -Lys or -Pro.Release of a C-terminal amino acid, but little or no action with -Asp, -Glu, -Arg, -Lys or -Pro.
Subunit
Monomer.Monomer. The zymogen is secreted as a ternary complex composed of procarboxypeptidase A, chymotrypsinogen C and proproteinase E.
Subcellular location
Secreted.Secreted, extracellular space.
Cofactor
Binds 1 zinc ion per subunit.Binds 1 zinc ion per subunit.


CofactorsSubstratesProductsintermediates
KEGG-idC00038C00017C00012C00001C00012C00151
CompoundZincProteinPeptideH2OPeptideL-Amino acidtetrahedral
Typeheavy metalpeptide/proteinpeptide/proteinH2Opeptide/proteinamino acids
1jqgA01UnboundUnboundUnbound
UnboundUnbound
1pcaAUnboundUnboundUnbound
UnboundUnbound
1pytAUnboundUnboundUnbound
UnboundUnbound
1jqgA02Bound:_ZNUnboundUnbound
UnboundUnbound
1pcaBBound:_ZNUnboundUnbound
UnboundBound:VAL
1arlAUnboundUnboundUnbound
UnboundUnbound
1armAAnalogue:_HG 308UnboundUnbound
UnboundUnboundTransition-state-analogue:TRS
1bavABound:_ZNUnboundUnbound
UnboundAnalogue:BIP
1bavBBound:_ZNUnboundUnbound
UnboundAnalogue:BIP
1bavCBound:_ZNUnboundUnbound
UnboundAnalogue:BIP
1bavDBound:_ZNUnboundUnbound
UnboundAnalogue:BIP
1cbxABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:BZS
1cpaABound:_ZNUnboundBound:GLY-TYR(chain S)
UnboundUnbound
1cpsABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:CPM
1cpxABound:_ZN 308UnboundUnboundAnalogue:_OHUnboundUnbound
1ee3PAnalogue:_CD 350UnboundUnbound
UnboundUnbound
1ellPAnalogue:_CD 350UnboundUnbound
UnboundUnbound
1elmPAnalogue:_CD 350UnboundUnbound
UnboundUnbound
1f57ABound:_ZNUnboundUnbound
UnboundAnalogue:DCY
1hdqABound:_ZNUnboundAnalogue:INF
UnboundUnbound
1hduABound:_ZNUnboundAnalogue:ING
UnboundUnbound
1hduBBound:_ZNUnboundAnalogue:ING
UnboundUnbound
1hduDBound:_ZNUnboundAnalogue:ING
UnboundUnbound
1hduEBound:_ZNUnboundAnalogue:ING
UnboundUnbound
1heeABound:_ZNUnboundAnalogue:LHY
UnboundUnbound
1heeBBound:_ZNUnboundAnalogue:LHY
UnboundUnbound
1heeDBound:_ZNUnboundAnalogue:LHY
UnboundUnbound
1heeEBound:_ZNUnboundAnalogue:LHY
UnboundUnbound
1iy7ABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:CXA
1m4lABound:_ZNUnboundUnbound
UnboundUnbound
1pytBBound:_ZNUnboundUnbound
UnboundUnbound
1ymeABound:_ZNUnboundUnbound
UnboundUnbound
1zlhABound:_ZN 555UnboundUnbound
Analogue:LEU 74(chain B)Unbound
2abzABound:_ZNUnboundUnbound
Analogue:VAL 66(chain C)Unbound
2abzBBound:_ZNUnboundUnbound
Analogue:VAL 66(chain E)Unbound
2ctbABound:_ZNUnboundUnbound
UnboundUnbound
2ctcABound:_ZNUnboundUnbound
UnboundAnalogue:HFA
3cpaABound:_ZNUnboundBound:GLY-TYR(chain S)
UnboundUnbound
4cpaABound:_ZNUnboundUnbound
Bound:VAL 38(chain I)Bound:GLY(chain G)
5cpaABound:_ZNUnboundUnbound
UnboundUnbound
6cpaABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:ZAF
7cpaABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:FVF
8cpaABound:_ZNUnboundUnbound
UnboundUnboundTransition-state-analogue:AGF

Active-site residues
resource
Swiss-prot;P00730, P09954
pdbCatalytic residuesCofactor-binding residuesMain-chain involved in catalysis
1jqgA01


1pcaA


1pytA


1jqgA02ARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1pcaBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1arlAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1armAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1bavAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1bavBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1bavCARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1bavDARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1cbxAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1cpsAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1cpxAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1ee3PARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1ellPARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1elmPARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1f57AARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1hdqAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1hduAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1hduBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1hduDARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1hduEARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1heeAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1heeBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1heeDARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1heeEARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1iy7AARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1m4lAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1pytBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1ymeAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
1zlhAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
2abzAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
2abzBARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
2ctbAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
2ctcAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
3cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
4cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
5cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
6cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
7cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197
8cpaAARG 127;GLU 270
HIS 69;GLU 72;HIS 196(Zinc binding)
SER 197

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]p.3877
[4]p.495-497
[6]p.20-24
[10]p.7571-7572
[13]Fig.10, p.63-69
[15]Fig.4, p.128521
[17]Fig.8, p.5551-5553
[18]Fig.2, p.206982
[21]p.8178-8179
[22]Fig.6, p.6396-6399
[26]

[27]p.146-150
[28]p.576-577
[32]p.383-384
[34]p.4592-4594
[37]p.2381-2382
[39]p.8714
[47]p.285
[48]Fig.5, p.821
[49]Fig.2, p.10199
[51]p.1196-1199
[55]Fig.8, p.497-499
[57]p.327-332

references
[1]
PubMed ID6933442
JournalProc Natl Acad Sci U S A
Year1980
Volume77
Pages3875-8
AuthorsLipscomb WN
TitleCarboxypeptidase A mechanisms.
[2]
PubMed ID7274452
JournalFEBS Lett
Year1981
Volume128
Pages13-6
AuthorsWicker C, Puigserver A
TitleFurther studies on subunit III of bovine procarboxypeptidase A. Structure and reactivity of the weakly functional active site.
[3]
PubMed ID7152041
JournalFEBS Lett
Year1982
Volume149
Pages257-60
AuthorsAviles FX, Segundo BS, Vilanova M, Cuchillo CM, Turner C
TitleThe activation segment of procarboxypeptidase A from porcine pancreas constitutes a folded structural domain.
[4]
CommentsX-ray Diffraction
PubMed ID7154070
JournalJ Mol Biol
Year1982
Volume160
Pages475-98
AuthorsRees DC, Lipscomb WN
TitleRefined crystal structure of the potato inhibitor complex of carboxypeptidase A at 2.5 A resolution.
Related PDB4cpa
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS).
PubMed ID6887246
JournalJ Mol Biol
Year1983
Volume168
Pages367-87
AuthorsRees DC, Lewis M, Lipscomb WN
TitleRefined crystal structure of carboxypeptidase A at 1.54 A resolution.
Related PDB5cpa
Related Swiss-protP00730
[6]
PubMed ID2994404
JournalAdv Enzymol Relat Areas Mol Biol
Year1985
Volume57
Pages1-84
AuthorsPatchett AA, Cordes EH
TitleThe design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme.
[7]
PubMed ID4026847
JournalBiochem Biophys Res Commun
Year1985
Volume130
Pages97-103
AuthorsAviles FX, Vendrell J, Burgos FJ, Soriano F, Mendez E
TitleSequential homologies between procarboxypeptidases A and B from porcine pancreas.
[8]
PubMed ID3636229
JournalEur J Biochem
Year1986
Volume157
Pages531-8
AuthorsKerfelec B, Cambillau C, Puigserver A, Chapus C
TitleThe inactive subunit of ruminant procarboxypeptidase A-S6 complexes. Structural basis of inactivity and physiological role.
[9]
PubMed ID3783689
JournalJ Mol Biol
Year1986
Volume189
Pages709-10
AuthorsCambillau C, Kerfelec B, Foglizzo E, Chapus C
TitleCrystallization and preliminary X-ray study of subunit III of the bovine pancreatic procarboxypeptidase A-S6 ternary complex.
[10]
CommentsX-ray Diffraction
PubMed ID3463986
JournalProc Natl Acad Sci U S A
Year1986
Volume83
Pages7568-72
AuthorsChristianson DW, Lipscomb WN
TitleX-ray crystallographic investigation of substrate binding to carboxypeptidase A at subzero temperature.
Related PDB1cpa,3cpa
[11]
PubMed ID2458099
JournalBiochem J
Year1988
Volume251
Pages901-5
AuthorsVilanova M, Vendrell J, Cuchillo CM, Aviles FX
TitleAnalysis of the conformation and ligand-binding properties of the activation segment of pig procarboxypeptidase A.
[12]
PubMed ID3208711
JournalEur Biophys J
Year1988
Volume16
Pages95-100
AuthorsKerfelec B, Chapus C, Vachette P
TitleMorphology of the procarboxypeptidase A-S6 complex. A solution X-ray scattering study.
[13]
JournalAcc Chem Res
Year1989
Volume22
Pages62-69
AuthorsChristianson DW, Lipscomb WN
TitleCarboxypeptidase A
[14]
PubMed ID2920728
JournalEur J Biochem
Year1989
Volume179
Pages609-16
AuthorsPascual R, Burgos FJ, Salva M, Soriano F, Mendez E, Aviles FX
TitlePurification and properties of five different forms of human procarboxypeptidases.
[15]
PubMed ID2568989
JournalJ Biol Chem
Year1989
Volume264
Pages12849-53
AuthorsChristianson DW, Mangani S, Shoham G, Lipscomb WN
TitleBinding of D-phenylalanine and D-tyrosine to carboxypeptidase A.
[16]
PubMed ID2327981
JournalBiochem J
Year1990
Volume267
Pages213-20
AuthorsVendrell J, Aviles FX, Vilanova M, Turner CH, Crane-Robinson C
Title1H-n.m.r. studies of the isolated activation segment from pig procarboxypeptidase A.
[17]
CommentsX-ray Diffraction
PubMed ID2386784
JournalBiochemistry
Year1990
Volume29
Pages5546-55
AuthorsKim H, Lipscomb WN
TitleCrystal structure of the complex of carboxypeptidase A with a strongly bound phosphonate in a new crystalline form: comparison with structures of other complexes.
Related PDB6cpa
[18]
PubMed ID2243116
JournalJ Biol Chem
Year1990
Volume265
Pages20692-8
AuthorsPhillips MA, Fletterick R, Rutter WJ
TitleArginine 127 stabilizes the transition state in carboxypeptidase.
[19]
PubMed ID2324107
JournalJ Biol Chem
Year1990
Volume265
Pages6949-53
AuthorsVendrell J, Cuchillo CM, Aviles FX
TitleThe tryptic activation pathway of monomeric procarboxypeptidase A.
[20]
PubMed ID2104979
JournalProc Natl Acad Sci U S A
Year1990
Volume87
Pages220-4
AuthorsVallee BL, Auld DS
TitleActive-site zinc ligands and activated H2O of zinc enzymes.
[21]
CommentsX-ray Diffraction
PubMed ID1868092
JournalBiochemistry
Year1991
Volume30
Pages8171-80
AuthorsKim H, Lipscomb WN
TitleComparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography.
Related PDB7cpa,8cpa
[22]
PubMed ID2007591
JournalJ Biol Chem
Year1991
Volume266
Pages6393-400
AuthorsMock WL, Zhang JZ
TitleMechanistically significant diastereoselection in the sulfoximine inhibition of carboxypeptidase A.
[23]
PubMed ID1515065
JournalBiol Chem Hoppe Seyler
Year1992
Volume373
Pages387-92
AuthorsVendrell J, Guasch A, Coll M, Villegas V, Billeter M, Wider G, Huber R, Wuthrich K, Aviles FX
TitlePancreatic procarboxypeptidases: their activation processes related to the structural features of the zymogens and activation segments.
[24]
JournalJ Am Chem Soc
Year1992
Volume114
Pages5295-5303
AuthorsBritt BM, Peticolas WL
TitleRaman spectral evidence for an anhydride intermediate in the catalysis of ester hydrolysis by carboxypeptidase A
[25]
JournalJ Am Chem Soc
Year1992
Volume114
Pages2281-2282
AuthorsYun M, Park C, Kim S, Nam D, Kim SC, Kim H
TitleThe x-ray crystallographic study of covalently modified carboxypeptidase A by 2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator
[26]
CommentsX-ray Diffraction
PubMed ID1527041
JournalJ Biol Chem
Year1992
Volume267
Pages19192-7
AuthorsCappalonga AM, Alexander RS, Christianson DW
TitleStructural comparison of sulfodiimine and sulfonamide inhibitors in their complexes with zinc enzymes.
Related PDB1cps
[27]
CommentsX-RAY CRYSTALLOGRAPHY (2 ANGSTROMS) OF 17-419.
PubMed ID1548696
JournalJ Mol Biol
Year1992
Volume224
Pages141-57
AuthorsGuasch A, Coll M, Aviles FX, Huber R
TitleThree-dimensional structure of porcine pancreatic procarboxypeptidase A. A comparison of the A and B zymogens and their determinants for inhibition and activation.
Related PDB1pca
Related Swiss-protP09954
[28]
CommentsX-ray Diffraction
PubMed ID1738164
JournalJ Mol Biol
Year1992
Volume223
Pages573-8
AuthorsMangani S, Carloni P, Orioli P
TitleCrystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate at 2.0 A resolution.
Related PDB1cbx
[29]
PubMed ID1304353
JournalProtein Sci
Year1992
Volume1
Pages517-21
AuthorsPhillips MA, Hedstrom L, Rutter WJ
TitleGuanidine derivatives restore activity to carboxypeptidase lacking arginine-127.
[30]
CommentsX-ray Diffraction
PubMed ID15299490
JournalActa Crystallogr D Biol Crystallogr
Year1993
Volume49
Pages534-40
AuthorsTeplyakov A, Wilson KS, Orioli P, Mangani S
TitleHigh-resolution structure of the complex between carboxypeptidase A and L-phenyl lactate.
Related PDB2ctb,2ctc
[31]
PubMed ID8424757
JournalBiochem J
Year1993
Volume289
Pages185-93
AuthorsMock WL, Freeman DJ, Aksamawati M
TitleFluxionate Lewis acidity of the Zn2+ ion in carboxypeptidase A.
[32]
PubMed ID8436102
JournalEur J Biochem
Year1993
Volume211
Pages381-9
AuthorsAviles FX, Vendrell J, Guasch A, Coll M, Huber R
TitleAdvances in metallo-procarboxypeptidases. Emerging details on the inhibition mechanism and on the activation process.
[33]
PubMed ID8200353
JournalEur J Biochem
Year1994
Volume222
Pages55-63
AuthorsOppezzo O, Ventura S, Bergman T, Vendrell J, Jornvall H, Aviles FX
TitleProcarboxypeptidase in rat pancreas. Overall characterization and comparison of the activation processes.
[34]
PubMed ID8308030
JournalJ Biol Chem
Year1994
Volume269
Pages4587-95
AuthorsMustafi D, Makinen MW
TitleCatalytic conformation of carboxypeptidase A. Structure of a true enzyme reaction intermediate determined by electron nuclear double resonance.
[35]
CommentsX-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF TERNARY COMPLEX.
Medline ID96003618
PubMed ID7556081
JournalEMBO J
Year1995
Volume14
Pages4387-94
AuthorsGomis-Ruth FX, Gomez M, Bode W, Huber R, Aviles FX
TitleThe three-dimensional structure of the native ternary complex of bovine pancreatic procarboxypeptidase A with proproteinase E and chymotrypsinogen C.
Related PDB1pyt
Related Swiss-protP00730
[36]
PubMed ID7607308
JournalFEBS Lett
Year1995
Volume367
Pages211-3
AuthorsGomis-Ruth FX, Gomez M, Ventura S, Vendrell J, Aviles FX
TitleCrystallization and preliminary X-ray analysis of the ternary complex of procarboxypeptidase A from bovine pancreas.
[37]
PubMed ID11848831
JournalChem Rev
Year1996
Volume96
Pages2375-2434
AuthorsLipscomb WN, Strater N
TitleRecent Advances in Zinc Enzymology.
[38]
CommentsX-ray Diffraction
JournalJ Am Chem Soc
Year1996
Volume118
Pages12479-12480
AuthorsIrina Massova, Philip Martin, Srini de Mel, Yasuhiro Tanaka, Brian Edwards, and Shahriar Mobashery
TitleCrystallographic and Computational Insight on the Mechanism of Zinc-Ion-Dependent Inactivation of Carboxypeptidase A by 2-Benzyl-3-iodopropanoate
Related PDB1bav
[39]
PubMed ID9220957
JournalBiochemistry
Year1997
Volume36
Pages8710-5
AuthorsAsante-Appiah E, Seetharaman J, Sicheri F, Yang DS, Chan WW
TitleGem-dialkyl succinic acids: a novel class of inhibitors for carboxypeptidases.
[40]
PubMed ID9009226
JournalFEBS Lett
Year1997
Volume400
Pages336-40
AuthorsGomez-Ortiz M, Gomis-Ruth FX, Huber R, Aviles FX
TitleInhibition of carboxypeptidase A by excess zinc: analysis of the structural determinants by X-ray crystallography.
[41]
CommentsX-ray Diffraction
PubMed ID9867434
JournalActa Crystallogr D Biol Crystallogr
Year1998
Volume54
Pages289-305
AuthorsGreenblatt HM, Feinberg H, Tucker PA, Shoham G
TitleCarboxypeptidase A: native, zinc-removed and mercury-replaced forms.
Related PDB1arl,1arm,1yme
[42]
CommentsX-ray Diffraction
PubMed ID9843422
JournalBiochemistry
Year1998
Volume37
Pages16555-64
AuthorsBukrinsky JT, Bjerrum MJ, Kadziola A
TitleNative carboxypeptidase A in a new crystal environment reveals a different conformation of the important tyrosine 248.
Related PDB1cpx
[43]
PubMed ID9862201
JournalProtein Eng
Year1998
Volume11
Pages841-5
AuthorsChai JJ, He C, Li M, Tang L, Luo M
TitleCrystal structure of carboxypeptidase A complexed with an inactivator in two crystal forms.
[44]
PubMed ID10493853
JournalJ Mol Biol
Year1999
Volume292
Pages11-7
AuthorsMakarova KS, Grishin NV
TitleThe Zn-peptidase superfamily: functional convergence after evolutionary divergence.
[45]
PubMed ID11076537
JournalBiochemistry
Year2000
Volume39
Pages13945-52
AuthorsMock WL, Cheng H
TitlePrinciples of hydroxamate inhibition of metalloproteases: carboxypeptidase A.
[46]
CommentsX-ray Diffraction
PubMed ID10955996
JournalBiochemistry
Year2000
Volume39
Pages10082-9
Authorsvan Aalten DM, Chong CR, Joshua-Tor L
TitleCrystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes.
Related PDB1f57
[47]
PubMed ID10708864
JournalBiochim Biophys Acta
Year2000
Volume1477
Pages284-98
AuthorsVendrell J, Querol E, Aviles FX
TitleMetallocarboxypeptidases and their protein inhibitors. Structure, function and biomedical properties.
[48]
PubMed ID10819170
JournalBioorg Med Chem
Year2000
Volume8
Pages815-23
AuthorsLee M, Kim DH
TitleHippuryl-alpha-methylphenylalanine and hippuryl-alpha-methylphenyllactic acid as substrates for carboxypeptidase A. Syntheses, kinetic evaluation and mechanistic implication.
[49]
PubMed ID11513597
JournalBiochemistry
Year2001
Volume40
Pages10197-203
AuthorsCho JH, Kim DH, Lee KJ, Kim DH, Choi KY
TitleThe role of Tyr248 probed by mutant bovine carboxypeptidase A: insight into the catalytic mechanism of carboxypeptidase A.
[50]
PubMed ID11249116
JournalBioorg Med Chem
Year2001
Volume9
Pages237-43
AuthorsPark JD, Lee KJ, Kim DH
TitleA new inhibitor design strategy for carboxypeptidase A as exemplified by N-(2-chloroethyl)-N-methylphenylalanine.
[51]
PubMed ID11743734
JournalJ Mol Biol
Year2001
Volume314
Pages1191-207
AuthorsWouters MA, Husain A
TitleChanges in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily.
[52]
PubMed ID11676544
JournalJ Mol Biol
Year2001
Volume313
Pages629-38
AuthorsEstebanez-Perpina E, Bayes A, Vendrell J, Jongsma MA, Bown DP, Gatehouse JA, Huber R, Bode W, Aviles FX, Reverter D
TitleCrystal structure of a novel mid-gut procarboxypeptidase from the cotton pest Helicoverpa armigera.
Related PDB1jqg
[53]
CommentsX-ray Diffraction
PubMed ID11937361
JournalBioorg Med Chem
Year2002
Volume10
Pages2015-22
AuthorsCho JH, Kim DH, Chung SJ, Ha NC, Oh BH, Yong Choi K
TitleInsight into the stereochemistry in the inhibition of carboxypeptidase A with N-(hydroxyaminocarbonyl)phenylalanine: binding modes of an enantiomeric pair of the inhibitor to carboxypeptidase A.
Related PDB1hdq,1hdu,1hee
[54]
PubMed ID11836098
JournalBioorg Med Chem
Year2002
Volume10
Pages913-22
AuthorsLee M, Kim DH
TitleSyntheses and kinetic evaluation of racemic and optically active 2-benzyl-2-methyl-3,4-epoxybutanoic acids as irreversible inactivators for carboxypeptidase A.
[55]
CommentsX-ray Diffraction
PubMed ID11941507
JournalJ Biol Inorg Chem
Year2002
Volume7
Pages490-9
AuthorsJensen F, Bukrinsky T, Bjerrum J, Larsen S
TitleThree high-resolution crystal structures of cadmium-substituted carboxypeptidase A provide insight into the enzymatic function.
Related PDB1ee3,1ell,1elm
[56]
CommentsX-ray Diffraction
PubMed ID12431056
JournalJ Med Chem
Year2002
Volume45
Pages5295-302
AuthorsPark JD, Kim DH, Kim SJ, Woo JR, Ryu SE
TitleSulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.
Related PDB1iy7
[57]
CommentsX-ray Diffraction
PubMed ID12554943
JournalActa Crystallogr D Biol Crystallogr
Year2003
Volume59
Pages323-33
AuthorsKilshtain-Vardi A, Glick M, Greenblatt HM, Goldblum A, Shoham G
TitleRefined structure of bovine carboxypeptidase A at 1.25 A resolution.
Related PDB1m4l
[58]
PubMed ID15080932
JournalBioorg Med Chem
Year2004
Volume12
Pages2349-56
AuthorsPark JD, Kim DH
TitleSulfamide derivatives as transition state analogue inhibitors for carboxypeptidase A.
[59]
PubMed ID15198587
JournalJ Am Chem Soc
Year2004
Volume126
Pages7452-3
AuthorsLiu JQ, Wulff G
TitleFunctional mimicry of the active site of carboxypeptidase a by a molecular imprinting strategy: cooperativity of an amidinium and a copper ion in a transition-state imprinted cavity giving rise to high catalytic activity.
[60]
CommentsX-ray Diffraction
PubMed ID15961103
JournalJ Mol Biol
Year2005
Volume350
Pages489-98
AuthorsArolas JL, Popowicz GM, Lorenzo J, Sommerhoff CP, Huber R, Aviles FX, Holak TA
TitleThe three-dimensional structures of tick carboxypeptidase inhibitor in complex with A/B carboxypeptidases reveal a novel double-headed binding mode.
Related PDB1zlh
[61]
PubMed ID16126224
JournalJ Mol Biol
Year2005
Volume352
Pages961-75
AuthorsArolas JL, Popowicz GM, Bronsoms S, Aviles FX, Huber R, Holak TA, Ventura S
TitleStudy of a major intermediate in the oxidative folding of leech carboxypeptidase inhibitor: contribution of the fourth disulfide bond.
Related PDB2abz

comments
This enzyme belongs to the peptidase family-M14.
Moreover, this enzyme is homologous to carboxypeptidase A2 (E.C. 3.4.17.15; D00193 in EzCatDB), carboxypeptidase B (E.C. 3.4.17.2; D00512), carboxypeptidase T (E.C. 3.4.17.18; S00407) with conserved catalytic residues. Thus, they might have the same catalytic mechanism.
There have been two proposed mechanisms: a nucleophilic mechanism (double-displacement mechanism forming a covalent-bonded intermediate) and a promoted-water mechanism (single-displacement mechanism) (see [13]). However, many reports, including literature [13], support the promoted-water mechanism. In the promoted-water mechanism, Glu270 acts as a general base to activate the hydrolytic water together with the zinc ion. However, the literature [22] mentioned that the C-terminal carboxylate of the substrate peptid could also play such a role.
According to the literature [13], [17], [18], [21], [32], [37], [39], [51], [52], and [55], the catalytic reaction proceeds as follows:
(1) Glu270 acts as a general base to activate the hydrolytic water, along with the Zinc ion bound to His69/Glu72/His196.
(2) The activated water makes a nucleophilic attack on the target carbonyl carbon, whilst Arg127 is hydrogen bonded to the carbonyl oxygen, facilitating the formation of the tetrahedral (or gem-diolate) transition-state.
(3) The transition-state is stabilized by both Zinc ion and Arg127, along with the mainchain carbonyl of Ser197 and the sidechain oxygen of Glu270.
(4) Glu270 acts as a general acid to protonate the leaving amine group, completing the hydrolysis.

createdupdated
2005-10-262009-02-26


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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