DB code: D00467

RLCP classification 1.13.11110.262 : Hydrolysis
CATH domain 3.30.70.340 : Alpha-Beta Plaits
3.40.630.10 : Aminopeptidase Catalytic domain
E.C. 3.4.17.1
CSA 1cbx 5cpa
M-CSA 1cbx 5cpa
MACiE M0171

CATH domain Related DB codes (homologues)
3.30.70.340 : Alpha-Beta Plaits D00512 D00193
3.40.630.10 : Aminopeptidase D00512 S00406 S00407 D00192 D00193

Uniprot Enzyme Name
UniprotKB Protein name Synonyms MEROPS Pfam RefSeq
O97389
Carboxypeptidase A
EC 3.4.17.1
M14.024 (Metallo)
PF00246 (Peptidase_M14)
PF02244 (Propep_M14)
[Graphical View]
P09954 Carboxypeptidase A1
EC 3.4.17.1
M14.001 (Metallo)
PF00246 (Peptidase_M14)
PF02244 (Propep_M14)
[Graphical View] 		NP_999409.1 (Protein)
NM_214244.1 (DNA/RNA sequence)
P00730 Carboxypeptidase A1
EC 3.4.17.1
M14.001 (Metallo)
PF00246 (Peptidase_M14)
PF02244 (Propep_M14)
[Graphical View] 		NP_777175.1 (Protein)
NM_174750.2 (DNA/RNA sequence)

KEGG enzyme name
carboxypeptidase A
carboxypolypeptidase
pancreatic carboxypeptidase A
tissue carboxypeptidase A

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
O97389 O97389_HELAM
P09954 CBPA1_PIG Release of a C-terminal amino acid, but little or no action with -Asp, -Glu, -Arg, -Lys or -Pro. Monomer. Secreted. Binds 1 zinc ion per subunit.
P00730 CBPA1_BOVIN Release of a C-terminal amino acid, but little or no action with -Asp, -Glu, -Arg, -Lys or -Pro. Monomer. The zymogen is secreted as a ternary complex composed of procarboxypeptidase A, chymotrypsinogen C and proproteinase E. Secreted, extracellular space. Binds 1 zinc ion per subunit.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00038 C00017 C00012 C00001 C00012 C00151
E.C. (gem-diolate) transition-state
Compound Zinc Protein Peptide H2O Peptide L-Amino acid tetrahedral
Type heavy metal peptide/protein peptide/protein H2O peptide/protein amino acids
ChEBI 29105
 29105
 		15377
 15377
PubChem 32051
 32051
 		22247451
 962
 22247451
 962
1jqgA01 Unbound Unbound Unbound Unbound Unbound
1pcaA Unbound Unbound Unbound Unbound Unbound
1pytA Unbound Unbound Unbound Unbound Unbound
1jqgA02 Bound:_ZN Unbound Unbound Unbound Unbound
1pcaB Bound:_ZN Unbound Unbound Unbound Bound:VAL
1arlA Unbound Unbound Unbound Unbound Unbound
1armA Analogue:_HG_308 Unbound Unbound Unbound Unbound Transition-state-analogue:TRS
1bavA Bound:_ZN Unbound Unbound Unbound Analogue:BIP
1bavB Bound:_ZN Unbound Unbound Unbound Analogue:BIP
1bavC Bound:_ZN Unbound Unbound Unbound Analogue:BIP
1bavD Bound:_ZN Unbound Unbound Unbound Analogue:BIP
1cbxA Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:BZS
1cpaA Bound:_ZN Unbound Bound:GLY-TYR (chain S) Unbound Unbound
1cpsA Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:CPM
1cpxA Bound:_ZN_308 Unbound Unbound Analogue:_OH Unbound Unbound
1ee3P Analogue:_CD_350 Unbound Unbound Unbound Unbound
1ellP Analogue:_CD_350 Unbound Unbound Unbound Unbound
1elmP Analogue:_CD_350 Unbound Unbound Unbound Unbound
1f57A Bound:_ZN Unbound Unbound Unbound Analogue:DCY
1hdqA Bound:_ZN Unbound Analogue:INF Unbound Unbound
1hduA Bound:_ZN Unbound Analogue:ING Unbound Unbound
1hduB Bound:_ZN Unbound Analogue:ING Unbound Unbound
1hduD Bound:_ZN Unbound Analogue:ING Unbound Unbound
1hduE Bound:_ZN Unbound Analogue:ING Unbound Unbound
1heeA Bound:_ZN Unbound Analogue:LHY Unbound Unbound
1heeB Bound:_ZN Unbound Analogue:LHY Unbound Unbound
1heeD Bound:_ZN Unbound Analogue:LHY Unbound Unbound
1heeE Bound:_ZN Unbound Analogue:LHY Unbound Unbound
1iy7A Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:CXA
1m4lA Bound:_ZN Unbound Unbound Unbound Unbound
1pytB Bound:_ZN Unbound Unbound Unbound Unbound
1ymeA Bound:_ZN Unbound Unbound Unbound Unbound
1zlhA Bound:_ZN_555 Unbound Unbound Analogue:LEU_74 (chain B) Unbound
2abzA Bound:_ZN Unbound Unbound Analogue:VAL_66 (chain C) Unbound
2abzB Bound:_ZN Unbound Unbound Analogue:VAL_66 (chain E) Unbound
2ctbA Bound:_ZN Unbound Unbound Unbound Unbound
2ctcA Bound:_ZN Unbound Unbound Unbound Analogue:HFA
3cpaA Bound:_ZN Unbound Bound:GLY-TYR (chain S) Unbound Unbound
4cpaA Bound:_ZN Unbound Unbound Bound:VAL_38 (chain I) Bound:GLY (chain G)
5cpaA Bound:_ZN Unbound Unbound Unbound Unbound
6cpaA Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:ZAF
7cpaA Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:FVF
8cpaA Bound:_ZN Unbound Unbound Unbound Unbound Transition-state-analogue:AGF

Reference for Active-site residues
resource references E.C.
Swiss-prot;P00730, P09954

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1jqgA01
1pcaA
1pytA
1jqgA02 ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1pcaB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1arlA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1armA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1bavA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1bavB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1bavC ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1bavD ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1cbxA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1cpsA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1cpxA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1ee3P ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1ellP ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1elmP ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1f57A ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1hdqA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1hduA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1hduB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1hduD ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1hduE ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1heeA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1heeB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1heeD ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1heeE ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1iy7A ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1m4lA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1pytB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1ymeA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
1zlhA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
2abzA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
2abzB ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
2ctbA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
2ctcA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
3cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
4cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
5cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
6cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
7cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197
8cpaA ARG 127;GLU 270 HIS 69;GLU 72;HIS 196(Zinc binding) SER 197

References for Catalytic Mechanism
References Sections No. 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.12852 1
[17]
Fig.8, p.5551-5553
[18]
Fig.2, p.20698 2
[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]
Resource
Comments
Medline ID
PubMed ID 6933442
Journal Proc Natl Acad Sci U S A
Year 1980
Volume 77
Pages 3875-8
Authors Lipscomb WN
Title Carboxypeptidase A mechanisms.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 7274452
Journal FEBS Lett
Year 1981
Volume 128
Pages 13-6
Authors Wicker C, Puigserver A
Title Further studies on subunit III of bovine procarboxypeptidase A. Structure and reactivity of the weakly functional active site.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7152041
Journal FEBS Lett
Year 1982
Volume 149
Pages 257-60
Authors Aviles FX, Segundo BS, Vilanova M, Cuchillo CM, Turner C
Title The activation segment of procarboxypeptidase A from porcine pancreas constitutes a folded structural domain.
Related PDB
Related UniProtKB
[4]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 7154070
Journal J Mol Biol
Year 1982
Volume 160
Pages 475-98
Authors Rees DC, Lipscomb WN
Title Refined crystal structure of the potato inhibitor complex of carboxypeptidase A at 2.5 A resolution.
Related PDB 4cpa
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS).
Medline ID
PubMed ID 6887246
Journal J Mol Biol
Year 1983
Volume 168
Pages 367-87
Authors Rees DC, Lewis M, Lipscomb WN
Title Refined crystal structure of carboxypeptidase A at 1.54 A resolution.
Related PDB 5cpa
Related UniProtKB P00730
[6]
Resource
Comments
Medline ID
PubMed ID 2994404
Journal Adv Enzymol Relat Areas Mol Biol
Year 1985
Volume 57
Pages 1-84
Authors Patchett AA, Cordes EH
Title The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 4026847
Journal Biochem Biophys Res Commun
Year 1985
Volume 130
Pages 97-103
Authors Aviles FX, Vendrell J, Burgos FJ, Soriano F, Mendez E
Title Sequential homologies between procarboxypeptidases A and B from porcine pancreas.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 3636229
Journal Eur J Biochem
Year 1986
Volume 157
Pages 531-8
Authors Kerfelec B, Cambillau C, Puigserver A, Chapus C
Title The inactive subunit of ruminant procarboxypeptidase A-S6 complexes. Structural basis of inactivity and physiological role.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 3783689
Journal J Mol Biol
Year 1986
Volume 189
Pages 709-10
Authors Cambillau C, Kerfelec B, Foglizzo E, Chapus C
Title Crystallization and preliminary X-ray study of subunit III of the bovine pancreatic procarboxypeptidase A-S6 ternary complex.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 3463986
Journal Proc Natl Acad Sci U S A
Year 1986
Volume 83
Pages 7568-72
Authors Christianson DW, Lipscomb WN
Title X-ray crystallographic investigation of substrate binding to carboxypeptidase A at subzero temperature.
Related PDB 1cpa 3cpa
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 2458099
Journal Biochem J
Year 1988
Volume 251
Pages 901-5
Authors Vilanova M, Vendrell J, Cuchillo CM, Aviles FX
Title Analysis of the conformation and ligand-binding properties of the activation segment of pig procarboxypeptidase A.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 3208711
Journal Eur Biophys J
Year 1988
Volume 16
Pages 95-100
Authors Kerfelec B, Chapus C, Vachette P
Title Morphology of the procarboxypeptidase A-S6 complex. A solution X-ray scattering study.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID
Journal Acc Chem Res
Year 1989
Volume 22
Pages 62-69
Authors Christianson DW, Lipscomb WN
Title Carboxypeptidase A
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 2920728
Journal Eur J Biochem
Year 1989
Volume 179
Pages 609-16
Authors Pascual R, Burgos FJ, Salva M, Soriano F, Mendez E, Aviles FX
Title Purification and properties of five different forms of human procarboxypeptidases.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 2568989
Journal J Biol Chem
Year 1989
Volume 264
Pages 12849-53
Authors Christianson DW, Mangani S, Shoham G, Lipscomb WN
Title Binding of D-phenylalanine and D-tyrosine to carboxypeptidase A.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 2327981
Journal Biochem J
Year 1990
Volume 267
Pages 213-20
Authors Vendrell J, Aviles FX, Vilanova M, Turner CH, Crane-Robinson C
Title 1H-n.m.r. studies of the isolated activation segment from pig procarboxypeptidase A.
Related PDB
Related UniProtKB
[17]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 2386784
Journal Biochemistry
Year 1990
Volume 29
Pages 5546-55
Authors Kim H, Lipscomb WN
Title Crystal structure of the complex of carboxypeptidase A with a strongly bound phosphonate in a new crystalline form: comparison with structures of other complexes.
Related PDB 6cpa
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 2243116
Journal J Biol Chem
Year 1990
Volume 265
Pages 20692-8
Authors Phillips MA, Fletterick R, Rutter WJ
Title Arginine 127 stabilizes the transition state in carboxypeptidase.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 2324107
Journal J Biol Chem
Year 1990
Volume 265
Pages 6949-53
Authors Vendrell J, Cuchillo CM, Aviles FX
Title The tryptic activation pathway of monomeric procarboxypeptidase A.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 2104979
Journal Proc Natl Acad Sci U S A
Year 1990
Volume 87
Pages 220-4
Authors Vallee BL, Auld DS
Title Active-site zinc ligands and activated H2O of zinc enzymes.
Related PDB
Related UniProtKB
[21]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 1868092
Journal Biochemistry
Year 1991
Volume 30
Pages 8171-80
Authors Kim H, Lipscomb WN
Title Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography.
Related PDB 7cpa 8cpa
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 2007591
Journal J Biol Chem
Year 1991
Volume 266
Pages 6393-400
Authors Mock WL, Zhang JZ
Title Mechanistically significant diastereoselection in the sulfoximine inhibition of carboxypeptidase A.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 1515065
Journal Biol Chem Hoppe Seyler
Year 1992
Volume 373
Pages 387-92
Authors Vendrell J, Guasch A, Coll M, Villegas V, Billeter M, Wider G, Huber R, Wuthrich K, Aviles FX
Title Pancreatic procarboxypeptidases: their activation processes related to the structural features of the zymogens and activation segments.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID
Journal J Am Chem Soc
Year 1992
Volume 114
Pages 5295-5303
Authors Britt BM, Peticolas WL
Title Raman spectral evidence for an anhydride intermediate in the catalysis of ester hydrolysis by carboxypeptidase A
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID
Journal J Am Chem Soc
Year 1992
Volume 114
Pages 2281-2282
Authors Yun M, Park C, Kim S, Nam D, Kim SC, Kim H
Title The x-ray crystallographic study of covalently modified carboxypeptidase A by 2-benzyl-3,4-epoxybutanoic acid, a pseudomechanism-based inactivator
Related PDB
Related UniProtKB
[26]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 1527041
Journal J Biol Chem
Year 1992
Volume 267
Pages 19192-7
Authors Cappalonga AM, Alexander RS, Christianson DW
Title Structural comparison of sulfodiimine and sulfonamide inhibitors in their complexes with zinc enzymes.
Related PDB 1cps
Related UniProtKB
[27]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2 ANGSTROMS) OF 17-419.
Medline ID
PubMed ID 1548696
Journal J Mol Biol
Year 1992
Volume 224
Pages 141-57
Authors Guasch A, Coll M, Aviles FX, Huber R
Title Three-dimensional structure of porcine pancreatic procarboxypeptidase A. A comparison of the A and B zymogens and their determinants for inhibition and activation.
Related PDB 1pca
Related UniProtKB P09954
[28]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 1738164
Journal J Mol Biol
Year 1992
Volume 223
Pages 573-8
Authors Mangani S, Carloni P, Orioli P
Title Crystal structure of the complex between carboxypeptidase A and the biproduct analog inhibitor L-benzylsuccinate at 2.0 A resolution.
Related PDB 1cbx
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 1304353
Journal Protein Sci
Year 1992
Volume 1
Pages 517-21
Authors Phillips MA, Hedstrom L, Rutter WJ
Title Guanidine derivatives restore activity to carboxypeptidase lacking arginine-127.
Related PDB
Related UniProtKB
[30]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 15299490
Journal Acta Crystallogr D Biol Crystallogr
Year 1993
Volume 49
Pages 534-40
Authors Teplyakov A, Wilson KS, Orioli P, Mangani S
Title High-resolution structure of the complex between carboxypeptidase A and L-phenyl lactate.
Related PDB 2ctb 2ctc
Related UniProtKB
[31]
Resource
Comments
Medline ID
PubMed ID 8424757
Journal Biochem J
Year 1993
Volume 289
Pages 185-93
Authors Mock WL, Freeman DJ, Aksamawati M
Title Fluxionate Lewis acidity of the Zn2+ ion in carboxypeptidase A.
Related PDB
Related UniProtKB
[32]
Resource
Comments
Medline ID
PubMed ID 8436102
Journal Eur J Biochem
Year 1993
Volume 211
Pages 381-9
Authors Aviles FX, Vendrell J, Guasch A, Coll M, Huber R
Title Advances in metallo-procarboxypeptidases. Emerging details on the inhibition mechanism and on the activation process.
Related PDB
Related UniProtKB
[33]
Resource
Comments
Medline ID
PubMed ID 8200353
Journal Eur J Biochem
Year 1994
Volume 222
Pages 55-63
Authors Oppezzo O, Ventura S, Bergman T, Vendrell J, Jornvall H, Aviles FX
Title Procarboxypeptidase in rat pancreas. Overall characterization and comparison of the activation processes.
Related PDB
Related UniProtKB
[34]
Resource
Comments
Medline ID
PubMed ID 8308030
Journal J Biol Chem
Year 1994
Volume 269
Pages 4587-95
Authors Mustafi D, Makinen MW
Title Catalytic conformation of carboxypeptidase A. Structure of a true enzyme reaction intermediate determined by electron nuclear double resonance.
Related PDB
Related UniProtKB
[35]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF TERNARY COMPLEX.
Medline ID 96003618
PubMed ID 7556081
Journal EMBO J
Year 1995
Volume 14
Pages 4387-94
Authors Gomis-Ruth FX, Gomez M, Bode W, Huber R, Aviles FX
Title The three-dimensional structure of the native ternary complex of bovine pancreatic procarboxypeptidase A with proproteinase E and chymotrypsinogen C.
Related PDB 1pyt
Related UniProtKB P00730
[36]
Resource
Comments
Medline ID
PubMed ID 7607308
Journal FEBS Lett
Year 1995
Volume 367
Pages 211-3
Authors Gomis-Ruth FX, Gomez M, Ventura S, Vendrell J, Aviles FX
Title Crystallization and preliminary X-ray analysis of the ternary complex of procarboxypeptidase A from bovine pancreas.
Related PDB
Related UniProtKB
[37]
Resource
Comments
Medline ID
PubMed ID 11848831
Journal Chem Rev
Year 1996
Volume 96
Pages 2375-2434
Authors Lipscomb WN, Strater N
Title Recent Advances in Zinc Enzymology.
Related PDB
Related UniProtKB
[38]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID
Journal J Am Chem Soc
Year 1996
Volume 118
Pages 12479-12480
Authors Irina Massova, Philip Martin, Srini de Mel, Yasuhiro Tanaka, Brian Edwards, and Shahriar Mobashery
Title Crystallographic and Computational Insight on the Mechanism of Zinc-Ion-Dependent Inactivation of Carboxypeptidase A by 2-Benzyl-3-iodopropanoate
Related PDB 1bav
Related UniProtKB
[39]
Resource
Comments
Medline ID
PubMed ID 9220957
Journal Biochemistry
Year 1997
Volume 36
Pages 8710-5
Authors Asante-Appiah E, Seetharaman J, Sicheri F, Yang DS, Chan WW
Title Gem-dialkyl succinic acids: a novel class of inhibitors for carboxypeptidases.
Related PDB
Related UniProtKB
[40]
Resource
Comments
Medline ID
PubMed ID 9009226
Journal FEBS Lett
Year 1997
Volume 400
Pages 336-40
Authors Gomez-Ortiz M, Gomis-Ruth FX, Huber R, Aviles FX
Title Inhibition of carboxypeptidase A by excess zinc: analysis of the structural determinants by X-ray crystallography.
Related PDB
Related UniProtKB
[41]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 9867434
Journal Acta Crystallogr D Biol Crystallogr
Year 1998
Volume 54
Pages 289-305
Authors Greenblatt HM, Feinberg H, Tucker PA, Shoham G
Title Carboxypeptidase A: native, zinc-removed and mercury-replaced forms.
Related PDB 1arl 1arm 1yme
Related UniProtKB
[42]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 9843422
Journal Biochemistry
Year 1998
Volume 37
Pages 16555-64
Authors Bukrinsky JT, Bjerrum MJ, Kadziola A
Title Native carboxypeptidase A in a new crystal environment reveals a different conformation of the important tyrosine 248.
Related PDB 1cpx
Related UniProtKB
[43]
Resource
Comments
Medline ID
PubMed ID 9862201
Journal Protein Eng
Year 1998
Volume 11
Pages 841-5
Authors Chai JJ, He C, Li M, Tang L, Luo M
Title Crystal structure of carboxypeptidase A complexed with an inactivator in two crystal forms.
Related PDB
Related UniProtKB
[44]
Resource
Comments
Medline ID
PubMed ID 10493853
Journal J Mol Biol
Year 1999
Volume 292
Pages 11-7
Authors Makarova KS, Grishin NV
Title The Zn-peptidase superfamily: functional convergence after evolutionary divergence.
Related PDB
Related UniProtKB
[45]
Resource
Comments
Medline ID
PubMed ID 11076537
Journal Biochemistry
Year 2000
Volume 39
Pages 13945-52
Authors Mock WL, Cheng H
Title Principles of hydroxamate inhibition of metalloproteases: carboxypeptidase A.
Related PDB
Related UniProtKB
[46]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 10955996
Journal Biochemistry
Year 2000
Volume 39
Pages 10082-9
Authors van Aalten DM, Chong CR, Joshua-Tor L
Title Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes.
Related PDB 1f57
Related UniProtKB
[47]
Resource
Comments
Medline ID
PubMed ID 10708864
Journal Biochim Biophys Acta
Year 2000
Volume 1477
Pages 284-98
Authors Vendrell J, Querol E, Aviles FX
Title Metallocarboxypeptidases and their protein inhibitors. Structure, function and biomedical properties.
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[48]
Resource
Comments
Medline ID
PubMed ID 10819170
Journal Bioorg Med Chem
Year 2000
Volume 8
Pages 815-23
Authors Lee M, Kim DH
Title Hippuryl-alpha-methylphenylalanine and hippuryl-alpha-methylphenyllactic acid as substrates for carboxypeptidase A. Syntheses, kinetic evaluation and mechanistic implication.
Related PDB
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[49]
Resource
Comments
Medline ID
PubMed ID 11513597
Journal Biochemistry
Year 2001
Volume 40
Pages 10197-203
Authors Cho JH, Kim DH, Lee KJ, Kim DH, Choi KY
Title The role of Tyr248 probed by mutant bovine carboxypeptidase A: insight into the catalytic mechanism of carboxypeptidase A.
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[50]
Resource
Comments
Medline ID
PubMed ID 11249116
Journal Bioorg Med Chem
Year 2001
Volume 9
Pages 237-43
Authors Park JD, Lee KJ, Kim DH
Title A new inhibitor design strategy for carboxypeptidase A as exemplified by N-(2-chloroethyl)-N-methylphenylalanine.
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[51]
Resource
Comments
Medline ID
PubMed ID 11743734
Journal J Mol Biol
Year 2001
Volume 314
Pages 1191-207
Authors Wouters MA, Husain A
Title Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily.
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[52]
Resource
Comments
Medline ID
PubMed ID 11676544
Journal J Mol Biol
Year 2001
Volume 313
Pages 629-38
Authors Estebanez-Perpina E, Bayes A, Vendrell J, Jongsma MA, Bown DP, Gatehouse JA, Huber R, Bode W, Aviles FX, Reverter D
Title Crystal structure of a novel mid-gut procarboxypeptidase from the cotton pest Helicoverpa armigera.
Related PDB 1jqg
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[53]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 11937361
Journal Bioorg Med Chem
Year 2002
Volume 10
Pages 2015-22
Authors Cho JH, Kim DH, Chung SJ, Ha NC, Oh BH, Yong Choi K
Title Insight 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 PDB 1hdq 1hdu 1hee
Related UniProtKB
[54]
Resource
Comments
Medline ID
PubMed ID 11836098
Journal Bioorg Med Chem
Year 2002
Volume 10
Pages 913-22
Authors Lee M, Kim DH
Title Syntheses and kinetic evaluation of racemic and optically active 2-benzyl-2-methyl-3,4-epoxybutanoic acids as irreversible inactivators for carboxypeptidase A.
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[55]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 11941507
Journal J Biol Inorg Chem
Year 2002
Volume 7
Pages 490-9
Authors Jensen F, Bukrinsky T, Bjerrum J, Larsen S
Title Three high-resolution crystal structures of cadmium-substituted carboxypeptidase A provide insight into the enzymatic function.
Related PDB 1ee3 1ell 1elm
Related UniProtKB
[56]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 12431056
Journal J Med Chem
Year 2002
Volume 45
Pages 5295-302
Authors Park JD, Kim DH, Kim SJ, Woo JR, Ryu SE
Title Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases.
Related PDB 1iy7
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[57]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 12554943
Journal Acta Crystallogr D Biol Crystallogr
Year 2003
Volume 59
Pages 323-33
Authors Kilshtain-Vardi A, Glick M, Greenblatt HM, Goldblum A, Shoham G
Title Refined structure of bovine carboxypeptidase A at 1.25 A resolution.
Related PDB 1m4l
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[58]
Resource
Comments
Medline ID
PubMed ID 15080932
Journal Bioorg Med Chem
Year 2004
Volume 12
Pages 2349-56
Authors Park JD, Kim DH
Title Sulfamide derivatives as transition state analogue inhibitors for carboxypeptidase A.
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[59]
Resource
Comments
Medline ID
PubMed ID 15198587
Journal J Am Chem Soc
Year 2004
Volume 126
Pages 7452-3
Authors Liu JQ, Wulff G
Title Functional 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.
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[60]
Resource
Comments X-ray Diffraction
Medline ID
PubMed ID 15961103
Journal J Mol Biol
Year 2005
Volume 350
Pages 489-98
Authors Arolas JL, Popowicz GM, Lorenzo J, Sommerhoff CP, Huber R, Aviles FX, Holak TA
Title The three-dimensional structures of tick carboxypeptidase inhibitor in complex with A/B carboxypeptidases reveal a novel double-headed binding mode.
Related PDB 1zlh
Related UniProtKB
[61]
Resource
Comments
Medline ID
PubMed ID 16126224
Journal J Mol Biol
Year 2005
Volume 352
Pages 961-75
Authors Arolas JL, Popowicz GM, Bronsoms S, Aviles FX, Huber R, Holak TA, Ventura S
Title Study of a major intermediate in the oxidative folding of leech carboxypeptidase inhibitor: contribution of the fourth disulfide bond.
Related PDB 2abz
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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.

Created Updated
2005-10-26 2009-02-26