EzCatDB D00467

EzCatDB: D00467

DB code	D00467
RLCP classification	1.13.11110.262
CATH domain	Domain 1	3.30.70.340
CATH domain	Domain 2	3.40.630.10		Catalytic domain
E.C.	3.4.17.1
CSA	1cbx,5cpa
MACiE	M0171

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

Enzyme Name
Swiss-prot				KEGG
	O97389	P09954	P00730	KEGG
Protein name		Carboxypeptidase A1	Carboxypeptidase A1	carboxypeptidase A carboxypolypeptidase pancreatic carboxypeptidase A tissue carboxypeptidase A
Synonyms	Carboxypeptidase A EC 3.4.17.1	EC 3.4.17.1	EC 3.4.17.1

Swiss-prot:Accession Number	O97389	P09954	P00730
Entry name	O97389_HELAM	CBPA1_PIG	CBPA1_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.

		Cofactors	Substrates			Products		intermediates
KEGG-id		C00038	C00017	C00012	C00001	C00012	C00151
Compound		Zinc	Protein	Peptide	H2O	Peptide	L-Amino acid	tetrahedral
Type		heavy metal	peptide/protein	peptide/protein	H2O	peptide/protein	amino acids
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

Active-site residues
resource
Swiss-prot;P00730, P09954
pdb		Catalytic residues	Cofactor-binding residues	Main-chain involved in catalysis
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]
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.
[2]
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.
[3]
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.
[4]
Comments	X-ray Diffraction
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
[5]
Comments	X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS).
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 Swiss-prot	P00730
[6]
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.
[7]
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.
[8]
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.
[9]
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.
[10]
Comments	X-ray Diffraction
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
[11]
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.
[12]
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.
[13]
Journal	Acc Chem Res
Year	1989
Volume	22
Pages	62-69
Authors	Christianson DW, Lipscomb WN
Title	Carboxypeptidase A
[14]
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.
[15]
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.
[16]
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.
[17]
Comments	X-ray Diffraction
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
[18]
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.
[19]
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.
[20]
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.
[21]
Comments	X-ray Diffraction
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
[22]
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.
[23]
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.
[24]
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
[25]
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
[26]
Comments	X-ray Diffraction
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
[27]
Comments	X-RAY CRYSTALLOGRAPHY (2 ANGSTROMS) OF 17-419.
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 Swiss-prot	P09954
[28]
Comments	X-ray Diffraction
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
[29]
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.
[30]
Comments	X-ray Diffraction
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
[31]
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.
[32]
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.
[33]
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.
[34]
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.
[35]
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 Swiss-prot	P00730
[36]
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.
[37]
PubMed ID	11848831
Journal	Chem Rev
Year	1996
Volume	96
Pages	2375-2434
Authors	Lipscomb WN, Strater N
Title	Recent Advances in Zinc Enzymology.
[38]
Comments	X-ray Diffraction
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
[39]
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.
[40]
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.
[41]
Comments	X-ray Diffraction
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
[42]
Comments	X-ray Diffraction
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
[43]
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.
[44]
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.
[45]
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.
[46]
Comments	X-ray Diffraction
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
[47]
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.
[48]
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.
[49]
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.
[50]
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.
[51]
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.
[52]
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
[53]
Comments	X-ray Diffraction
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
[54]
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.
[55]
Comments	X-ray Diffraction
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
[56]
Comments	X-ray Diffraction
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
[57]
Comments	X-ray Diffraction
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
[58]
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.
[59]
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.
[60]
Comments	X-ray Diffraction
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
[61]
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

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

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)

© Computational Biology Research Center, AIST, 2004 All Rights Reserved.