DB code: S00450

RLCP classification 1.13.30000.44 : Hydrolysis
CATH domain 3.90.70.10 : Cathepsin B; Chain A Catalytic domain
E.C. 3.4.22.30
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.90.70.10 : Cathepsin B; Chain A S00444 S00445 S00447 S00448 S00449 S00451 S00446 S00518

Uniprot Enzyme Name
UniprotKB Protein name Synonyms MEROPS Pfam
P10056 Caricain
EC 3.4.22.30
Papaya proteinase omega
Papaya proteinase III
PPIII
Papaya peptidase A
I29.003 ()
PF08246 (Inhibitor_I29)
PF00112 (Peptidase_C1)
[Graphical View]

KEGG enzyme name
caricain
papaya peptidase A
papaya peptidase II
papaya proteinase
papaya proteinase III
papaya proteinase 3
proteinase omega
papaya proteinase A
chymopapain S
Pp

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P10056 PAPA3_CARPA Hydrolysis of proteins with broad specificity for peptide bonds, similar to those of papain and chymopapain. Monomer.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00017 C00012 C00001 C00017 C00012 I00153 I00154 I00155
E.C.
Compound Protein Peptide H2O Protein Peptide Peptidyl-Cys-tetrahedral-intermediate (with previous peptide) Acyl-enzyme(Peptidyl-Cys-acyl group) Peptidyl-Cys-tetrahedral-intermediate
Type peptide/protein peptide/protein H2O peptide/protein peptide/protein
ChEBI 15377
PubChem 22247451
962
1megA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:E64
1ppoA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1pciA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1pciB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1pciC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P10056, PDB data & papers

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1megA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLN 19;CYS 25;HIS 159;ASN 179 CYS 25 mutant D158E
1ppoA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLN 19;CYS 25;HIS 159;ASN 179 CYS 25
1pciA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLN 19;CYS 25; ;ASN 179 CYS 25 mutant H159G
1pciB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLN 19;CYS 25; ;ASN 179 CYS 25 mutant H159G
1pciC Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain GLN 19;CYS 25; ;ASN 179 CYS 25 mutant H159G

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
p.209
[3]
p.1274-1276
[4]
p.14770-14771l

References
[1]
Resource
Comments
Medline ID
PubMed ID
Journal Acta Crystallogr B
Year 1991
Volume 47
Pages 766-771
Authors Pickersgill RW, Rizkallah P, Harris GW, Goodenough PW
Title Determination of the structure of papaya protease omega.
Related PDB 1ppo
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8103322
Journal Biochem J
Year 1993
Volume 294
Pages 201-10
Authors Mellor GW, Patel M, Thomas EW, Brocklehurst K
Title Clarification of the pH-dependent kinetic behaviour of papain by using reactivity probes and analysis of alkylation and catalysed acylation reactions in terms of multihydronic state models: implications for electrostatics calculations and interpretation of the consequences of site-specific mutations such as Asp-158-Asn and Asp-158-Glu.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7855143
Journal Protein Eng
Year 1994
Volume 7
Pages 1267-76
Authors Taylor MA, Baker KC, Connerton IF, Cummings NJ, Harris GW, Henderson IM, Jones ST, Pickersgill RW, Sumner IG, Warwicker J, et al
Title An unequivocal example of cysteine proteinase activity affected by multiple electrostatic interactions.
Related PDB
Related UniProtKB
[4]
Resource
Comments catalysis (rapid kinetic studies), X-ray crystallography
Medline ID
PubMed ID 8942638
Journal Biochemistry
Year 1996
Volume 35
Pages 14763-72
Authors Katerelos NA, Goodenough PW
Title Rapid kinetic studies and structural determination of a cysteine proteinase mutant imply that residue 158 in caricain has a major effect upon the ability of the active site histidine to protonate a dipyridyl probe.
Related PDB 1meg
Related UniProtKB
[5]
Resource
Comments X-ray crystallography (2.0 Angstroms)
Medline ID 96354872
PubMed ID 8769310
Journal FEBS Lett
Year 1996
Volume 392
Pages 35-9
Authors Katerelos NA, Taylor MA, Scott M, Goodenough PW, Pickersgill RW
Title Crystal structure of a caricain D158E mutant in complex with E-64.
Related PDB
Related UniProtKB P10056
[6]
Resource
Comments X-ray crystallography (3.2 Angstroms)
Medline ID 97094976
PubMed ID 8939744
Journal Structure
Year 1996
Volume 4
Pages 1193-203
Authors Groves MR, Taylor MA, Scott M, Cummings NJ, Pickersgill RW, Jenkins JA
Title The prosequence of procaricain forms an alpha-helical domain that prevents access to the substrate-binding cleft.
Related PDB 1pci
Related UniProtKB P10056

Comments
This enzyme belongs to the peptidase family-C1.
The paper [4] mentioned that cysteine ionization alone is not sufficient to support the catalysis. The paper [2] conculded that the formation of (Cys25)S-/(His159)ImH+ ion-pair state of papain is characterized by pKa value close to 3.4. Formation of the ion-pair state of the enzyme (pKa around 3.4) appears to be sufficient for the full development of nucleophilic reactivity of the thiolate anion component of the ion-pair in the reactions.
According to the paper [3], although there are various states of ionizations for Cys25 and His159, the essential thiolate-imidazolium ion pair of cysteine proteinases must be in the form S-_ImH+ for catalytic activity to be exhibited. A negative charge at Asp158 enhances catalytic competence over and above that produced by the Cys-His ion pair alone. Thus, Asp158 plays a role as pKa modulator.
On the other hand, considering the tertiary structure of this enzyme, Asp158 does not interact with His159 directly. From a structural viewpoint, Asn179 is more likely to be the modulator for His159, as its homologous enzymes (see S00444, S00445, S00447 in EzCatDB).

Created Updated
2002-07-01 2012-10-23