DB code: D00443

RLCP classification 1.13.200.966 : Hydrolysis
CATH domain 2.40.70.10 : Cathepsin D, subunit A; domain 1 Catalytic domain
2.40.70.10 : Cathepsin D, subunit A; domain 1 Catalytic domain
E.C. 3.4.23.24
CSA 1eag
M-CSA 1eag
MACiE

CATH domain Related DB codes (homologues)
2.40.70.10 : Cathepsin D, subunit A; domain 1 D00471 D00436 D00438 D00439 D00440 D00441 D00442 D00437 D00444 D00423 D00445 D00484 M00206 M00166 D00231 D00529

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Pfam MEROPS
P0CS83
None PF00026 (Asp)
[Graphical View]
Q00663 Candidapepsin
EC 3.4.23.24
Aspartate protease
ACP
PF00026 (Asp)
[Graphical View]
A01.037 (Aspartic)

KEGG enzyme name
candidapepsin
Candida albicans aspartic proteinase
Candida albicans carboxyl proteinase
Candida albicans secretory acid proteinase
Candida olea acid proteinase
Candida aspartic proteinase
Candida olea aspartic proteinase
Candida albicans aspartic proteinase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P0CS83 CARP2_CANAX Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades keratin. Monomer. Secreted.
Q00663 CARP_CANTR Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades keratin. Secreted.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00017 C00012 L00076 L00077 C00001 C00017 C00012 C00298 I00136
E.C.
Compound Protein Peptide Trypsinogen Keratin H2O Protein Peptide Trypsin Amino-diol-tetrahedral intermediate
Type peptide/protein peptide/protein peptide/protein peptide/protein H2O peptide/protein peptide/protein peptide/protein
ChEBI 15377
PubChem 22247451
962
1eagA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Transition-state-analogue:A70
1zapA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Transition-state-analogue:A70
3pvkA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Analogue:BAM_3001 Unbound Unbound
3q70A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Transition-state-analogue:RIT
1j71A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Bound:THR-ILE-THR-SER (chain B) Unbound Unbound
1eagA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1zapA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3pvkA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3q70A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1j71A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Swiss-prot;P28871, Q00663

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1eagA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 32
1zapA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 32
3pvkA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 32
3q70A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 32
1j71A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 32
1eagA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 218
1zapA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 218
3pvkA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 218
3q70A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 218
1j71A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 218

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig.5, p.7010-7012 3
[6]
[9]
p.12706-12708

References
[1]
Resource
Comments
Medline ID
PubMed ID 3313384
Journal Proc Natl Acad Sci U S A
Year 1987
Volume 84
Pages 7009-13
Authors Suguna K, Padlan EA, Smith CW, Carlson WD, Davies DR
Title Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8263928
Journal J Mol Biol
Year 1993
Volume 234
Pages 1266-9
Authors Cutfield S, Marshall C, Moody P, Sullivan P, Cutfield J
Title Crystallization of inhibited aspartic proteinase from Candida albicans.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8162186
Journal Microbiology
Year 1994
Volume 140
Pages 167-71
Authors Tsushima H, Mine H, Kawakami Y, Hyodoh F, Ueki A
Title Candida albicans aspartic proteinase cleaves and inactivates human epidermal cysteine proteinase inhibitor, cystatin A.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8540363
Journal Adv Exp Med Biol
Year 1995
Volume 362
Pages 489-500
Authors Fusek M, Smith E, Foundling SI
Title Extracellular aspartic proteinases from Candida yeasts.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 7599606
Journal FEMS Immunol Med Microbiol
Year 1995
Volume 11
Pages 69-72
Authors Tsushima H, Mine H
Title Cleavage of human big endothelin-1 by Candida albicans aspartic proteinase.
Related PDB
Related UniProtKB
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
Medline ID 96164442
PubMed ID 8591036
Journal Structure
Year 1995
Volume 3
Pages 1261-71
Authors Cutfield SM, Dodson EJ, Anderson BF, Moody PC, Marshall CJ, Sullivan PA, Cutfield JF
Title The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors.
Related PDB 1eag
Related UniProtKB P28871
[7]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 8845753
Journal Protein Sci
Year 1996
Volume 5
Pages 640-52
Authors Abad-Zapatero C, Goldman R, Muchmore SW, Hutchins C, Stewart K, Navaza J, Payne CD, Ray TL
Title Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
Related PDB 1zap
Related UniProtKB
[8]
Resource
Comments CHARACTERIZATION.
Medline ID 97195781
PubMed ID 9043112
Journal Microbiology
Year 1997
Volume 143
Pages 349-56
Authors Smolenski G, Sullivan PA, Cutfield SM, Cutfield JF
Title Analysis of secreted aspartic proteinases from Candida albicans: purification and characterization of individual Sap1, Sap2 and Sap3 isoenzymes.
Related PDB
Related UniProtKB P28871
[9]
Resource
Comments
Medline ID
PubMed ID 9335526
Journal Biochemistry
Year 1997
Volume 36
Pages 12700-10
Authors Symersky J, Monod M, Foundling SI
Title High-resolution structure of the extracellular aspartic proteinase from Candida tropicalis yeast.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 9741846
Journal Proteins
Year 1998
Volume 33
Pages 74-87
Authors Schnecke V, Swanson CA, Getzoff ED, Tainer JA, Kuhn LA
Title Screening a peptidyl database for potential ligands to proteins with side-chain flexibility.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 11375761
Journal Curr Med Chem
Year 2001
Volume 8
Pages 941-8
Authors Stewart K, Abad-Zapatero C
Title Candida proteases and their inhibition: prospects for antifungal therapy.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 11678651
Journal J Nat Prod
Year 2001
Volume 64
Pages 1282-5
Authors Li XC, Jacob MR, Pasco DS, ElSohly HN, Nimrod AC, Walker LA, Clark AM
Title Phenolic compounds from Miconia myriantha inhibiting Candida aspartic proteases.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 12141856
Journal J Nat Prod
Year 2002
Volume 65
Pages 979-85
Authors Zhang Z, ElSohly HN, Jacob MR, Pasco DS, Walker LA, Clark AM
Title Natural products inhibiting Candida albicans secreted aspartic proteases from Lycopodium cernuum.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 12088427
Journal J Nat Prod
Year 2002
Volume 65
Pages 856-9
Authors Zhang Z, ElSohly HN, Jacob MR, Pasco DS, Walker LA, Clark AM
Title New sesquiterpenoids from the root of Guatteria multivenia.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 12637026
Journal Biochim Biophys Acta
Year 2003
Volume 1646
Pages 184-95
Authors Backman D, Danielson UH
Title Kinetic and mechanistic analysis of the association and dissociation of inhibitors interacting with secreted aspartic acid proteases 1 and 2 from Candida albicans.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 22213702
Journal ChemMedChem
Year 2012
Volume 7
Pages 248-61
Authors Behnen J, Koster H, Neudert G, Craan T, Heine A, Klebe G
Title Experimental and computational active site mapping as a starting point to fragment-based lead discovery.
Related PDB 3pvk
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-A1.
According to the literature [6] & [7], this enzyme has got a catalytic dyad composed of two aspartate residues, supporting the catalytic mechanism proposed by the paper [1].
Accoriding to the proposed mechanism (see [1]), the sidechains of both the aspartic acid residues are hydrogen-bonded to the catalytic water.
The sidechain of the ionized aspartate (possibly corresponding to Asp218 of 1eag) might act as a general base, which can abstract a proton from the water, which in turn would make a nucleophilic attack on the carbonyl carbon of the peptide bond.
Meanwhile, the protonated sidechain of the other aspartate (corresponding to Asp32 of 1eag) may stabilize the negative charge on the carbonyl oxygen of the scissile bond during the transition state.
At the next stage, the sidechain of the aspartate that had accepted a proton from water could protonate the leaving nitrogen atom, as a general acid, during the cleavage of the peptide bond.

Created Updated
2004-04-30 2012-06-26