D00444
type: Enzyme
rlcp: p966
cath: Cathepsin D, subunit A; domain 1
ec: https://purl.uniprot.org/enzyme/3.4.23.39
csa: 1sme
uniprot: P46925
kegg enzyme: plasmepsin II
kegg enzyme: aspartic hemoglobinase II
kegg enzyme: PFAPD
kegg substrate: Protein
kegg substrate: Peptide
kegg substrate: H2O
kegg product: Protein
kegg product: Peptide
kegg intermediate: Amino-diol-tetrahedral intermediate
pdb: 1pfzA01
pdb: 1pfzB01
pdb: 1pfzC01
pdb: 1pfzD01
pdb: 1smeA01
pdb: 1smeB01
pdb: 1leeA01
pdb: 1lf2A01
pdb: 1lf3A01
pdb: 1lf4A01
pdb: 1m43A01
pdb: 1m43B01
pdb: 1pfzA02
pdb: 1pfzB02
pdb: 1pfzC02
pdb: 1pfzD02
pdb: 1smeA02
pdb: 1smeB02
pdb: 1leeA02
pdb: 1lf2A02
pdb: 1lf3A02
pdb: 1lf4A02
pdb: 1m43A02
pdb: 1m43B02
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzB01
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzC01
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzD01
pdb bound state: Unbound
  compound: Protein
  pdb: 1smeA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1smeB01
pdb bound state: Unbound
  compound: Protein
  pdb: 1leeA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf2A01
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf3A01
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf4A01
pdb bound state: Unbound
  compound: Protein
  pdb: 1m43A01
pdb bound state: Unbound
  compound: Protein
  pdb: 1m43B01
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzB02
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzC02
pdb bound state: Unbound
  compound: Protein
  pdb: 1pfzD02
pdb bound state: Unbound
  compound: Protein
  pdb: 1smeA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1smeB02
pdb bound state: Unbound
  compound: Protein
  pdb: 1leeA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf2A02
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf3A02
pdb bound state: Unbound
  compound: Protein
  pdb: 1lf4A02
active site residues resources: P46925
active site residues resources: 1pfz
references: Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.
references: Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
references: Dissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues.
references: Structural analysis of plasmepsin II. A comparison with human aspartic proteases.
references: Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D.
references: Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.
references: Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II.
references: Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum.
references: Structural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors.
references: Active site specificity of plasmepsin II.
references: New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins.
references: Active site contribution to specificity of the aspartic proteases plasmepsins I and II.
references: New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea.
references: Spermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II.
references: Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370.
references: Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.
comment: This enzyme belongs to the peptidase family-A1. According to the literature [3] & [16], this enzyme has got a catalytic dyad, composed of two aspartate residues. One is ionized and the other is protonated around the physiological pH. The paper [1] proposed a catalytic mechanism for its homologous enzyme. Accoriding to the proposed mechanism, the sidechains of both the aspartic acid residues are hydrogen-bonded to the catalytic water. The sidechain of the ionized aspartate (possibly corresponding to Asp214) 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 Asp34) 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.

Cathepsin D, subunit A; domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.40.70.10
catalytic domain: index.html

Protein
type: KeggSubstrate
references: KEGG:C00017
compound type: peptide/protein
type: KeggProduct

Peptide
type: KeggSubstrate
references: KEGG:C00012
compound type: peptide/protein
type: KeggProduct

H2O
type: KeggSubstrate
references: KEGG:C00001
compound type: H2O
references: CHEBI:15377
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Amino-diol-tetrahedral intermediate
type: KeggIntermediate
references: KEGG:I00136

1pfzA01
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 34

1pfzB01
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 34

1pfzC01
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 34

1pfzD01
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 34

1smeA01
type: Pdb
references: 1sme
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1sme
catalytic residue: ASP 34

1smeB01
type: Pdb
references: 1sme
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1sme
catalytic residue: ASP 34

1leeA01
type: Pdb
references: 1lee
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lee
catalytic residue: ASP 34

1lf2A01
type: Pdb
references: 1lf2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf2
catalytic residue: ASP 34

1lf3A01
type: Pdb
references: 1lf3
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf3
catalytic residue: ASP 34

1lf4A01
type: Pdb
references: 1lf4
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf4
catalytic residue: ASP 34

1m43A01
type: Pdb
references: 1m43
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1m43
catalytic residue: ASP 34

1m43B01
type: Pdb
references: 1m43
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1m43
catalytic residue: ASP 34

1pfzA02
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 214

1pfzB02
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 214

1pfzC02
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 214

1pfzD02
type: Pdb
references: 1pfz
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1pfz
catalytic residue: ASP 214

1smeA02
type: Pdb
references: 1sme
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1sme
catalytic residue: ASP 214

1smeB02
type: Pdb
references: 1sme
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1sme
catalytic residue: ASP 214

1leeA02
type: Pdb
references: 1lee
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lee
catalytic residue: ASP 214

1lf2A02
type: Pdb
references: 1lf2
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf2
catalytic residue: ASP 214

1lf3A02
type: Pdb
references: 1lf3
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf3
catalytic residue: ASP 214

1lf4A02
type: Pdb
references: 1lf4
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1lf4
catalytic residue: ASP 214

1m43A02
type: Pdb
references: 1m43
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1m43
catalytic residue: ASP 214

1m43B02
type: Pdb
references: 1m43
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1m43
catalytic residue: ASP 214

Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/3313384
journal: Proc Natl Acad Sci U S A
volume: 84
pages: 7009-13
published year: 1987
authors:
  item: Suguna K
  item: Padlan EA
  item: Smith CW
  item: Carlson WD
  item: Davies DR

Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
medline id: 96413592
references: http://www.ncbi.nlm.nih.gov/pubmed/8816746
journal: Proc Natl Acad Sci U S A
volume: 93
pages: 10034-9
published year: 1996
authors:
  item: Silva AM
  item: Lee AY
  item: Gulnik SV
  item: Maier P
  item: Collins J
  item: Bhat TN
  item: Collins PJ
  item: Cachau RE
  item: Luker KE
  item: Gluzman IY
  item: Francis SE
  item: Oksman A
  item: Goldberg DE
  item: Erickson JW
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P46925

Dissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9405050
journal: Biochemistry
volume: 36
pages: 16166-72
published year: 1997
authors:
  item: Xie D
  item: Gulnik S
  item: Collins L
  item: Gustchina E
  item: Suvorov L
  item: Erickson JW

Structural analysis of plasmepsin II. A comparison with human aspartic proteases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9561243
journal: Adv Exp Med Biol
volume: 436
pages: 363-73
published year: 1998
authors:
  item: Silva AM
  item: Lee AY
  item: Erickson JW
  item: Goldberg DE

Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9873703
journal: Bioorg Med Chem Lett
volume: 8
pages: 3203-6
published year: 1998
authors:
  item: Carroll CD
  item: Johnson TO
  item: Tao S
  item: Lauri G
  item: Orlowski M
  item: Gluzman IY
  item: Goldberg DE
  item: Dolle RE

Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9873534
journal: Bioorg Med Chem Lett
volume: 8
pages: 2315-20
published year: 1998
authors:
  item: Carroll CD
  item: Patel H
  item: Johnson TO
  item: Guo T
  item: Orlowski M
  item: He ZM
  item: Cavallaro CL
  item: Guo J
  item: Oksman A
  item: Gluzman IY
  item: Connelly J
  item: Chelsky D
  item: Goldberg DE
  item: Dolle RE

Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10212129
journal: J Med Chem
volume: 42
pages: 1428-40
published year: 1999
authors:
  item: Haque TS
  item: Skillman AG
  item: Lee CE
  item: Habashita H
  item: Gluzman IY
  item: Ewing TJ
  item: Goldberg DE
  item: Kuntz ID
  item: Ellman JA

Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF ZYMOGEN.
medline id: 99101380
references: http://www.ncbi.nlm.nih.gov/pubmed/9886289
journal: Nat Struct Biol
volume: 6
pages: 32-7
published year: 1999
authors:
  item: Bernstein NK
  item: Cherney MM
  item: Loetscher H
  item: Ridley RG
  item: James MN
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P46925

Structural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10500110
journal: Proc Natl Acad Sci U S A
volume: 96
pages: 10968-75
published year: 1999
authors:
  item: Khan AR
  item: Khazanovich-Bernstein N
  item: Bergmann EM
  item: James MN

Active site specificity of plasmepsin II.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/10548045
journal: Protein Sci
volume: 8
pages: 2001-9
published year: 1999
authors:
  item: Westling J
  item: Cipullo P
  item: Hung SH
  item: Saft H
  item: Dame JB
  item: Dunn BM

New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11502532
journal: Antimicrob Agents Chemother
volume: 45
pages: 2577-84
published year: 2001
authors:
  item: Jiang S
  item: Prigge ST
  item: Wei L
  item: Gao Ye
  item: Hudson TH
  item: Gerena L
  item: Dame JB
  item: Kyle DE
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

Active site contribution to specificity of the aspartic proteases plasmepsins I and II.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/12189138
journal: J Biol Chem
volume: 277
pages: 41009-13
published year: 2002
authors:
  item: Siripurkpong P
  item: Yuvaniyama J
  item: Wilairat P
  item: Goldberg DE

New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11975483
journal: J Nat Prod
volume: 65
pages: 476-80
published year: 2002
authors:
  item: Hu JF
  item: Schetz JA
  item: Kelly M
  item: Peng JN
  item: Ang KK
  item: Flotow H
  item: Leong CY
  item: Ng SB
  item: Buss AD
  item: Wilkins SP
  item: Hamann MT

Spermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/12009321
journal: Phytochemistry
volume: 60
pages: 175-7
published year: 2002
authors:
  item: Ovenden SP
  item: Cao S
  item: Leong C
  item: Flotow H
  item: Gupta MP
  item: Buss AD
  item: Butler MS

Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/12454457
journal: Acta Crystallogr D Biol Crystallogr
volume: 58
pages: 2001-8
published year: 2002
authors:
  item: Asojo OA
  item: Afonina E
  item: Gulnik SV
  item: Yu B
  item: Erickson JW
  item: Randad R
  item: Medjahed D
  item: Silva AM
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/12614616
journal: J Mol Biol
volume: 327
pages: 173-81
published year: 2003
authors:
  item: Asojo OA
  item: Gulnik SV
  item: Afonina E
  item: Yu B
  item: Ellman JA
  item: Haque TS
  item: Silva AM
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1smeA01
ligand het code: IVA-VAL-VAL-STA-ALA-STA (chain C)

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1smeB01
ligand het code: IVA-VAL-VAL-STA-ALA-STA (chain D)

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1leeA01
ligand het code: R36

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1lf2A01
ligand het code: R37

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1lf3A01
ligand het code: EH5

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1m43A01
ligand het code: IVA-VAL-VAL-STA-ALA-STA (chain C)

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1m43B01
ligand het code: IVA-VAL-VAL-STA-ALA-STA (chain D)

ReferenceForCatalyticMechanism
reference index: 1
reference section: Fig.5, p.7010-7011
reference step: 3

ReferenceForCatalyticMechanism
reference index: 3
reference section: p.16170-16172

ReferenceForCatalyticMechanism
reference index: 16
reference section: Scheme 1, p.175-176