DB code: D00444

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. 3.4.23.39
CSA 1sme
M-CSA 1sme
MACiE

CATH domain Related DB codes (homologues)
2.40.70.10 : Cathepsin D, subunit A; domain 1 D00471 D00436 D00438 D00439 D00440 D00441 D00442 D00443 D00437 D00423 D00445 D00484 M00206 M00166 D00231 D00529

Uniprot Enzyme Name
UniprotKB Protein name Synonyms MEROPS Pfam
P46925 Plasmepsin-2
EC 3.4.23.39
Aspartic hemoglobinase II
PFAPD
A01.023 (Aspartic)
PF00026 (Asp)
[Graphical View]

KEGG enzyme name
plasmepsin II
aspartic hemoglobinase II
PFAPD

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P46925 PLM2_PLAFA Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves small molecules substrates such as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO(2))- Ser-Phe-Pro-Thr. Vacuole.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00017 C00012 C00001 C00017 C00012 I00136
E.C.
Compound Protein Peptide H2O Protein Peptide Amino-diol-tetrahedral intermediate
Type peptide/protein peptide/protein H2O peptide/protein peptide/protein
ChEBI 15377
PubChem 962
22247451
1pfzA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzC01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzD01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1smeA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain C)
1smeB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain D)
1leeA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:R36
1lf2A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:R37
1lf3A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:EH5
1lf4A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1m43A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain C)
1m43B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain D)
1pfzA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzC02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1pfzD02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1smeA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1smeB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1leeA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1lf2A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1lf3A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1lf4A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1m43A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound
1m43B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
PDB;1pfz & Swiss-prot;P46925

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1pfzA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1pfzB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1pfzC01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1pfzD01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1smeA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1smeB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1leeA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1lf2A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1lf3A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1lf4A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1m43A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1m43B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 34
1pfzA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1pfzB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1pfzC02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1pfzD02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1smeA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1smeB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1leeA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1lf2A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1lf3A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1lf4A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1m43A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214
1m43B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 214

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig.5, p.7010-7011 3
[3]
p.16170-16172
[16]
Scheme 1, p.175-176

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 X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
Medline ID 96413592
PubMed ID 8816746
Journal Proc Natl Acad Sci U S A
Year 1996
Volume 93
Pages 10034-9
Authors Silva AM, Lee AY, Gulnik SV, Maier P, Collins J, Bhat TN, Collins PJ, Cachau RE, Luker KE, Gluzman IY, Francis SE, Oksman A, Goldberg DE, Erickson JW
Title Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
Related PDB 1sme
Related UniProtKB P46925
[3]
Resource
Comments
Medline ID
PubMed ID 9405050
Journal Biochemistry
Year 1997
Volume 36
Pages 16166-72
Authors Xie D, Gulnik S, Collins L, Gustchina E, Suvorov L, Erickson JW
Title 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.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9561243
Journal Adv Exp Med Biol
Year 1998
Volume 436
Pages 363-73
Authors Silva AM, Lee AY, Erickson JW, Goldberg DE
Title Structural analysis of plasmepsin II. A comparison with human aspartic proteases.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 9873703
Journal Bioorg Med Chem Lett
Year 1998
Volume 8
Pages 3203-6
Authors Carroll CD, Johnson TO, Tao S, Lauri G, Orlowski M, Gluzman IY, Goldberg DE, Dolle RE
Title Evaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 9873534
Journal Bioorg Med Chem Lett
Year 1998
Volume 8
Pages 2315-20
Authors Carroll CD, Patel H, Johnson TO, Guo T, Orlowski M, He ZM, Cavallaro CL, Guo J, Oksman A, Gluzman IY, Connelly J, Chelsky D, Goldberg DE, Dolle RE
Title Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 10212129
Journal J Med Chem
Year 1999
Volume 42
Pages 1428-40
Authors Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJ, Goldberg DE, Kuntz ID, Ellman JA
Title Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II.
Related PDB
Related UniProtKB
[8]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF ZYMOGEN.
Medline ID 99101380
PubMed ID 9886289
Journal Nat Struct Biol
Year 1999
Volume 6
Pages 32-7
Authors Bernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN
Title Crystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum.
Related PDB 1pfz
Related UniProtKB P46925
[9]
Resource
Comments
Medline ID
PubMed ID 10500110
Journal Proc Natl Acad Sci U S A
Year 1999
Volume 96
Pages 10968-75
Authors Khan AR, Khazanovich-Bernstein N, Bergmann EM, James MN
Title Structural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 10548045
Journal Protein Sci
Year 1999
Volume 8
Pages 2001-9
Authors Westling J, Cipullo P, Hung SH, Saft H, Dame JB, Dunn BM
Title Active site specificity of plasmepsin II.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 11502532
Journal Antimicrob Agents Chemother
Year 2001
Volume 45
Pages 2577-84
Authors Jiang S, Prigge ST, Wei L, Gao Ye, Hudson TH, Gerena L, Dame JB, Kyle DE
Title New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins.
Related PDB 1j8j
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 12189138
Journal J Biol Chem
Year 2002
Volume 277
Pages 41009-13
Authors Siripurkpong P, Yuvaniyama J, Wilairat P, Goldberg DE
Title Active site contribution to specificity of the aspartic proteases plasmepsins I and II.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 11975483
Journal J Nat Prod
Year 2002
Volume 65
Pages 476-80
Authors Hu JF, Schetz JA, Kelly M, Peng JN, Ang KK, Flotow H, Leong CY, Ng SB, Buss AD, Wilkins SP, Hamann MT
Title New antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 12009321
Journal Phytochemistry
Year 2002
Volume 60
Pages 175-7
Authors Ovenden SP, Cao S, Leong C, Flotow H, Gupta MP, Buss AD, Butler MS
Title Spermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 12454457
Journal Acta Crystallogr D Biol Crystallogr
Year 2002
Volume 58
Pages 2001-8
Authors Asojo OA, Afonina E, Gulnik SV, Yu B, Erickson JW, Randad R, Medjahed D, Silva AM
Title Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370.
Related PDB 1lee 1lf2
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 12614616
Journal J Mol Biol
Year 2003
Volume 327
Pages 173-81
Authors Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM
Title Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.
Related PDB 1m43 1lf3 1lf4
Related UniProtKB

Comments
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.

Created Updated
2003-10-17 2012-06-28