EzCatDB: D00444
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DB codeD00444
RLCP classification1.13.200.966 : Hydrolysis
CATH domainDomain 12.40.70.10 : Cathepsin D, subunit A; domain 1Catalytic domain
Domain 22.40.70.10 : Cathepsin D, subunit A; domain 1Catalytic domain
E.C.3.4.23.39
CSA1sme

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

Enzyme Name
UniProtKBKEGG

P46925
Protein namePlasmepsin-2plasmepsin II
aspartic hemoglobinase II
PFAPD
SynonymsEC 3.4.23.39
Aspartic hemoglobinase II
PFAPD
MEROPSA01.023 (Aspartic)
PfamPF00026 (Asp)
[Graphical view]


UniProtKB:Accession NumberP46925
Entry namePLM2_PLAFA
ActivityHydrolysis 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.
Subunit
Subcellular locationVacuole.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00017C00012C00001C00017C00012I00136
CompoundProteinPeptideH2OProteinPeptideAmino-diol-tetrahedral intermediate
Typepeptide/proteinpeptide/proteinH2Opeptide/proteinpeptide/protein
ChEBI

15377



PubChem

22247451
962



              
1pfzA01UnboundUnbound UnboundUnboundUnbound
1pfzB01UnboundUnbound UnboundUnboundUnbound
1pfzC01UnboundUnbound UnboundUnboundUnbound
1pfzD01UnboundUnbound UnboundUnboundUnbound
1smeA01UnboundUnbound UnboundUnboundTransition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain C)
1smeB01UnboundUnbound UnboundUnboundTransition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain D)
1leeA01UnboundUnbound UnboundUnboundTransition-state-analogue:R36
1lf2A01UnboundUnbound UnboundUnboundTransition-state-analogue:R37
1lf3A01UnboundUnbound UnboundUnboundTransition-state-analogue:EH5
1lf4A01UnboundUnbound UnboundUnboundUnbound
1m43A01UnboundUnbound UnboundUnboundTransition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain C)
1m43B01UnboundUnbound UnboundUnboundTransition-state-analogue:IVA-VAL-VAL-STA-ALA-STA(chain D)
1pfzA02UnboundUnbound UnboundUnboundUnbound
1pfzB02UnboundUnbound UnboundUnboundUnbound
1pfzC02UnboundUnbound UnboundUnboundUnbound
1pfzD02UnboundUnbound UnboundUnboundUnbound
1smeA02UnboundUnbound UnboundUnboundUnbound
1smeB02UnboundUnbound UnboundUnboundUnbound
1leeA02UnboundUnbound UnboundUnboundUnbound
1lf2A02UnboundUnbound UnboundUnboundUnbound
1lf3A02UnboundUnbound UnboundUnboundUnbound
1lf4A02UnboundUnbound UnboundUnboundUnbound
1m43A02UnboundUnbound UnboundUnboundUnbound
1m43B02UnboundUnbound UnboundUnboundUnbound

Active-site residues
resource
PDB;1pfz & Swiss-prot;P46925
pdbCatalytic residues
         
1pfzA01ASP  34
1pfzB01ASP  34
1pfzC01ASP  34
1pfzD01ASP  34
1smeA01ASP  34
1smeB01ASP  34
1leeA01ASP  34
1lf2A01ASP  34
1lf3A01ASP  34
1lf4A01ASP  34
1m43A01ASP  34
1m43B01ASP  34
1pfzA02ASP 214
1pfzB02ASP 214
1pfzC02ASP 214
1pfzD02ASP 214
1smeA02ASP 214
1smeB02ASP 214
1leeA02ASP 214
1lf2A02ASP 214
1lf3A02ASP 214
1lf4A02ASP 214
1m43A02ASP 214
1m43B02ASP 214

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Fig.5, p.7010-70113
[3]p.16170-16172
[16]Scheme 1, p.175-176

references
[1]
PubMed ID3313384
JournalProc Natl Acad Sci U S A
Year1987
Volume84
Pages7009-13
AuthorsSuguna K, Padlan EA, Smith CW, Carlson WD, Davies DR
TitleBinding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.
[2]
CommentsX-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
Medline ID96413592
PubMed ID8816746
JournalProc Natl Acad Sci U S A
Year1996
Volume93
Pages10034-9
AuthorsSilva 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
TitleStructure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum.
Related PDB1sme
Related UniProtKBP46925
[3]
PubMed ID9405050
JournalBiochemistry
Year1997
Volume36
Pages16166-72
AuthorsXie D, Gulnik S, Collins L, Gustchina E, Suvorov L, Erickson JW
TitleDissection of the pH dependence of inhibitor binding energetics for an aspartic protease: direct measurement of the protonation states of the catalytic aspartic acid residues.
[4]
PubMed ID9561243
JournalAdv Exp Med Biol
Year1998
Volume436
Pages363-73
AuthorsSilva AM, Lee AY, Erickson JW, Goldberg DE
TitleStructural analysis of plasmepsin II. A comparison with human aspartic proteases.
[5]
PubMed ID9873703
JournalBioorg Med Chem Lett
Year1998
Volume8
Pages3203-6
AuthorsCarroll CD, Johnson TO, Tao S, Lauri G, Orlowski M, Gluzman IY, Goldberg DE, Dolle RE
TitleEvaluation of a structure-based statine cyclic diamino amide encoded combinatorial library against plasmepsin II and cathepsin D.
[6]
PubMed ID9873534
JournalBioorg Med Chem Lett
Year1998
Volume8
Pages2315-20
AuthorsCarroll 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
TitleIdentification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.
[7]
PubMed ID10212129
JournalJ Med Chem
Year1999
Volume42
Pages1428-40
AuthorsHaque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJ, Goldberg DE, Kuntz ID, Ellman JA
TitlePotent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF ZYMOGEN.
Medline ID99101380
PubMed ID9886289
JournalNat Struct Biol
Year1999
Volume6
Pages32-7
AuthorsBernstein NK, Cherney MM, Loetscher H, Ridley RG, James MN
TitleCrystal structure of the novel aspartic proteinase zymogen proplasmepsin II from plasmodium falciparum.
Related PDB1pfz
Related UniProtKBP46925
[9]
PubMed ID10500110
JournalProc Natl Acad Sci U S A
Year1999
Volume96
Pages10968-75
AuthorsKhan AR, Khazanovich-Bernstein N, Bergmann EM, James MN
TitleStructural aspects of activation pathways of aspartic protease zymogens and viral 3C protease precursors.
[10]
PubMed ID10548045
JournalProtein Sci
Year1999
Volume8
Pages2001-9
AuthorsWestling J, Cipullo P, Hung SH, Saft H, Dame JB, Dunn BM
TitleActive site specificity of plasmepsin II.
[11]
PubMed ID11502532
JournalAntimicrob Agents Chemother
Year2001
Volume45
Pages2577-84
AuthorsJiang S, Prigge ST, Wei L, Gao Ye, Hudson TH, Gerena L, Dame JB, Kyle DE
TitleNew class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins.
Related PDB1j8j
[12]
PubMed ID12189138
JournalJ Biol Chem
Year2002
Volume277
Pages41009-13
AuthorsSiripurkpong P, Yuvaniyama J, Wilairat P, Goldberg DE
TitleActive site contribution to specificity of the aspartic proteases plasmepsins I and II.
[13]
PubMed ID11975483
JournalJ Nat Prod
Year2002
Volume65
Pages476-80
AuthorsHu JF, Schetz JA, Kelly M, Peng JN, Ang KK, Flotow H, Leong CY, Ng SB, Buss AD, Wilkins SP, Hamann MT
TitleNew antiinfective and human 5-HT2 receptor binding natural and semisynthetic compounds from the Jamaican sponge Smenospongia aurea.
[14]
PubMed ID12009321
JournalPhytochemistry
Year2002
Volume60
Pages175-7
AuthorsOvenden SP, Cao S, Leong C, Flotow H, Gupta MP, Buss AD, Butler MS
TitleSpermine alkaloids from Albizia adinocephala with activity against Plasmodium falciparum plasmepsin II.
[15]
PubMed ID12454457
JournalActa Crystallogr D Biol Crystallogr
Year2002
Volume58
Pages2001-8
AuthorsAsojo OA, Afonina E, Gulnik SV, Yu B, Erickson JW, Randad R, Medjahed D, Silva AM
TitleStructures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370.
Related PDB1lee,1lf2
[16]
PubMed ID12614616
JournalJ Mol Biol
Year2003
Volume327
Pages173-81
AuthorsAsojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM
TitleNovel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.
Related PDB1m43,1lf3,1lf4

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.

createdupdated
2003-10-172012-06-28
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 2008)
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)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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