DB code: D00444

RLCP classification	1.13.200.966 : Hydrolysis
CATH domain	2.40.70.10 : Cathepsin D, subunit A; domain 1	Catalytic domain
CATH 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 15377
PubChem			22247451 962 22247451 962

1pfzA01	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzB01	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzC01	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzD01	Unbound	Unbound		Unbound	Unbound	Unbound
1smeA01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain C)
1smeB01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain D)
1leeA01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:R36
1lf2A01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:R37
1lf3A01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:EH5
1lf4A01	Unbound	Unbound		Unbound	Unbound	Unbound
1m43A01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain C)
1m43B01	Unbound	Unbound		Unbound	Unbound	Transition-state-analogue:IVA-VAL-VAL-STA-ALA-STA (chain D)
1pfzA02	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzB02	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzC02	Unbound	Unbound		Unbound	Unbound	Unbound
1pfzD02	Unbound	Unbound		Unbound	Unbound	Unbound
1smeA02	Unbound	Unbound		Unbound	Unbound	Unbound
1smeB02	Unbound	Unbound		Unbound	Unbound	Unbound
1leeA02	Unbound	Unbound		Unbound	Unbound	Unbound
1lf2A02	Unbound	Unbound		Unbound	Unbound	Unbound
1lf3A02	Unbound	Unbound		Unbound	Unbound	Unbound
1lf4A02	Unbound	Unbound		Unbound	Unbound	Unbound
1m43A02	Unbound	Unbound		Unbound	Unbound	Unbound
1m43B02	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	ASP 34
1pfzB01	ASP 34
1pfzC01	ASP 34
1pfzD01	ASP 34
1smeA01	ASP 34
1smeB01	ASP 34
1leeA01	ASP 34
1lf2A01	ASP 34
1lf3A01	ASP 34
1lf4A01	ASP 34
1m43A01	ASP 34
1m43B01	ASP 34
1pfzA02	ASP 214
1pfzB02	ASP 214
1pfzC02	ASP 214
1pfzD02	ASP 214
1smeA02	ASP 214
1smeB02	ASP 214
1leeA02	ASP 214
1lf2A02	ASP 214
1lf3A02	ASP 214
1lf4A02	ASP 214
1m43A02	ASP 214
1m43B02	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.

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