Summary for peptidase A01.023: plasmepsin-2

Summary Alignment Sequences Sequence features Distribution Structure Literature Substrates Inhibitors Pharma

 

Names
MEROPS Nameplasmepsin-2
Other namesaspartic hemoglobinase II (Plasmodium falciparum), PFAPD, plasmepsin II, plasmepsin Pf-2
Name and HistoryPlasmepsins are pepsin homologues found in the food vacuoles of the intra-erythrocytic stages in the life cycle of malaria parasites (Plasmodium spp.). In the human parasite P. falciparum, there are four vacuolar plasmepsins I, II, IV and HAP (Banerjee et al., 2002). Plasmepsins I and II perform the initial stages of degradation of host hemoglobin, the only food source, and denatured hemoglobin is further degraded by plasmepsin IV, HAP, falcipains, falcilysin, dipeptidyl-peptidases and aminopeptidases (Gluzman et al., 1994).
Domain architecture
MEROPS Classification
Classification Clan AA >> Subclan (none) >> Family A1 >> Subfamily A >> A01.023
Holotypeplasmepsin-2 (Plasmodium falciparum), Uniprot accession P46925 (peptidase unit: 127-450), MERNUM MER0001988
History Identifier created: Handbook of Proteolytic Enzymes (1998) Academic Press, London.
Activity
Catalytic typeAspartic
PeplistIncluded in the Peplist with identifier PL00019
NC-IUBMBSubclass 3.4 (Peptidases) >> Sub-subclass 3.4.23 (Aspartic endopeptidases) >> Peptidase 3.4.23.39
EnzymologyBRENDA database
Proteolytic eventsCutDB database (1 cleavage)
SpecificityPlasmepsin II cleaves hemoglobin at three or four sites, including Phe33-Leu also cleaved by plasmepsin I, and has a preference for hydrophobic residues in P2, P1 and P1' (Gluzman et al., 1994). Other erythrocyte proteins, including spectrin, are also degraded in vitro (Le Bonniec et al., 1999).
pH optimumpH 5 (Goldberg et al., 1991).
StructureThe structure of plasmepsin II has been solved (Silva et al., 1996). It is a dimer in the crystals but is also active as a monomer (Liu et al., 2006). From the structure of a truncated zymogen, an inactive conformation is maintained by the propeptide forming a harness that interacts with the C-terminal domain, pulling the domains apart and increasing the separation of the catalytic dyad (Bernstein et al., 1999).
LocationPlasmepsin I is located in the food vacuole of intra-erythrocytic stages of the Plasmodium life cycle (Banerjee et al., 2002).
PhysiologyDigestion of haemoglobin in the nutrition of the malaria organism Plasmodium falciparum (Francis et al., 1997).
Biological aspectsPlasmepsin II is synthesized as a type II integral membrane precursor protein which is exported to the parasite surface and then internalized with host hemoglobin. Once inside the food vacuole, active plasmepsin II is released from the membrane by cleavage by falcipain 2 or 3 (Drew et al., 2008).
KnockoutAlthough knockout of all four plasmepsin genes results in slower growth, parasites are still viable (Bonilla et al., 2007). Dual knockouts of plasmepsin and falcipain genes are more effective, and pepstatin inhibition of plasmepsins in a falcipain 2 knockout is fatal (Sijwali & Rosenthal, 2004).
Pharmaceutical relevancePotential drug target for malaria (Haque et al., 1999).
Contributing authorsNeil D. Rawlings, InterPro, Proteins Cluster, EMBL European Bioinformatics Institute, Hinxton, Cambridgeshire, CB10 1SD, UK
Other databases WIKIPEDIAhttp://en.wikipedia.org/wiki/Plasmepsin
Cleavage site specificity Explanations of how to interpret the following cleavage site sequence logo and specificity matrix can be found here.
Cleavage patternel/rf/vl/FlScissile bondlsv/Sar/-/- (based on 15 cleavages)
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Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 2 0 0 1 0 0 0 0
Pro 2 0 0 0 0 0 0 4
Ala 0 1 1 0 0 5 1 0
Val 1 0 5 0 2 1 0 0
Leu 3 2 3 4 4 0 4 1
Ile 0 1 0 0 0 0 1 1
Met 0 0 2 0 0 0 0 0
Phe 0 3 0 8 0 0 3 0
Tyr 0 2 0 1 0 0 1 1
Trp 0 0 0 0 0 0 0 0
Ser 1 0 0 0 2 7 1 1
Thr 0 2 2 1 1 0 0 0
Cys 0 0 0 0 0 0 0 0
Asn 1 0 1 0 0 0 1 1
Gln 0 0 0 0 1 0 0 0
Asp 0 0 1 0 0 0 0 1
Glu 5 0 0 0 0 0 0 0
Lys 0 0 0 0 0 0 1 3
Arg 0 4 0 0 0 2 2 0
His 0 0 0 0 0 0 0 1