Summary for peptidase A01.022: plasmepsin-1

Summary Alignment Sequences Sequence features Distribution Structure Literature Substrates Inhibitors Pharma

 

Names
MEROPS Nameplasmepsin-1
Other namesaspartic hemoglobinase I (Plasmodium falciparum), PFAPG, plasmepsin I, plasmepsin Pf-I
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 >> A01.022
Holotypeplasmepsin-1 (Plasmodium falciparum), Uniprot accession P39898 (peptidase unit: 126-449), MERNUM MER0001799
History Identifier created: Handbook of Proteolytic Enzymes (1998) Academic Press, London.
Activity
Catalytic typeAspartic
PeplistIncluded in the Peplist with identifier PL00018
NC-IUBMBSubclass 3.4 (Peptidases) >> Sub-subclass 3.4.23 (Aspartic endopeptidases) >> Peptidase 3.4.23.38
EnzymologyBRENDA database
Proteolytic eventsCutDB database (1 cleavage)
SpecificityThere is a preference for Phe in P1 (Goldberg et al., 1991).
pH optimumpH 5 (Goldberg et al., 1991).
Special substrateDabcyl-GABA-Glu-Arg-Met-Phe-Leu-Ser-Phe-Pro-GABA-EDANS, which is based on the alpha hemoglobin Phe33+Leu cleavage site (Luker et al., 1996)which is also cleaved by plasmepsin II and histo-aspartic peptidase.
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 I 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 I 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 (Francis et al., 1997).
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 patterne/-/-/FScissile bond-/-/lf/- (based on 13 cleavages)
weblogo
Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 0 1 1 0 0 0 0 1
Pro 1 1 0 0 0 0 0 3
Ala 0 0 2 1 0 3 0 0
Val 1 1 1 0 0 1 1 1
Leu 1 2 0 2 3 2 4 0
Ile 0 0 1 0 0 0 0 0
Met 0 0 2 0 0 0 0 0
Phe 1 2 0 10 2 0 3 1
Tyr 0 0 0 0 1 0 0 1
Trp 0 0 0 0 0 0 0 0
Ser 1 0 0 0 0 3 2 1
Thr 1 1 0 0 1 0 1 0
Cys 0 0 0 0 0 0 0 0
Asn 0 0 2 0 0 0 0 0
Gln 0 2 0 0 0 2 0 0
Asp 0 0 0 0 1 0 0 0
Glu 6 0 0 0 0 1 0 0
Lys 1 0 1 0 1 1 2 3
Arg 0 3 2 0 0 0 0 0
His 0 0 1 0 0 0 0 1