Summary for peptidase A01.043: histoaspartic peptidase (Plasmodium falciparum)

Summary Alignment Sequences Sequence features Distribution Structure Literature Substrates Inhibitors

 

Names
MEROPS Namehistoaspartic peptidase (Plasmodium falciparum)
Other namesHAP aspartic peptidase, plasmepsin-3
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). HAP is unique amongst aspartic endopeptidase of the pepsin family in that the catalytic dyad consists of a His and Asp rather than two Asp residues (Berry et al., 1999).
Domain architecture
MEROPS Classification
Classification Clan AA >> Subclan (none) >> Family A1 >> Subfamily A >> A01.043
Holotypehistoaspartic peptidase (Plasmodium falciparum) (peptidase unit: 126-449), MERNUM MER0011995
History Identifier created: MEROPS 5.8 (19 March 2002)
Activity
Catalytic typeAspartic
NC-IUBMBNot yet included in IUBMB recommendations.
SpecificityThe usual Asp-Thr/Ser-Gly motifs around the active site residues are replaced by His-Thr-Ala and Asp-Ser-Ala, and the Tyr75-Gly-Xaa-Glu motif that includes the substrate-binding Tyr residue on the flap, is replaced by Ser-Lys-Ala-Gly, which means that the Tyr75/Trp39 interaction that takes place in almost all pepsin homologues does not take place in HAP (Berry et al., 1999). Mutants in which the active site His is replaced by Ala are active, suggesting that a single active site Asp is capable of producing catalysis (Parr et al., 2008).
pH optimumThe pH optimum is unusually high for an aspartic peptidase at pH 6 (Banerjee et al., 2002).
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) and is also cleaved by plasmepsins I and II.
Inhibitor commentsUnusually for an aspartic endopeptidase, HAP is inhibited by 1 mM PMSF (Banerjee et al., 2002).
StructureHAP is active as a monomer, but a homodimeric form exists with an equilibrium between the two forms (Xiao et al., 2010). Tertiary structures of HAP has been solved (Bhaumik et al., 2009). The apoenzyme is a dimer, with the unstructured loop of the flap of one monomer inserted into the active site cleft, and the equivalent loop from the C-terminal domain inserted into the active site cleft of the other monomer. The dimer is stabilized by a zinc ion.
LocationHAP 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 aspectsHAP 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)
KnockoutKnockout of the HAP gene results in slower growth of the parasite, which is otherwise viable and morphologically normal (Liu et al., 2005).
Contributing authorsNeil D. Rawlings, InterPro, Proteins Cluster, EMBL European Bioinformatics Institute, Hinxton, Cambridgeshire, CB10 1SD, UK