Affinage · Plasmodium

PF3D7_1018300

peptidase, putative

Annotated
2026-09-08
13 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The corpus does not resolve the precise molecular identity of PF3D7_1018300 within the P. falciparum peptidase family, because it mixes findings on signal peptide peptidase (PfSPP), the signal peptidase complex catalytic subunit (PfSP21), and type I signal peptidase. The most specific and best-supported evidence describes PfSPP, an endoplasmic reticulum-resident intramembrane protease that remains intracellular throughout erythrocyte invasion (PMID:22844982, PMID:25017910). Chemical-genetic and pharmacological data establish that this activity is dispensable for erythrocyte invasion but required for intra-erythrocytic parasite development, since SPP-specific inhibitors block growth at low micromolar concentrations without affecting invasion (PMID:22844982). PfSPP exists as monomer and dimer forms and cleaves malaria heat shock protein 101 (HSP101) as an in vivo substrate, with partial inhibition correlating with gametocyte emergence (PMID:25017910). A gamma-secretase/SPP-class inhibitor also blocks Plasmodium liver-stage development without affecting hepatocyte invasion or host Notch signaling, consistent with a parasite SPP target (PMID:19337374). Whether these SPP-attributed properties, or the distinct in vitro cleavage and E. coli complementation activities described for signal peptidase complex members (PMID:18054093, PMID:16489263), correspond to PF3D7_1018300 specifically cannot be determined from the available abstracts.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2005 Medium

    Establishing that a Plasmodium type I signal peptidase is a catalytically active serine protease addressed whether the parasite encodes a functional preprotein-processing enzyme.

    Evidence Gene cloning, sequence analysis, E. coli signal peptidase complementation, and self-cleavage assay

    PMID:16489263

    Open questions at the time
    • Does not identify whether this gene is PF3D7_1018300
    • No endogenous parasite substrate identified
    • Activity shown only by heterologous complementation
  2. 2007 Medium

    Characterizing PfSP21, the catalytic subunit of the signal peptidase complex, addressed whether signal peptidase activity is enzymatically active, regulated, and required for growth.

    Evidence In vitro peptide cleavage assay, protein kinase C phosphorylation assay, immunofluorescence, and dsRNA knockdown growth assay in P. falciparum

    PMID:18054093

    Open questions at the time
    • Does not establish that PfSP21 is PF3D7_1018300
    • Substrate specificity limited to a peptide model
    • Physiological relevance of PKC phosphorylation not resolved in vivo
  3. 2009 Low

    Testing a gamma-secretase/SPP inhibitor against liver-stage parasites addressed whether SPP-class protease activity is a druggable requirement for development in a stage other than blood.

    Evidence Cell-based growth inhibition in hepatoma lines and primary hepatocytes, in vivo rodent liver-load quantification, and Notch reporter assay

    PMID:19337374

    Open questions at the time
    • Pharmacological inference only; no direct target engagement demonstrated
    • Does not identify PF3D7_1018300 as the target
    • Effect attributed to parasite SPP by exclusion of Notch, not by direct assay
  4. 2012 Medium

    Combining subcellular localization with SPP-specific inhibition addressed at which stage and compartment the peptidase acts, showing it is intracellular and required for growth but not invasion.

    Evidence Immunofluorescence localization and SPP-specific chemical inhibitor invasion/growth assays in cultured P. falciparum

    PMID:22844982

    Open questions at the time
    • Does not confirm the ER identity biochemically in this study
    • Inhibitor specificity for a single family member unresolved
    • Does not tie the phenotype to PF3D7_1018300 by gene knockout
  5. 2014 Medium

    Identifying HSP101 as an in vivo substrate and confirming ER residence and oligomeric state addressed the molecular function and cellular localization of PfSPP.

    Evidence Immunofluorescence, immunogold electron microscopy, western blot for monomer/dimer, and transfection-based in vivo cleavage assay in P. falciparum

    PMID:25017910

    Open questions at the time
    • Substrate repertoire beyond HSP101 unknown
    • Does not resolve whether PfSPP corresponds to PF3D7_1018300
    • Mechanistic link between inhibition and gametocyte emergence uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise molecular identity of PF3D7_1018300 within the parasite peptidase family, and whether any of the SPP or signal peptidase activities in the corpus are attributable specifically to this gene, remain unestablished.
  • No study genetically ties any characterized activity to the PF3D7_1018300 locus
  • Corpus conflates SPP, PfSP21, and type I signal peptidase
  • No direct knockout or tagging of PF3D7_1018300 reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
HSP101 (IN VIVO SUBSTRATE OF PFSPP) [#1]
Complex memberships
Signal peptidase complex (SPC), catalytic subunit PfSP21 [#2]

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 PfSPP (signal peptide peptidase) is an ER-resident intramembrane protease that remains intracellular throughout erythrocyte invasion; SPP-specific chemical inhibition has no effect on erythrocyte invasion but inhibits intra-erythrocytic parasite development at low micromolar concentrations, demonstrating that PfSPP is required for growth but not invasion. Immunofluorescence microscopy (subcellular localization), SPP-specific chemical inhibitors (invasion and growth assays in cultured P. falciparum) Traffic (Copenhagen, Denmark) Medium 22844982
2014 PfSPP localizes to the endoplasmic reticulum (confirmed by immunofluorescence and immunogold electron microscopy), exists as monomer and dimer forms in parasite lysate, and cleaves malaria heat shock protein 101 (HSP101) as an in vivo substrate; partial inhibition of PfSPP correlates with gametocyte emergence. Immunofluorescence microscopy, immunogold electron microscopy, SDS-PAGE/western blot (monomer/dimer), transfection-based in vivo luminescence cleavage assay for substrate identification Biochemical and biophysical research communications Medium 25017910
2007 PfSP21, the catalytic subunit of the signal peptidase complex (SPC) from P. falciparum, cleaves a peptide substrate containing the signal peptidase cleavage site in vitro; it is phosphorylated by protein kinase C and its enzymatic activity is upregulated after this phosphorylation; it localizes to the ER by immunofluorescence; dsRNA knockdown of PfSP21 inhibits parasite growth in culture. In vitro peptide cleavage assay, protein kinase C phosphorylation assay, immunofluorescence assay (ER localization), dsRNA-mediated knockdown with growth inhibition readout Molecular and biochemical parasitology Medium 18054093
2005 Type I signal peptidase from P. falciparum is an intron-less, single-copy gene encoding a serine protease with a serine/lysine catalytic dyad; the enzyme undergoes self-cleavage and was demonstrated to possess type I signal peptidase activity by complementation of E. coli signal peptidase mutants (in vivo preprotein processing assay). Gene cloning and sequence analysis, E. coli complementation assay for in vivo signal peptidase activity, self-cleavage assay Journal of biomedicine & biotechnology Medium 16489263
2009 The gamma-secretase/SPP inhibitor LY411,575 prevents Plasmodium development in the liver (IC50 ~80 nM in hepatoma cells and primary hepatocytes) without affecting hepatocyte invasion, and decreases parasite liver load in vivo; the effect does not operate via the host Notch signaling pathway, suggesting it acts through inhibition of the parasite's signal peptide peptidase. Cell-based growth inhibition assay (human hepatoma lines and mouse primary hepatocytes), in vivo rodent malaria model (parasite liver load quantification), Notch pathway reporter assay (negative result for Notch involvement) PloS one Low 19337374

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 A small molecule inhibitor of signal peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity. PloS one 24 19337374
2012 Malaria parasite signal peptide peptidase is an ER-resident protease required for growth but not for invasion. Traffic (Copenhagen, Denmark) 23 22844982
2010 Downstream effects of haemoglobinase inhibition in Plasmodium falciparum-infected erythrocytes. Molecular and biochemical parasitology 23 20478341
2016 New directions for protease inhibitors directed drug discovery. Biopolymers 21 26584340
2007 Plasmodium falciparum signal peptidase is regulated by phosphorylation and required for intra-erythrocytic growth. Molecular and biochemical parasitology 19 18054093
2015 Differential Inhibition of Signal Peptide Peptidase Family Members by Established γ-Secretase Inhibitors. PloS one 18 26046535
2013 Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo. Proceedings of the National Academy of Sciences of the United States of America 15 24145449
2012 Host targeting of virulence determinants and phosphoinositides in blood stage malaria parasites. Trends in parasitology 15 23084821
2017 The Widespread Anti-Protozoal Action of HIV Aspartic Peptidase Inhibitors: Focus on Plasmodium spp., Leishmania spp. and Trypanosoma cruzi. Current topics in medicinal chemistry 11 27784256
2017 Characterization of SPP inhibitors suppressing propagation of HCV and protozoa. Proceedings of the National Academy of Sciences of the United States of America 10 29187532
2005 Isolation and characterization of type I signal peptidase of different malaria parasites. Journal of biomedicine & biotechnology 9 16489263
2014 Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis. Biochemical and biophysical research communications 8 25017910
1997 Electrophoretic variations of peptidase E (PEPE) in characterizing clones and isolates of Plasmodium falciparum from different geographical areas. Folia parasitologica 0 9269721