Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of deproteinated malaria exoantigens from Plasmodium falciparum (Pf-MT) and P. berghei ANKA (PbA-MT) to activate murine haematopoietic cells was analysed in vitro. Malaria toxins (MT) of both plasmodium species induced cell proliferation and the production of IFN-gamma in overnight and long-term (5 days) spleen and bone marrow cultures and a reduction of the number of TNF-alpha spot forming cells (SFC). When added to cells of malaria-experienced animals, MT decreased the number of IL-4 SPC and increased the number of IL-5 SPC. However, the same proliferative and IFN-gamma induction properties as in naive cells were observed. Simultaneous addition of IL-2 and PbA-MT to spleen cells inhibited the proliferation but increased the IFN-gamma production usually induced by IL-2. Flow cytometric analysis revealed that the addition of MT triggered an expansion of CD3+ and GR1+ cell populations. Our results suggest that malaria toxins of different species can induce an immediate and strong proliferation and a TH1-type cytokine release by murine cells, independently of previous in vivo priming.
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PMID:Malaria toxins: effects on murine spleen and bone marrow cell proliferation and cytokine production in vitro. 936 98

Type I signal peptidases are important membrane-bound serine proteases responsible for the cleavage of the signal peptide of the proteins. These enzymes are unique serine proteases that carry out catalysis using a serine/lysine catalytic dyad. In the present study, we report the isolation of type I signal peptidase from the malaria parasites Plasmodium falciparum, Plasmodium knowlesi, and Plasmodium yoelii and some characterization of type I signal peptidase of Plasmodium falciparum. We show that these enzymes are homologous to signal peptidases from various sources and also contain the conserved boxes present in other type I signal peptidases. The type I signal peptidase from P falciparum is an intron-less and a single-copy gene. The results also show that the enzyme from Plasmodium falciparum is subject to self-cleavage and it has been demonstrated to possess type I signal peptidase activity in E coli preprotein processing in vivo by complementation assay. This study will be helpful in understanding one of the important metabolic pathways "the secretory pathway" in the parasite and should make an important contribution in understanding the complex process of protein targeting in the parasite.
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PMID:Isolation and characterization of type I signal peptidase of different malaria parasites. 1648 63

Signal peptide peptidase (SPP) is an intramembrane cleaving protease (I-CLiP) identified by its cleavage of several type II membrane signal peptides. To date, only human SPP has been directly shown to have proteolytic activity. Here we demonstrate that the most closely related human homologue of SPP, signal peptide peptidase like 3 (SPPL3), cleaves a SPP substrate, but a more distantly related homologue, signal peptide peptidase like 2b (SPPL2b), does not. These data provide strong evidence that the SPP and SPPL3 have conserved active sites and suggest that the active sites SPPL2b is distinct. We have also synthesized a cDNA designed to express the single SPP gene present in Plasmodium falciparum and cloned this into a mammalian expression vector. When the malaria SPP protein is expressed in mammalian cells it cleaves a SPP substrate. Notably, several human SPP inhibitors block the proteolytic activity of malarial SPP (mSPP). Studies from several model organisms that express multiple SPP homologs demonstrate that the silencing of a single SPP homologue is lethal. Based on these data, we hypothesize that mSPP is a potential a novel therapeutic target for malaria.
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PMID:Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase. 1687 90

The human malaria parasite Plasmodium falciparum exports a variety of its proteins through its endoplasmic reticulum (ER) based secretory pathway in order to survive in the host erythrocyte. Signal peptidases are membrane-bound endopeptidases and have an important role in the transport and maturation of these parasite proteins. Prokaryotic signal peptidases are indispensable enzymes required for the removal of N-terminal signal peptide from the secretory proteins. Eukaryotic signal peptidases exist as multimeric protein complex in the ER and the catalytic subunit of this complex catalyzes removal of the N-terminal signal peptide from preproteins. All the signal peptidases contain five regions of high-sequence similarity referred to as boxes A-E. Here we report characterization of the catalytic subunit of signal peptidase complex (SPC) from P. falciparum. This protein designated as PfSP21 shows homology with the similar subunit from other sources and contains all the conserved boxes A-E. PfSP21 is able to cleave the peptide substrate containing the signal peptidase cleavage site. PfSP21 is phosphorylated by protein kinase C and its enzyme activity was upregulated after this phosphorylation. Immunofluorescence assay studies revealed that PfSP21 is localized in the ER of P. falciparum. PfSP21 dsRNA specifically inhibits the growth of P. falciparum in culture and this inhibition is most likely due to the decrease in the amount of endogenous PfSP21 protein. These studies demonstrate the characterization of a functional subunit of SPC from P. falciparum and should make an important contribution in our better understanding of the complex process of protein translocation in the parasite.
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PMID:Plasmodium falciparum signal peptidase is regulated by phosphorylation and required for intra-erythrocytic growth. 1805 93

The resistance of malaria parasites to current anti-malarial drugs is an issue of major concern globally. Recently we identified a Plasmodium falciparum cell membrane aspartyl protease, which binds to erythrocyte band 3, and is involved in merozoite invasion. Here we report the complete primary structure of P. falciparum signal peptide peptidase (PfSPP), and demonstrate that it is essential for parasite invasion and growth in human erythrocytes. Gene silencing suggests that PfSPP may be essential for parasite survival in human erythrocytes. Remarkably, mammalian signal peptide peptidase inhibitors (Z-LL)(2)-ketone and L-685,458 effectively inhibited malaria parasite invasion as well as growth in human erythrocytes. In contrast, DAPT, an inhibitor of a related gamma-secretase/presenilin-1, was ineffective. Thus, SPP inhibitors specific for PfSPP may function as potent anti-malarial drugs against the blood stage malaria.
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PMID:Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria. 1917 48

The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC(50) of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans.
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PMID:A small molecule inhibitor of signal peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity. 1933 74

Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. To survive and evade host responses the parasite remodels the erythrocyte by exporting several hundred effector proteins beyond the surrounding parasitophorous vacuole membrane. A feature of exported proteins is a pentameric motif (RxLxE/Q/D) that is a substrate for an unknown protease. Here we show that the protein responsible for cleavage of this motif is plasmepsin V (PMV), an aspartic acid protease located in the endoplasmic reticulum. PMV cleavage reveals the export signal (xE/Q/D) at the amino terminus of cargo proteins. Expression of an identical mature protein with xQ at the N terminus generated by signal peptidase was not exported, demonstrating that PMV activity is essential and linked with other key export events. Identification of the protease responsible for export into erythrocytes provides a novel target for therapeutic intervention against this devastating disease.
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PMID:An aspartyl protease directs malaria effector proteins to the host cell. 2013 Jun 43

The establishment of parasite infection within the human erythrocyte is an essential stage in the development of malaria disease. As such, significant interest has focused on the mechanics that underpin invasion and on characterization of parasite molecules involved. Previous evidence has implicated a presenilin-like signal peptide peptidase (SPP) from the most virulent human malaria parasite, Plasmodium falciparum, in the process of invasion where it has been proposed to function in the cleavage of the erythrocyte cytoskeletal protein Band 3. The role of a traditionally endoplasmic reticulum (ER) protease in the process of red blood cell invasion is unexpected. Here, using a combination of molecular, cellular and chemical approaches we provide evidence that PfSPP is, instead, a bona fide ER-resident peptidase that remains intracellular throughout the invasion process. Furthermore, SPP-specific drug inhibition has no effect on erythrocyte invasion whilst having low micromolar potency against intra-erythrocytic development. Contrary to previous reports, these results show that PfSPP plays no role in erythrocyte invasion. Nonetheless, PfSPP clearly represents a potential chemotherapeutic target to block parasite growth, supporting ongoing efforts to develop antimalarial-targeting protein maturation and trafficking during intra-erythrocytic development.
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PMID:Malaria parasite signal peptide peptidase is an ER-resident protease required for growth but not for invasion. 2284 82

Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein's ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential pan-protozoan drug target.
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PMID:Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design. 2323 86

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.
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PMID:Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. 2498 61


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