Plasmodium falciparum: The fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum

Hatabu, Toshimitsu; Hagiwara, Makoto; Taguchi, Nao; Kiyozawa, Masayuki; Suzuki, Mamoru; Kano, Shigeyuki; Sato, Kumiko

doi:10.1016/j.exppara.2005.11.012

Cited by 25 publications

(20 citation statements)

References 16 publications

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“…Mass spectrometric identification of the products of PfAPP-mediated hydrolysis is consistent with strict X-Pro aminopeptidase activity. We found that PfAPP can slowly hydrolyze the Pro-Pro bond in bradykinin (2)(3)(4)(5)(6)(7)(8)(9). This finding is significant as the sequence Pro-Pro is found in ␤-globin.…”

supporting

confidence: 62%

“…During the asexual erythrocytic replication cycle of the malaria parasite, aminopeptidases contribute to the catabolism of peptides generated by two major proteolytic pathways. One of these is initiated at the proteasome, a multifunctional protease that plays an important role in the turnover of ubiquitinated cellular proteins in the cytosol (3)(4)(5). In addition, the parasite transports host red blood cell cytosol (consisting primarily of hemoglobin) to an acidic degradative organelle, the food vacuole, where it is degraded in a proteasome-independent pathway (6, 7).…”

mentioning

confidence: 99%

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Evidence for Catalytic Roles for Plasmodium falciparum Aminopeptidase P in the Food Vacuole and Cytosol

Ragheb

Bompiani

Dalal

et al. 2009

Journal of Biological Chemistry

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The metalloenzyme aminopeptidase P catalyzes the hydrolysis of amino acids from the amino termini of peptides with a prolyl residue in the second position. The human malaria parasite Plasmodium falciparum expresses a homolog of aminopeptidase P during its asexual intraerythrocytic cycle. P. falciparum aminopeptidase P (PfAPP) shares with mammalian cytosolic aminopeptidase P a three-domain, homodimeric organization and is most active with Mn(II) as the cofactor. A distinguishing feature of PfAPP is a 120-amino acid amino-terminal extension that appears to be removed from the mature protein. PfAPP is present in the food vacuole and cytosol of the parasite, a distribution that suggests roles in vacuolar hemoglobin catabolism and cytosolic peptide turnover. To evaluate the plausibility of these putative functions, the stability and kinetic properties of recombinant PfAPP were evaluated at the acidic pH of the food vacuole and at the near-neutral pH of the cytosol. PfAPP exhibited high stability at 37°C in the pH range 5.0 -7.5. In contrast, recombinant human cytosolic APP1 was unstable and formed a high molecular weight aggregate at acidic pH. At both acidic and slightly basic pH values, PfAPP efficiently hydrolyzed the amino-terminal X-Pro bond of the nonapeptide bradykinin and of two globin pentapeptides that are potential in vivo substrates. These results provide support for roles for PfAPP in peptide catabolism in both the food vacuole and the cytosol and suggest that PfAPP has evolved a dual distribution in response to the metabolic needs of the intraerythrocytic parasite.Malaria remains one of the most deadly global infectious diseases with an estimated 500 million clinical cases and 2 million deaths annually (1, 2). Clinical manifestations of the disease arise as the protozoan malaria parasite replicates asexually within human erythrocytes. Five species of the genus Plasmodium infect humans. The cytoadherent properties of red blood cells infected with Plasmodium falciparum, coupled with the ability of the parasite to reach high parasitemia, make it the most virulent species. The emergence of strains of P. falciparum that are resistant to affordable anti-malarial drugs such as chloroquine has complicated efforts to manage malaria, and new drugs are urgently needed.Aminopeptidases catalyze the hydrolysis of amino acids from the amino termini of proteins and peptides. They participate in a wide range of biological processes, including peptide catabolism, protein maturation, antigen presentation on immune cells, and regulation of hormone activity. During the asexual erythrocytic replication cycle of the malaria parasite, aminopeptidases contribute to the catabolism of peptides generated by two major proteolytic pathways. One of these is initiated at the proteasome, a multifunctional protease that plays an important role in the turnover of ubiquitinated cellular proteins in the cytosol (3-5). In addition, the parasite transports host red blood cell cytosol (consisting primarily of hemoglobin) to an acidic degradat...

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supporting

confidence: 62%

mentioning

confidence: 99%

Evidence for Catalytic Roles for Plasmodium falciparum Aminopeptidase P in the Food Vacuole and Cytosol

Ragheb

Bompiani

Dalal

et al. 2009

Journal of Biological Chemistry

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“…In addition, the parasite also has a ClpQY complex, which is expressed only in the schizont and merozoite stages (Mordmüller et al 2006). The importance of protein degradation by these proteasomes is reiterated by the plasmodicidal effects of several proteosome inhibitors such as lactacystin, gliotoxin, and epoxomicin (Gantt et al 1998;Hatabu et al 2006;Kreidenweiss et al 2008). Interestingly, an open-reading frame (ORF; PlasmoDB GeneID: PFC0310c) encoding for a putatively annotated ClpP is also found in the P. falciparum genome.…”

Section: Introductionmentioning

confidence: 97%

Atypical caseinolytic protease homolog from Plasmodium falciparum possesses unusual substrate preference and a functional nuclear localization signal

2009

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Although ATP-dependent caseinolytic protease (Clp) complexes are important for regulating the pathogenicity, survival, and development of many pathogens, their physiological roles in the pathogenicity of malarial parasites remain unknown. This study reports the cloning, authentication, and characterization of a putative Clp protease subunit from Plasmodium falciparum (PfClpP). Heterologous expression studies showed that signal peptide hindered the soluble expression of the full-length PfClpP. Biochemical analyses of the recombinant PfClpP showed that it did not cleave the known ClpP substrate, succinyl-leucine-tyrosine-7-amido-4-methylcoumarin hydrochloride (AMC). Instead, PfClpP readily hydrolyzed a different substrate, glycine-arginine-AMC. The distinctive substrate preference of PfClpP suggests structural uniqueness in its substrate-binding sites that might be exploitable in anti-malarial drug development. Whether PfClpP resembles most eukaryotic ClpPs in being localized to the mitochondria and chloroplasts was also investigated using a mammalian surrogate host system. The results observed showed that green-fluorescence protein tagged PfClpP proteins were localized to the nucleus. PfClpP may have a unique and specialized role in the plasmodial nucleus. Taken together, this study has shown that PfClpP has a unique peptide cleavage function that is localized at the plasmodial nucleus, probably positioned to elicit a regulatory role in the parasite's pathogenicity.

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“…N-carbobenzoxyl-Lleucyl-L-leucyl-L-leucinal (MG132) and N-carbobenzoxy-Lisoleucyl-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI)], gliotoxin (Hatabu et al 2006), and lactacystin, has helped to define the role of proteasomes in various parasitic protozoa processes, including replication and differentiation (Nkemngu et al 2002). Lactacystin was originally isolated from Actinomycetes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of proteasome activity blocks Trypanosoma cruzi growth and metacyclogenesis

et al. 2008

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Proteasomes are intracellular complexes that control protein degradation in organisms ranging from Archaebacteria to mammals. In some parasitic protozoa, the proteasome is involved in cell differentiation and replication. In this study, we have used proteasome inhibitors to determine the biological role of proteasomes during the replication and in vitro metacyclogenesis of Trypanosoma cruzi. We used light and transmission electron microscopy to analyze morphological data and flow cytometry to analyze changes in the cell cycle. The growth of T. cruzi epimastigote culture forms in liver infusion tryptose medium was inhibited by the presence of up to 10 microM lactacystin. Inhibition was dose-dependent, with IC50 (50% inhibitory concentration) of 4.35 microM after 24 or 72 h. The metacyclogenesis process in vitro was strongly (95%) inhibited by 5 microM lactacystin treatment. The adhesion phase was not affected, but the epimastigotes did not differentiate into metacyclic trypomastigotes. Most treated epimastigotes had replicated DNA, with swelling of the mitochondrion and an altered distribution of nuclear and kinetoplast DNA. Our findings suggest that inhibition of the ubiquitin-proteasome pathway in T. cruzi epimastigotes does not block adhesion, but disrupts cell division and affects factors triggering differentiation.

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Plasmodium falciparum: The fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum

Cited by 25 publications

References 16 publications

Evidence for Catalytic Roles for Plasmodium falciparum Aminopeptidase P in the Food Vacuole and Cytosol

Evidence for Catalytic Roles for Plasmodium falciparum Aminopeptidase P in the Food Vacuole and Cytosol

Atypical caseinolytic protease homolog from Plasmodium falciparum possesses unusual substrate preference and a functional nuclear localization signal

Inhibition of proteasome activity blocks Trypanosoma cruzi growth and metacyclogenesis

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