The proteasome plays a vital role throughout the life cycle as Plasmodium parasites
quickly adapt to a new host and undergo a series of morphologic changes during asexual
replication and sexual differentiation. Plasmodium carries 3 different types of protease
complexes: typical eukaryotic proteasome (26S) that resides in the cytoplasm and the
nucleus, a prokaryotic proteasome homolog ClpQ that resides in the mitochondria, and
a caseinolytic protease complex ClpP that resides in the apicoplast. In silico prediction
in conjunction with immunoprecipitation analysis of ubiquitin conjugates have suggested
that over half of the Plasmodium falciparum proteome during asexual reproduction are
potential targets for ubiquitination. The marked potency of multiple classes of proteasome
inhibitors against all stages of the life cycle, synergy with the current frontline
antimalarial, artemisinin, and recent advances identifying differences between Plasmodium
and human proteasomes strongly support further drug development efforts.
Abbreviations:
PfPMT (phosphoethanolamine methyltransferase), UPS (uUbiquitin proteasome system), ART (artemisinin), ACT (artemisinin-based combination therapy), FDA (food and drug administration), DHA (dihydroartemisinin)To read this article in full you will need to make a payment
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References
- Malaria: Biology and Disease.Cell. 2016; 167: 610-624
- Characterization and localization of Plasmodium falciparum homolog of prokaryotic ClpQ/HslV protease.Mol Biochem Parasitol. 2007; 152: 139-148
- Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death.Cell Death Dis. 2011; 2: e231
- Mitochondrial localization of the threonine peptidase PfHslV, a ClpQ ortholog in Plasmodium falciparum.Int J Parasitol. 2010; 40: 1517-1523
- Plasmodia express two threonine-peptidase complexes during asexual development.Mol Biochem Parasitol. 2006; 148: 79-85
- Unraveling the ubiquitome of the human malaria parasite.J Biol Chem. 2011; 286: 40320-40330
- Thiostrepton and derivatives exhibit antimalarial and gametocytocidal activity by dually targeting parasite proteasome and apicoplast.Antimicrob Agents Chemother. 2011; 55: 1338-1348
- Choline induces transcriptional repression and proteasomal degradation of the malarial phosphoethanolamine methyltransferase.Eukaryot Cell. 2007; 6: 1618-1624
- Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase- phosphoethanolamine-methyltransferase pathway and severe growth and survival defects.J Biol Chem. 2008; 283: 27636-27643
- The proteasome of malaria parasites: a multi-stage drug target for chemotherapeutic intervention?.Int J Parasitol Drugs Drug Resist. 2012; 2 (Available from:): 1-10
- The proteasome inhibitor epoxomicin has potent Plasmodium falciparum gametocytocidal activity.Antimicrob Agents Chemother. 2009; 53: 4080-4085
- Male and female Plasmodium falciparum mature gametocytes show different responses to antimalarial drugs.Antimicrob Agents Chemother. 2013; 57: 3268-3274
- Changes in the transcriptome of the malaria parasite Plasmodium falciparum during the initial phase of transmission from the human to the mosquito.BMC Genomics. 2013; 14: 256
- Proteasome inhibitors block development of Plasmodium spp.Antimicrob Agents Chemother. 1998; 42: 2731-2738
- The Plasmodium eukaryotic initiation factor-2α kinase IK2 controls the latency of sporozoites in the mosquito salivary glands.J Exp Med. 2010; 207 (Available from:): 1465-1474
- Metamorphosis of the malaria parasite in the liver is associated with organelle clearance.Cell Res. 2010; 20 (Available from:): 1043-1059
- The ubiquitin system.Annu Rev Biochem. 1998; 67 (Available from: ): 425-479
- Proteasome inhibitors: valuable new tools for cell biologists.Trends Cell Biol. 1998; 8 (Available from:): 397-403
- Proteasome inhibitors: complex tools for a complex enzyme.Curr Top Microbiol Immunol. 2002; 268: 185-208
- Targeting proteasomes in infectious organisms to combat disease.FEBS J. 2017; 284: 1503-1517
- Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance.Jpn J Infect Dis. 2012; 65: 465-475
- Artemisinin action and resistance in Plasmodium falciparum.Trends Parasitol. 2016; 32: 682-696
- Review article plasmodium falciparum resistance to artemisinin derivatives and piperaquine: a major challenge for malaria elimination in Cambodia.Am J Trop Med Hyg. 2016; 95: 1228-1238
- Emerging artemisinin resistance in the border areas of Thailand.Expert Rev Clin Pharmacol. 2013; 6: 307-322
- The cryo-EM structure of the Plasmodium falciparum 20S proteasome and its use in the fight against malaria.FEBS J. 2016; 283 (Available from:): 4238-4243
- Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance.Science. 2015; 347 (Available from:): 431-435
- A molecular marker of artemisinin-resistant Plasmodium falciparum.Nature. 2016; 505: 50-55
- Plasmodium falciparum kelch 13: a potential molecular marker for tackling artemisinin-resistant malaria parasites.Expert Rev Anti Infect Ther. 2016; 14: 125-135
- Targeting the cell stress response of Plasmodium falciparum to Overcome artemisinin resistance.PLoS Biol. 2015; 13: 1-26
- Protein degradation systems as antimalarial therapeutic targets.Trends Parasitol. 2017; 33 (Available from:): 731-743
- Marine actinomycetes: a new source of compounds against the human malaria parasite.PLoS One. 2008; 3: e2335
- Analysis of bortezomib inhibitor docked within the catalytic subunits of the Plasmodium falciparum 20S proteasome.Springerplus. 2013; 2: 1-11
- Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin.Science. 1995; 268 (80-): 726-731
- Comprehensive study of proteasome inhibitors against Plasmodium falciparum laboratory strains and field isolates from Gabon.Malar J. 2008; 7: 1-8
- Salinosporamide natural products: Potent 20 S proteasome inhibitors as promising cancer chemotherapeutics.Angew Chem Int Ed Engl. 2010; 49 (Available from:): 9346-9367
- Epoxomicin, a new antitumor agent of microbial origin.J Antibiot. 1992; 45: 1746-1752
- Eponemycin, a new antibiotic active against B16 melanoma. I. Production, isolation, structure and biological activity.J Antibiot. 1990; 43: 8-18
- Analysis of eponemycin (α’β’ epoxyketone) analog compound from streptomyces hygroscopicus subsp hygroscopicus extracts and its antiplasmodial activity during plasmodium berghei infection.Biomed Res. 2017; 28: 164-172
- From epoxomicin to carfilzomib: chemistry, biology, and medical outcomes.Nat Prod Rep. 2013; 30 (Available from:): 600-604
- Validation of the proteasome as a therapeutic target in plasmodium using an epoxyketone inhibitor with parasite-specific toxicity.Chem Biol. 2012; 19 (Available from:): 1535-1545
- Development of a potent inhibitor of the Plasmodium proteasome with reduced mammalian toxicity.J Med Chem. 2017; 60: 6721-6732
- Vinyl sulfones as mechanism-based cysteine protease inhibitors.J Med Chem. 1995; 38: 3193-3196
- Covalent modification of the active site threonine of proteasomal β subunits and the Escherichia coli homolog HsIV by a new class of inhibitors.Proc Natl Acad Sci USA. 1997; 94: 6629-6634
- Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.Antimicrob Agents Chemother. 1996; 40 (Available from:): 1600-1603
- Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors.Antimicrob Agents Chemother. 2013; 57: 3576-3584
- Inhibition of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex.Biochemistry. 1992; 31 (Available from:): 9421-9428
- Purification and characterization of a Z-Leu-Leu-Leu-MCA degrading protease expected to regulate neurite formation: a novel catalytic activity in proteasome.Biochem Biophys Res Commun. 1993; 196 (Available from:): 1195-1201
- Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.Cell. 1994; 78 (Available from:): 761-771
- Structure and functions of the 20S and 26S proteasomes.Annu Rev Biochem. 1996; 65 (Available from:): 801-847
- Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine.J Biochem. 1996; 119: 572-576
- Tyropeptins A and B, new proteasome inhibitors produced by Kitasatospora sp. MK993-dF2. II. Structure determination and synthesis.J Antibiot. 2001; 54 (Available from: ): 1004-1012
- Blocking Plasmodium falciparum development via dual inhibition of hemoglobin degradation and the ubiquitin proteasome system by MG132.PLoS One. 2013; 8 (Available from: ): e73530
- Molecular basis of bortezomib resistance: proteasome subunit25 (PSMB5) gene mutation and overexpression of PSMB5 protein.Blood. 2008; 112: 2489-2499
- Advances in and applications of proteasome inhibitors.Curr Opin Chem Biol. 2008; 12 (Available from:): 434-440
- The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites.Parasitology. 2005; 131: 37-44
- Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B.BMC Clin Pharmacol. 2007; 7: 1-6
- Emerging therapeutic strategies for overcoming proteasome inhibitor resistance.Adv Cancer Res. 2015; 127 (Available from:): 191-226
- Novel proteasome inhibitors to overcome bortezomib resistance.J Natl Cancer Inst. 2011; 103: 1007-1017
- TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities.J Antibiot. 2000; 53: 105-109
- Identification of potent and selective non-covalent inhibitors of the Plasmodium falciparum proteasome.J Am Chem Soc. 2014; 136 (Available from:): 13562-13565
- Synthesis and evaluation of macrocyclic peptide aldehydes as potent and selective inhibitors of the 20S proteasome.ACS Med Chem Lett. 2016; 7: 250-255
- Characterization and role of protozoan parasite proteasomes.Trends Parasitol. 2003; 19: 55-59
- Effect of proteasome inhibitors on the growth, encystation, and excystation of Entamoeba histolytica and Entamoeba invadens.Parasitol Res. 2002; 88: 454-459
- The Leishmania mexicana proteasome.Mol Biochem Parasitol. 1999; 103: 49-60
- The ubiquitin-proteasome pathway plays an essential role in proteolysis during Trypanosoma cruzi remodeling.Biochemistry. 2001; 40: 1053-1062
- Proteasome inhibitors block intracellular growth and replication of Toxoplasma gondii.Parasitology. 2000; 121: 35-47
- The Leishmania chagasi proteasome: role in promastigotes growth and amastigotes survival within murine macrophages.Acta Trop. 2004; 91: 121-130
- Knockdown of LdMC1 and Hsp70 by antisense oligonucleotides causes cell-cycle defects and programmed cell death in Leishmania donovani.Mol Cell Biochem. 2012; 359: 135-149
- Evaluation of the in vitro growth-inhibitory effect of epoxomicin on Babesia parasites.Vet Parasitol. 2010; 167: 19-27
- Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness.Nature. 2016; 537 (Available from:): 229-233
- Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome.Arch Biochem Biophys. 2010; 501: 214-220
- Rational design of selective and bioactive inhibitors of the mycobacterium tuberculosis proteasome.ACS Infect Dis. 2017; 3: 176-181
- Structural basis for the species-selective binding of N, C-Capped dipeptides to the mycobacterium tuberculosis proteasome.Biochemistry. 2017; 56: 324-333
- The prokaryotic ClpQ protease plays a key role in growth and development of mitochondria in Plasmodium falciparum.Cell Microbiol. 2013; 15: 1660-1673
- A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents.Bioorganic Med Chem. 2017; 25 (Available from:): 5662-5677
Article info
Publication history
Published online: May 03, 2018
Accepted:
April 30,
2018
Received in revised form:
April 26,
2018
Received:
February 12,
2018
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