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https://www.readbyqxmd.com/read/29435408/a-putative-rna-binding-protein-from-plasmodium-vivax-apicoplast
#1
Sofía M García-Mauriño, Antonio Díaz-Quintana, Francisco Rivero-Rodríguez, Isabel Cruz-Gallardo, Christian Grüttner, Marian Hernández-Vellisca, Irene Díaz-Moreno
Malaria is caused by Apicomplexa protozoans from the Plasmodium genus entering the bloodstream of humans and animals through the bite of the female mosquitoes. The annotation of the Plasmodium vivax genome revealed a putative RNA binding protein (apiRBP) that was predicted to be trafficked into the apicoplast, a plastid organelle unique to Apicomplexa protozoans. Although a 3D structural model of the apiRBP corresponds to a noncanonical RNA recognition motif with an additional C-terminal α-helix (α3), preliminary protein production trials were nevertheless unsuccessful...
February 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29359192/targeted-phenotypic-screening-in-plasmodium-falciparum-and-toxoplasma-gondii-reveals-novel-modes-of-action-of-medicines-for-malaria-venture-malaria-box-molecules
#2
Gowtham Subramanian, Meenakshi A Belekar, Anurag Shukla, Jie Xin Tong, Ameya Sinha, Trang T T Chu, Akshay S Kulkarni, Peter R Preiser, D Srinivasa Reddy, Kevin S W Tan, Dhanasekaran Shanmugam, Rajesh Chandramohanadas
The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii, we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T...
January 2018: MSphere
https://www.readbyqxmd.com/read/29354648/the-cytosolic-glyoxalases-of-plasmodium-falciparum-are-dispensable-during-asexual-blood-stage-development
#3
Cletus A Wezena, Romy Alisch, Alexandra Golzmann, Linda Liedgens, Verena Staudacher, Gabriele Pradel, Marcel Deponte
The enzymes glyoxalase 1 and 2 (Glo1 and Glo2) are found in most eukaryotes and catalyze the glutathione-dependent conversion of 2-oxoaldehydes to 2-hydroxycarboxylic acids. Four glyoxalases are encoded in the genome of the malaria parasite Plasmodium falciparum, the cytosolic enzymes PfGlo1 and PfcGlo2, the apicoplast enzyme PftGlo2, and an inactive Glo1-like protein that also carries an apicoplast-targeting sequence. Inhibition or knockout of the Plasmodium glyoxalases was hypothesized to lead to an accumulation of 2-oxoaldehydes and advanced glycation end-products (AGE) in the host-parasite unit and to result in parasite death...
November 20, 2017: Microbial Cell
https://www.readbyqxmd.com/read/29311075/phytohormones-isoprenoids-and-role-of-the-apicoplast-in-recovery-from-dihydroartemisinin-induced-dormancy-of-plasmodium-falciparum
#4
Marvin Duvalsaint, Dennis E Kyle
Many organisms undergo dormancy as a stress response to survive under unfavorable conditions that might impede development. This is observed in seed and buds of plants and has been proposed as mechanism of drug evasion and resistance formation in Plasmodium falciparum We explored the effects of the phytohormones, abscisic acid (ABA) and gibberellic acid (GA), on dihydroartemisinin induced dormant erythrocytic stages of P. falciparum parasites. Dormant ring stages exposed to ABA and GA recovered from dormancy up to 48 hr earlier than parasites exposed to DHA alone...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29295911/atg8-is-essential-specifically-for-an-autophagy-independent-function-in-apicoplast-biogenesis-in-blood-stage-malaria-parasites
#5
Marta Walczak, Suresh M Ganesan, Jacquin C Niles, Ellen Yeh
Plasmodium parasites and related pathogens contain an essential nonphotosynthetic plastid organelle, the apicoplast, derived from secondary endosymbiosis. Intriguingly, a highly conserved eukaryotic protein, autophagy-related protein 8 (ATG8), has an autophagy-independent function in the apicoplast. Little is known about the novel apicoplast function of ATG8 and its importance in blood-stage Plasmodium falciparum Using a P. falciparum strain in which ATG8 expression was conditionally regulated, we showed that P...
January 2, 2018: MBio
https://www.readbyqxmd.com/read/29287981/exploiting-the-apicoplast-apicoplast-targeting-drugs-and-malaria-vaccine-development
#6
Leanne M Low, Danielle I Stanisic, Michael F Good
The apicoplast, a relic plastid found in most Apicomplexan parasites, is a notable drug target. Certain antibiotics elicit a delayed death phenotype by targeting this organelle. Here, we review apicoplast targeting drugs and their targets, particularly those that cause delayed death, and highlight its potential uses in malaria vaccine development.
December 26, 2017: Microbes and Infection
https://www.readbyqxmd.com/read/29156781/toxoplasma-gondii-clp-family-protein-tgclpb1-plays-a-crucial-role-in-thermotolerance
#7
Shinuo Cao, Nali Du, Heming Chen, Yu Pang, Zhaoxia Zhang, Jun Zheng, Honglin Jia
Caseinolytic peptidase B (ClpB) plays a pivotal role in suppressing and reversing protein aggregation. Toxoplasma gondii is an intracellular parasitic protozoan that infects a wide variety of mammals and birds and therefore is exposed to a broad range of living condition. We screened ToxoDB (http://ToxoDB.org) and identified 10 putative T. gondii genes encoding members of the Clp superfamily of caseinolytic proteases and chaperones. Of these, we focused on characterizing the Class I ATP-dependent molecular chaperones TgClpB1, TgClpB2, and TgClpB3...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29154995/a-map-of-the-subcellular-distribution-of-phosphoinositides-in-the-erythrocytic-cycle-of-the-malaria-parasite-plasmodium-falciparum
#8
Zeinab Ebrahimzadeh, Angana Mukherjee, Dave Richard
Despite representing a small percentage of the cellular lipids of eukaryotic cells, phosphoinositides (PIPs) are critical in various processes such as intracellular trafficking and signal transduction. Central to their various functions is the differential distribution of PIP species to specific membrane compartments through the actions of kinases, phosphatases and lipases. Despite their importance in the malaria parasite lifecycle, the subcellular distribution of most PIP species in this organism is still unknown...
November 15, 2017: International Journal for Parasitology
https://www.readbyqxmd.com/read/29141210/pfclpc-is-an-essential-clp-chaperone-required-for-plastid-integrity-and-clp-protease-stability-in-plasmodium-falciparum
#9
Anat Florentin, David W Cobb, Jillian D Fishburn, Michael J Cipriano, Paul S Kim, Manuel A Fierro, Boris Striepen, Vasant Muralidharan
The deadly malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid, known as the apicoplast, that functions to produce essential metabolites, and drugs that target the apicoplast are clinically effective. Several prokaryotic caseinolytic protease (Clp) genes have been identified in the Plasmodium genome. Using phylogenetic analysis, we focused on the Clp members that may form a regulated proteolytic complex in the apicoplast. We genetically targeted members of this complex and generated conditional mutants of the apicoplast-localized PfClpC chaperone and PfClpP protease...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29109165/validation-of-putative-apicoplast-targeting-drugs-using-a-chemical-supplementation-assay-in-cultured-human-malaria-parasites
#10
Taher Uddin, Geoffrey Ian McFadden, Christopher Dean Goodman
Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a non-apicoplast target...
November 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29099876/archigregarines-of-the-english-channel-revisited-new-molecular-data-on-selenidium-species-including-early-described-and-new-species-and-the-uncertainties-of-phylogenetic-relationships
#11
Sonja Rueckert, Aleš Horák
BACKGROUND: Gregarines represent an important transition step from free-living predatory (colpodellids s.l.) and/or photosynthetic (Chromera and Vitrella) apicomplexan lineages to the most important pathogens, obligate intracellular parasites of humans and domestic animals such as coccidians and haemosporidians (Plasmodium, Toxoplasma, Eimeria, Babesia, etc.). While dozens of genomes of other apicomplexan groups are available, gregarines are barely entering the molecular age. Among the gregarines, archigregarines possess a unique mixture of ancestral (myzocytosis) and derived (lack of apicoplast, presence of subpellicular microtubules) features...
2017: PloS One
https://www.readbyqxmd.com/read/29096193/autophagy-in-apicomplexan-parasites
#12
REVIEW
Sébastien Besteiro
Autophagy is a highly conserved eukaryotic degradation process that permits the recycling of intracellular components. The molecular machinery and the functions of autophagy have been classically characterized in mammalian cells and yeast, but have long remained unexplored in less-studied eukaryotes. Apicomplexan parasites are early-diverging eukaryotes responsible for a number of important human and veterinary diseases. In light of recent investigations into autophagy function in two of these pathogens, Plasmodium and Toxoplasma, it seems their autophagy-related machinery could be involved in both a canonical degradative function, and a non-canonical role related to the apicoplast, a metabolically important organelle of endosymbiotic origin...
October 30, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29089429/autophagy-related-protein-atg18-regulates-apicoplast-biogenesis-in-apicomplexan-parasites
#13
Priyanka Bansal, Anuj Tripathi, Vandana Thakur, Asif Mohmmed, Pushkar Sharma
Mechanisms by which 3'-phosphorylated phosphoinositides (3'-PIPs) regulate the development of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are poorly understood. The catabolic process of autophagy, which is dependent on autophagy-related proteins (ATGs), is one of the major targets of 3'-PIPs in yeast and mammals. In the present study, we identified autophagy-related protein ATG18 as an effector of 3'-PIPs in these parasites. Pfalciparum ATG18 (PfATG18) and Tgondii ATG18 (TgATG18) interact with 3'-PIPs but exhibited differences in their specificity of interaction with the ligand PIP...
October 31, 2017: MBio
https://www.readbyqxmd.com/read/29072835/biological-studies-and-target-engagement-of-the-2-c-methyl-d-erythritol-4-phosphate-cytidylyltransferase-ispd-targeting-antimalarial-agent-1r-3s-mmv008138-and-analogs
#14
Maryam Ghavami, Emilio F Merino, Zhong-Ke Yao, Rubayet Elahi, Morgan E Simpson, Maria L Fernández-Murga, Joshua H Butler, Michael A Casasanta, Priscilla M Krai, Maxim M Totrov, Daniel J Slade, Paul R Carlier, Maria Belen Cassera
Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP...
November 7, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28987288/relict-plastidic-metabolic-process-as-a-potential-therapeutic-target
#15
REVIEW
Drista Sharma, Rani Soni, Praveen Rai, Bhaskar Sharma, Tarun Kumar Bhatt
The alignment of the evolutionary history of parasites with that of plants provides a different panorama in the drug development process. The housing of different metabolic processes, essential for parasite survival, adds to the indispensability of the apicoplast. The different pathways responsible for fueling the apicoplast and parasite offer a myriad of proteins responsible for the apicoplast function. The studies emphasizing the target-based approaches might help in the discovery of antimalarials. The different putative drug targets and their roles are highlighted...
October 5, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28976181/exploring-the-untapped-biosynthetic-potential-of-apicomplexan-parasites
#16
Jack Ganley, Maria Toro-Moreno, Emily R Derbyshire
Apicomplexan parasites encompass a diverse group of eukaryotic intracellular pathogens that infect various animal hosts to cause disease. Intriguingly, apicomplexans possess a unique organelle of algal origin, the apicoplast, which phylogenetically links these parasites to dinoflagellates and photosynthetic, coral-associated organisms. While production of secondary metabolites in closely-related organisms has been thoroughly examined, it remains widely unexplored in apicomplexans. In this perspective, we discuss previous work toward understanding secondary metabolite building block biosynthesis in apicomplexans and highlight the unexplored enzymology and biosynthetic potential of these parasites in the context of evolution...
October 4, 2017: Biochemistry
https://www.readbyqxmd.com/read/28974215/species-and-genotype-diversity-of-plasmodium-in-malaria-patients-from-gabon-analysed-by-next-generation-sequencing
#17
Albert Lalremruata, Sankarganesh Jeyaraj, Thomas Engleitner, Fanny Joanny, Annika Lang, Sabine Bélard, Ghyslain Mombo-Ngoma, Michael Ramharter, Peter G Kremsner, Benjamin Mordmüller, Jana Held
BACKGROUND: Six Plasmodium species are known to naturally infect humans. Mixed species infections occur regularly but morphological discrimination by microscopy is difficult and multiplicity of infection (MOI) can only be evaluated by molecular methods. This study investigated the complexity of Plasmodium infections in patients treated for microscopically detected non-falciparum or mixed species malaria in Gabon. METHODS: Ultra-deep sequencing of nucleus (18S rRNA), mitochondrion, and apicoplast encoded genes was used to evaluate Plasmodium species diversity and MOI in 46 symptomatic Gabonese patients with microscopically diagnosed non-falciparum or mixed species malaria...
October 3, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28931453/molecular-characterization-and-distribution-of-plasmodium-matutinum-a-common-avian-malaria-parasite
#18
Gediminas Valkiūnas, Mikas Ilgūnas, Dovilė Bukauskaitė, Vaidas Palinauskas, Rasa Bernotienė, Tatjana A Iezhova
Species of Plasmodium (Plasmodiidae, Haemosporida) are widespread and cause malaria, which can be severe in avian hosts. Molecular markers are essential to detect and identify parasites, but still absent for many avian malaria and related haemosporidian species. Here, we provide first molecular characterization of Plasmodium matutinum, a common agent of avian malaria. This parasite was isolated from a naturally infected thrush nightingale Luscinia luscinia (Muscicapidae). Fragments of mitochondrial, apicoplast and nuclear genomes were obtained...
November 2017: Parasitology
https://www.readbyqxmd.com/read/28917450/a-novel-class-of-plasmodial-clpp-protease-inhibitors-as-potential-antimalarial-agents
#19
Sourabh Mundra, Vandana Thakur, Angelica M Bello, Sumit Rathore, Mohd Asad, Lianhu Wei, Jane Yang, Sai Kumar Chakka, Radhakrishnan Mahesh, Pawan Malhotra, Asif Mohmmed, Lakshmi P Kotra
The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure-activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity...
September 5, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28902970/a-genetic-screen-in-rodent-malaria-parasites-identifies-five-new-apicoplast-putative-membrane-transporters-one-of-which-is-essential-in-human-malaria-parasites
#20
Claire P Sayers, Vanessa Mollard, Hayley D Buchanan, Geoffrey I McFadden, Christopher D Goodman
The malaria-causing parasite, Plasmodium, contains a unique non-photosynthetic plastid known as the apicoplast. The apicoplast is an essential organelle bound by four membranes. Although membrane transporters are attractive drug targets, only two transporters have been characterised in the malaria parasite apicoplast membranes. We selected 27 candidate apicoplast membrane proteins, 20 of which are annotated as putative membrane transporters, and performed a genetic screen in P. berghei to determine blood stage essentiality and subcellular localisation...
September 13, 2017: Cellular Microbiology
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