Sulfur Cluster Synthesis in Toxoplasma
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Against the Plasmodium Falciparum Apicoplast
A Systematic In Silico Search for Target Similarity Identifies Several Approved Drugs with Potential Activity against the Plasmodium falciparum Apicoplast Nadlla Alves Bispo1, Richard Culleton2, Lourival Almeida Silva1, Pedro Cravo1,3* 1 Instituto de Patologia Tropical e Sau´de Pu´blica/Universidade Federal de Goia´s/Goiaˆnia, Brazil, 2 Malaria Unit/Institute of Tropical Medicine (NEKKEN)/Nagasaki University/ Nagasaki, Japan, 3 Centro de Mala´ria e Doenc¸as Tropicais.LA/IHMT/Universidade Nova de Lisboa/Lisboa, Portugal Abstract Most of the drugs in use against Plasmodium falciparum share similar modes of action and, consequently, there is a need to identify alternative potential drug targets. Here, we focus on the apicoplast, a malarial plastid-like organelle of algal source which evolved through secondary endosymbiosis. We undertake a systematic in silico target-based identification approach for detecting drugs already approved for clinical use in humans that may be able to interfere with the P. falciparum apicoplast. The P. falciparum genome database GeneDB was used to compile a list of <600 proteins containing apicoplast signal peptides. Each of these proteins was treated as a potential drug target and its predicted sequence was used to interrogate three different freely available databases (Therapeutic Target Database, DrugBank and STITCH3.1) that provide synoptic data on drugs and their primary or putative drug targets. We were able to identify several drugs that are expected to interact with forty-seven (47) peptides predicted to be involved in the biology of the P. falciparum apicoplast. Fifteen (15) of these putative targets are predicted to have affinity to drugs that are already approved for clinical use but have never been evaluated against malaria parasites. -
The Apicoplast: a Review of the Derived Plastid of Apicomplexan Parasites
Curr. Issues Mol. Biol. 7: 57-80. Online journalThe Apicoplastat www.cimb.org 57 The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites Ross F. Waller1 and Geoffrey I. McFadden2,* way to apicoplast discovery with studies of extra- chromosomal DNAs recovered from isopycnic density 1Botany, University of British Columbia, 3529-6270 gradient fractionation of total Plasmodium DNA. This University Boulevard, Vancouver, BC, V6T 1Z4, Canada group recovered two DNA forms; one a 6kb tandemly 2Plant Cell Biology Research Centre, Botany, University repeated element that was later identifed as the of Melbourne, 3010, Australia mitochondrial genome, and a second, 35kb circle that was supposed to represent the DNA circles previously observed by microscopists (Wilson et al., 1996b; Wilson Abstract and Williamson, 1997). This molecule was also thought The apicoplast is a plastid organelle, homologous to to be mitochondrial DNA, and early sequence data of chloroplasts of plants, that is found in apicomplexan eubacterial-like rRNA genes supported this organellar parasites such as the causative agents of Malaria conclusion. However, as the sequencing effort continued Plasmodium spp. It occurs throughout the Apicomplexa a new conclusion, that was originally embraced with and is an ancient feature of this group acquired by the some awkwardness (“Have malaria parasites three process of endosymbiosis. Like plant chloroplasts, genomes?”, Wilson et al., 1991), began to emerge. apicoplasts are semi-autonomous with their own genome Gradually, evermore convincing character traits of a and expression machinery. In addition, apicoplasts import plastid genome were uncovered, and strong parallels numerous proteins encoded by nuclear genes. These with plastid genomes from non-photosynthetic plants nuclear genes largely derive from the endosymbiont (Epifagus virginiana) and algae (Astasia longa) became through a process of intracellular gene relocation. -
Reevaluation of the Toxoplasma Gondii and Neospora Caninum Genomes Reveals Misassembly, Karyotype Differences and Chromosomal Rearrangements
bioRxiv preprint doi: https://doi.org/10.1101/2020.05.22.111195; this version posted May 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Reevaluation of the Toxoplasma gondii and Neospora caninum genomes reveals misassembly, karyotype differences and chromosomal rearrangements Luisa Berna1, Pablo Marquez1, Andrés Cabrera1, Gonzalo Greif1, María E. Francia2,3,*, Carlos Robello1,4,* AUTHORS AFFILIATIONS 1 Laboratory of Host Pathogen Interactions-Molecular Biology Unit. Institut Pasteur de Montevideo. Montevideo, Uruguay 2 Laboratory of Apicomplexan Biology. Institut Pasteur de Montevideo. Montevideo, Uruguay. 3 Departamento de Parasitología y Micología. Facultad de Medicina-Universidad de la República. Montevideo, Uruguay. 4 Departamento de Bioquímica. Facultad de Medicina-Universidad de la República. Montevideo, Uruguay. *Corresponding authors ABSTRACT Neospora caninum primarily infects cattle causing abortions with an estimated impact of a billion dollars on worldwide economy, annually. However, the study of its biology has been unheeded by the established paradigm that it is virtually identical to its close relative, the widely studied human pathogen, Toxoplasma gondii. By revisiting the genome sequence, assembly and annotation using third generation sequencing technologies, here we show that the N. caninum genome was originally incorrectly assembled under the presumption of synteny with T. gondii. We show that major chromosomal rearrangements have occurred between these species. Importantly, we show that chromosomes originally annotated as ChrVIIb and VIII are indeed fused, reducing the karyotype of both N. -
The NTP Generating Activity of Pyruvate Kinase II Is Critical
RESEARCH ARTICLE The NTP generating activity of pyruvate kinase II is critical for apicoplast maintenance in Plasmodium falciparum Russell P Swift, Krithika Rajaram, Cyrianne Keutcha, Hans B Liu, Bobby Kwan, Amanda Dziedzic, Anne E Jedlicka, Sean T Prigge* Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States Abstract The apicoplast of Plasmodium falciparum parasites is believed to rely on the import of three-carbon phosphate compounds for use in organelle anabolic pathways, in addition to the generation of energy and reducing power within the organelle. We generated a series of genetic deletions in an apicoplast metabolic bypass line to determine which genes involved in apicoplast carbon metabolism are required for blood-stage parasite survival and organelle maintenance. We found that pyruvate kinase II (PyrKII) is essential for organelle maintenance, but that production of pyruvate by PyrKII is not responsible for this phenomenon. Enzymatic characterization of PyrKII revealed activity against all NDPs and dNDPs tested, suggesting that it may be capable of generating a broad range of nucleotide triphosphates. Conditional mislocalization of PyrKII resulted in decreased transcript levels within the apicoplast that preceded organelle disruption, suggesting that PyrKII is required for organelle maintenance due to its role in nucleotide triphosphate generation. Introduction *For correspondence: With increasing resistance to current front-line antimalarials, there is a crucial need to find new thera- [email protected] peutic interventions with novel mechanisms of action (Dondorp et al., 2009; Trape, 2001). The api- coplast organelle within the parasite has often been considered as a source of new drug targets Competing interests: The since it is required for blood-stage survival, in addition to possessing evolutionarily distinct biochem- authors declare that no ical pathways that are not present in the human host (Goodman and McFadden, 2013; competing interests exist. -
The Protozoan Nucleus. Molecular and Biochemical Parasitology, 209(1-2), Pp
McCulloch, R., and Navarro, M. (2016) The protozoan nucleus. Molecular and Biochemical Parasitology, 209(1-2), pp. 76-87. (doi:10.1016/j.molbiopara.2016.05.002) This is the author’s final accepted version. There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it. http://eprints.gla.ac.uk/135296/ Deposited on: 22 February 2017 Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk *Manuscript Click here to view linked References The protozoan nucleus Richard McCulloch1 and Miguel Navarro2 1. The Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davis Building, 120 University Place, Glasgow, G12 8TA, U.K. Telephone: 01413305946 Fax: 01413305422 Email: [email protected] 2. Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Avda. del Conocimiento s/n, 18100 Granada, Spain. Email: [email protected] Correspondence can be sent to either of above authors Keywords: nucleus; mitosis; nuclear envelope; chromosome; DNA replication; gene expression; nucleolus; expression site body 1 Abstract The nucleus is arguably the defining characteristic of eukaryotes, distinguishing their cell organisation from both bacteria and archaea. Though the evolutionary history of the nucleus remains the subject of debate, its emergence differs from several other eukaryotic organelles in that it appears not to have evolved through symbiosis, but by cell membrane elaboration from an archaeal ancestor. Evolution of the nucleus has been accompanied by elaboration of nuclear structures that are intimately linked with most aspects of nuclear genome function, including chromosome organisation, DNA maintenance, replication and segregation, and gene expression controls. -
Five Questions About Non-Mevalonate Isoprenoid Biosynthesis
Pearls Five Questions about Non-Mevalonate Isoprenoid Biosynthesis Audrey R. Odom* Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America What Is an Isoprenoid? which have retained the MVA pathway, and several obligate intracellular organisms, including rickettsiae and mycoplasmas, Isoprenoids (also referred to as terpenoids) are the largest group which have lost de novo isoprenoid metabolism altogether. of natural products, comprising over 25,000 known compounds While most eukaryotes use the MVA pathway, phyla that have [1]. Each member of this class is assembled from 5-carbon (C5) acquired a plastid organelle (either a true chloroplast, such as in isoprene units and derived metabolically from the basic building plants, or a non-photosynthetic relic plastid) possess the eubacte- block isopentenyl pyrophosphate (IPP) and its isomer, dimethy- ria-like MEP pathway. In microbes, this includes the Apicom- lallyl pyrophosphate (DMAPP). Subsequent metabolic reactions plexan protozoan pathogens Toxoplasma gondii (which causes (such as cyclization) generate enormous complexity and diversity toxoplasmosis) and the malaria-causing Plasmodia species, including from these basic starting materials. Isoprenoids are vital to all the agent of severe malaria, Plasmodium falciparum. While plants organismal classes, supporting core cellular functions such as contain both the MVA and MEP pathways, the Apicomplexans do aerobic respiration (ubiquinones) and membrane stability (choles- not contain the MVA pathway and exclusively generate terol) (Figure 1). Isoprenoids also form the largest group of so- isoprenoids via the MEP pathway. called secondary metabolites, such as the extremely diverse classes of plant defensive terpenoids that are widely exploited as perfumes, Why Are Isoprenoids Essential in Pathogenic food additives, and pharmaceutical agents (e.g., the antimalarial compound artemisinin) [2]. -
Genomes and Genome Projects of Protozoan Parasites
Curr. Issues Mol. Biol. (2003) 5: 61-74. Genomes of Protozoan Parasites 61 Genomes and Genome Projects of Protozoan Parasites Klaus Ersfeld other projects (Table 1) are at various stages of progress, but the reasoning and motivations for genomic research is School of Biological Sciences, 2.205 Stopford Building, virtually identical between all of them (Tarleton and University of Manchester, Oxford Road, Manchester M13 Kissinger, 2001). 9PT, UK. The Plasmodium falciparum genome Abstract More than 1 billion people are estimated to carry malaria- causing parasites at any one time. The annual mortality Protozoan parasites are causing some of the most rate is between 0.5-3 million people. A massive increase devastating diseases world-wide. It has now been in population, a deterioration in public health services and recognised that a major effort is needed to be able to infrastructures and the problems associated with now control or eliminate these diseases. Genome projects widespread drug resistance has led to a re-emergence of for the most important protozoan parasites have been malaria as one of the most serious diseases world-wide initiated in the hope that the read-out of these projects (http://www.who.int/tdr/diseases/malaria/default.htm). After will help to understand the biology of the parasites a period of optimism, mainly due to the relatively successful and identify new targets for urgently needed drugs. reduction of the malaria-transmitting mosquitoes with the Here, I will review the current status of protozoan pesticide DDT, more people die know of the disease than parasite genome projects, present findings obtained 40 years ago (Guerin et al., 2002a; Miller and Greenwood, as a result of the availability of genomic data and 2002). -
Apicoplast Fatty Acid Synthesis Is Essential for Pellicle Formation at the End of Cytokinesis in Toxoplasma Gondii Érica S
© 2016. Published by The Company of Biologists Ltd | Journal of Cell Science (2016) 129, 3320-3331 doi:10.1242/jcs.185223 RESEARCH ARTICLE Apicoplast fatty acid synthesis is essential for pellicle formation at the end of cytokinesis in Toxoplasma gondii Érica S. Martins-Duarte1,2,*, Maira Carias1,2, Rossiane Vommaro1,2, Namita Surolia3 and Wanderley de Souza1,2,* ABSTRACT an ‘apicoplast’, a non-photosynthetic secondary plastid originating The apicomplexan protozoan Toxoplasma gondii, the causative agent from a red algae plastid that was engulfed by an apicomplexan of toxoplasmosis, harbors an apicoplast, a plastid-like organelle with ancestor (Williamson et al., 1994; Köhler et al., 1997). Besides the essential metabolic functions. Although the FASII fatty acid evolutionary importance of the apicoplast, its discovery brought biosynthesis pathway located in the apicoplast is essential for new opportunities for the development of novel therapy targeting parasite survival, the cellular effects of FASII disruption in T. gondii diseases caused by apicomplexan parasites (Wiesner et al., 2008; had not been examined in detail. Here, we combined light and electron Goodman and McFadden, 2013). As in plant plastids, the apicoplast microscopy techniques – including focused ion beam scanning contains its own genome and pathways for the synthesis of electron microscopy (FIB-SEM) – to characterize the effect of FASII isoprenoids, fatty acids and iron-sulfur (Fe-S) clusters (Sheiner disruption in T. gondii, by treatment with the FASII inhibitor triclosan or et al., 2013; van Dooren and Striepen, 2013). More importantly, by inducible knockdown of the FASII component acyl carrier protein. owing to the prokaryotic ancestry of the apicoplast, its pathways are Morphological analyses showed that FASII disruption prevented divergent from the eukaryotic counterparts found in the mammalian cytokinesis completion in T. -
WO 2016/033635 Al 10 March 2016 (10.03.2016) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2016/033635 Al 10 March 2016 (10.03.2016) P O P C T (51) International Patent Classification: AN, Martine; Epichem Pty Ltd, Murdoch University Cam Λ 61Κ 31/155 (2006.01) C07D 249/14 (2006.01) pus, 70 South Street, Murdoch, Western Australia 6150 A61K 31/4045 (2006.01) C07D 407/12 (2006.01) (AU). ABRAHAM, Rebecca; School of Animal and A61K 31/4192 (2006.01) C07D 403/12 (2006.01) Veterinary Science, The University of Adelaide, Adelaide, A61K 31/341 (2006.01) C07D 409/12 (2006.01) South Australia 5005 (AU). A61K 31/381 (2006.01) C07D 401/12 (2006.01) (74) Agent: WRAYS; Groud Floor, 56 Ord Street, West Perth, A61K 31/498 (2006.01) C07D 241/20 (2006.01) Western Australia 6005 (AU). A61K 31/44 (2006.01) C07C 211/27 (2006.01) A61K 31/137 (2006.01) C07C 275/68 (2006.01) (81) Designated States (unless otherwise indicated, for every C07C 279/02 (2006.01) C07C 251/24 (2006.01) kind of national protection available): AE, AG, AL, AM, C07C 241/04 (2006.01) A61P 33/02 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07C 281/08 (2006.01) A61P 33/04 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07C 337/08 (2006.01) A61P 33/06 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07C 281/18 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (21) International Application Number: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PCT/AU20 15/000527 PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 28 August 2015 (28.08.2015) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. -
Evolution of Carotenoid and Isoprenoid Biosynthesis in Photosynthetic and Non-Photosynthetic Organisms
EVOLUTION OF CAROTENOID AND ISOPRENOID BIOSYNTHESIS IN PHOTOSYNTHETIC AND NON-PHOTOSYNTHETIC ORGANISMS HARTMUT K. LICHTENTHALER Botanisches Institut II, University of Karlsruhe, Kaiserstr. 12, D-76128 Karlsruhe, Germany Email: [email protected] Abstract Sterols and carotenoids are typical representatives of the group of isoprenoid lipids in plants. All isoprenoids are synthesized by condensation of the two active C5-units: dimethylallyl diphosphate, DMAPP, and isopentenyl diphosphate, IPP. Like animals, higher plants form their sterols via the classical cytosolic acetate/mevalonate (MVA) pathway of IPP biosynthesis. Plants as photosynthetic organisms, however possess a second, non- mevalonate pathway for IPP biosynthesis, the DOXP/MEP pathway. The latter operates in the chloroplasts and is responsible for the formation of carotenoids and all other plastidic isoprenoid lipids (phytol, prenylquinones). Although there exists some cooperation between both IPP producing pathways, one can never fully compensate for the other. Thus, in higher plants sterols are primarily made via the MVA pathway and carotenoids via the DOXP pathway. This also applies to several algae groups, such as red algae and Heterokontophyta. In the large and diverging group of 'Green Algae' the situation is more complex. The more advanced evolutionary groups (Charales, Zygnematales) possess, like higher plants, both IPP forming pathways and represent an evolutionary link to these. In contrast, the proper Chlorophyta, often single cell organisms (Chlorella, Scenedesmus, Trebouxia), represent a separate phylum and synthesize sterols and carotenoids via the DOXP pathway whereas the MVA pathway is lost. The common ancestor of both groups, Mesostigma viride, again exhibits both IPP pathways. In the photosynthetic Euglenophyta the situation is inverse, both the sterols and the carotenoids are formed exclusively via the MVA pathway, the DOXP pathway is lost during the secondary endosymbiosis. -
Book Reviews
BOOK REVIEWS INTERNATIONAL MICROBIOLOGY (2005) 8:71-76 www.im.microbios.org Malaria Parasites. mosomes. The following chapter (The genome of model Genomes and malaria parasites, and comparative genomics, by J. Carlton, J. Molecular Biology Silva, and N. Hall) explores general aspects of the compara- tive genomics and chromosome structure of P. falciparum and other protozoans from the same genus, including P. ANDREW P. WATERS, vivax, P. yoelii, P. chabaudi, P. berghei, and P. knowlesi. Com- CHRIS J. JANSE (EDS) plementing the data provided in those chapters, A. Scherf, 2004. Caister Academic Press, Norfolk, UK L.M. Figueiredo, and L.H. Freitas, Jr., present an in-depth 546 pp, 24 × 16 cm study of the subtelomeric regions of the Plasmodium chromo- Price: US$ 230 ISBN 0-9542464-6-2 somes (Chap. 7). In Chap. 8, there is another excellent review, by K.W. Deitsch, on the regulation of gene expression in Plasmodium, in which both the epigenetic control of gene expression and the transcriptional control of the var genes, responsible for antigenic variation and escape of the parasite The book Malaria Parasites: Genomes and Molecular from the host’s immune response, are emphasized. The Biology presents an overview of the tasks that were involved genome analyses carried out thus far have been limited com- in obtaining and deciphering parasite DNA sequences that pared to the promise of those that can be done on whole led to the completion of the Plasmodium falciparum Genome genomes of the various malaria parasites that have already been Project. It represents a complete guide for researchers inter- sequenced or that are currently in development. -
The Maintenance and Replication of the Apicoplast Genome In
THE MAINTENANCE AND REPLICATION OF THE APICOPLAST GENOME IN TOXOPLASMA GONDII by SARAH BAKER REIFF (Under the Direction of Boris Striepen) ABSTRACT The phylum Apicomplexa comprises a group of intracellular parasites of significant global health and economic concern. Most apicomplexan parasites possess a relict plastid organelle, which no longer performs photosynthesis but still retains important metabolic functions. This organelle, known as the apicoplast, also contains its own genome which is required for parasite viability. The apicoplast and its genome have been shown to be useful as therapeutic targets. However, limited information is available about the replication and maintenance of plastid DNA, not just in apicomplexan parasites but also in plants and algae. Here we use the genetic tools available in the model apicomplexan Toxoplasma gondii to examine putative apicoplast DNA replication and condensation factors, including homologs of DNA polymerase I, single-stranded DNA binding protein, DNA gyrase, and the histone-like protein HU. We confirm targeting to the apicoplast of these candidates, which are all encoded in the nucleus and must be imported. We created a genetic knockout of the Toxoplasma HU gene, which encodes a homolog of a bacterial protein that helps condense the bacterial nucleoid. We show that loss of HU in Toxoplasma results in a strong decrease in apicoplast DNA content, accompanied by biogenesis and segregation defects of the organelle. We were also interested in examining the roles of enzymes that might be more directly involved in DNA replication. To this end we constructed conditional mutants of the Toxoplasma gyrase B homolog and the DNA polymerase I homolog, which appears to be the result of a gene fusion and contains multiple different catalytic domains.