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Joel Barratt, Alexa Kaufer, Bryce Peters, Douglas Craig, Andrea Lawrence, Tamalee Roberts, Rogan Lee, Gary McAuliffe, Damien Stark, John Ellis
The genus Leishmania includes approximately 53 species, 20 of which cause human leishmaniais; a significant albeit neglected tropical disease. Leishmaniasis has afflicted humans for millennia, but how ancient is Leishmania and where did it arise? These questions have been hotly debated for decades and several theories have been proposed. One theory suggests Leishmania originated in the Palearctic, and dispersed to the New World via the Bering land bridge. Others propose that Leishmania evolved in the Neotropics...
January 2017: PLoS Neglected Tropical Diseases
Gisele F A Picchi, Vanessa Zulkievicz, Marco Aurelio Krieger, Nilson T Zanchin, Samuel Goldenberg, Lyris M F de Godoy
Chagas disease, caused by Trypanosoma cruzi, still affects millions of people around the world. No vaccines neither treatment for chronic Chagas disease are available, and chemotherapy for the acute phase is hindered by limited efficacy and severe side effects. The processes by which the parasite acquires infectivity and survives in different hosts involve tight regulation of gene expression, mainly post-transcriptionally. Nevertheless, chromatin structure/organization of trypanosomatids is similar to other eukaryotes, including histone variants and post-translational modifications...
January 11, 2017: Journal of Proteome Research
Alexander O Frolov, Marina N Malysheva, Anna I Ganyukova, Vyacheslav Yurchenko, Alexei Y Kostygov
Blastocrithidia papi sp. n. is a cyst-forming trypanosomatid parasitizing firebugs (Pyrrhocoris apterus). It is a member of the Blastocrithidia clade and a very close relative of B. largi, to which it is almost identical through its SSU rRNA gene sequence. However, considering the SL RNA gene these two species represent quite distinct, not even related typing units. Morphological analysis of the new species revealed peculiar or even unique features, which may be useful for future taxonomic revision of the genus Blastocrithidia...
November 16, 2016: European Journal of Protistology
Tamila Galaka, Mariana Ferrer Casal, Melissa Storey, Catherine Li, María N Chao, Sergio H Szajnman, Roberto Docampo, Silvia N J Moreno, Juan B Rodriguez
Based on crystallographic data of the complexes 2-alkyl(amino)ethyl-1,1-bisphosphonates-Trypanosoma cruzi farnesyl diphosphate synthase, some linear 1,1-bisphosphonic acids and other closely related derivatives were designed, synthesized and biologically evaluated against T. cruzi, the responsible agent of Chagas disease and against Toxoplasma gondii, the etiologic agent of toxoplasmosis and also towards the target enzymes farnesyl pyrophosphate synthase of T. cruzi (TcFPPS) and T gondii (TgFPPS), respectively...
January 4, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Michel Batista, Fernanda G Kugeratski, Carla V de Paula Lima, Christian M Probst, Rafael L Kessler, Lyris M de Godoy, Marco A Krieger, Fabricio K Marchini
: Protein phosphorylation and dephosphorylation events regulate many cellular processes. The identification of all phosphorylation sites and their association to a respective protein kinase or phosphatase is a challenging and crucial step to have a deeper understanding of the effects of signaling networks on cells. Pathogenic trypanosomatids have a large number of protein kinases and phosphatases in comparison to other organisms, which reinforces the relevance of the phosphorylation process in these early eukaryotes, nevertheless little is known about protein phosphorylation in these protozoa...
December 27, 2016: Journal of Proteomics
Anke Harsman, Silke Oeljeklaus, Christoph Wenger, Jonathan L Huot, Bettina Warscheid, André Schneider
Mitochondrial protein import is essential for all eukaryotes. Here we show that the early diverging eukaryote Trypanosoma brucei has a non-canonical inner membrane (IM) protein translocation machinery. Besides TbTim17, the single member of the Tim17/22/23 family in trypanosomes, the presequence translocase contains nine subunits that co-purify in reciprocal immunoprecipitations and with a presequence-containing substrate that is trapped in the translocation channel. Two of the newly discovered subunits are rhomboid-like proteins, which are essential for growth and mitochondrial protein import...
December 19, 2016: Nature Communications
Amir Zaidi, Krishn Pratap Singh, Vahab Ali
Parasites of genus Leishmania are the causative agents of complex neglected diseases called leishmaniasis and continue to be a significant health concern globally. Iron is a vital nutritional requirement for virtually all organisms, including pathogenic trypanosomatid parasites, and plays a crucial role in many facets of cellular metabolism as a cofactor of several enzymes. Iron acquisition is essential for the survival of parasites. Yet parasites are also vulnerable to the toxicity of iron and reactive oxygen species...
January 2017: Molecular and Biochemical Parasitology
Anyango D Kamina, Noreen Williams
In Liu et al., the authors present a 2.5-Å structure of the Trypanosoma cruzi 60S ribosomal subunit and propose a model for the stepwise assembly of the large-subunit ribosomal RNA (rRNA). Based on this study, we discuss how the unique features of trypanosomatid ribosome assembly offer potential drug targets.
December 14, 2016: Trends in Parasitology
Raphael Souza Pavani, Marcelo Santos da Silva, Carlos Alexandre Henrique Fernandes, Flavia Souza Morini, Christiane Bezerra Araujo, Marcos Roberto de Mattos Fontes, Osvaldo Augusto Sant'Anna, Carlos Renato Machado, Maria Isabel Cano, Stenio Perdigão Fragoso, Maria Carolina Elias
Replication Protein A (RPA), the major single stranded DNA binding protein in eukaryotes, is composed of three subunits and is a fundamental player in DNA metabolism, participating in replication, transcription, repair, and the DNA damage response. In human pathogenic trypanosomatids, only limited studies have been performed on RPA-1 from Leishmania. Here, we performed in silico, in vitro and in vivo analysis of Trypanosoma cruzi RPA-1 and RPA-2 subunits. Although computational analysis suggests similarities in DNA binding and Ob-fold structures of RPA from T...
December 2016: PLoS Neglected Tropical Diseases
O A Espinosa, M G Serrano, E P Camargo, M M G Teixeira, J J Shaw
We propose a taxonomic revision of the dixenous trypanosomatids currently classified as Endotrypanum and Leishmania, including parasites that do not fall within the subgenera L. (Leishmania) and L. (Viannia) related to human leishmaniasis or L. (Sauroleishmania) formed by leishmanias of lizards: L. colombiensis, L. equatorensis, L. herreri, L. hertigi, L. deanei, L. enriettii and L. martiniquensis. The comparison of these species with newly characterized isolates from sloths, porcupines and phlebotomines from central and South America unveiled new genera and subgenera supported by past (RNA PolII gene) and present (V7V8 SSU rRNA, Hsp70 and gGAPDH) phylogenetic analyses of the organisms...
December 15, 2016: Parasitology
Douglas S Moreira, Silvane M F Murta
BACKGROUND: Nucleoside diphosphate kinase b (NDKb) is responsible for nucleoside triphosphates synthesis and it has key role in the purine metabolism in trypanosomatid protozoans. Elongation factor 2 (EF2) is an important factor for protein synthesis. Recently, our phosphoproteomic analysis demonstrated that NDKb and EF2 proteins were phosphorylated and dephosphorylated in antimony (Sb(III))-resistant L. braziliensis line compared to its Sb(III)-susceptible pair, respectively. METHODS: In this study, the overexpression of NDKb and EF2 genes in L...
December 13, 2016: Parasites & Vectors
Graciela Uzcanga, Eliana Lara, Fernanda Gutiérrez, Doyle Beaty, Timo Beske, Rommy Teran, Juan-Carlos Navarro, Philippe Pasero, Washington Benítez, Ana Poveda
Leishmaniasis is a common tropical disease that affects mainly poor people in underdeveloped and developing countries. This largely neglected infection is caused by Leishmania spp, a parasite from the Trypanosomatidae family. This parasitic disease has different clinical manifestations, ranging from localized cutaneous to more harmful visceral forms. The main limitations of the current treatments are their high cost, toxicity, lack of specificity, and long duration. Efforts to improve treatments are necessary to deal with this infectious disease...
December 14, 2016: Critical Reviews in Microbiology
Andrea Ilari, Annarita Fiorillo, Ilaria Genovese, Gianni Colotti
In trypanosomatids, polyamine and trypanothione pathways can be considered as a whole unique metabolism, where most enzymes are essential for parasitic survival and infectivity. Leishmania parasites and all the other members of the Trypanosomatids family depend on polyamines for growth and survival: the enzymes involved in the synthesis and utilization of spermidine and trypanothione, i.e., arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase and in particular trypanothione synthetase-amidase, trypanothione reductase and tryparedoxin-dependent peroxidase are promising targets for drug development...
January 2017: Future Medicinal Chemistry
Ivan Ponce, Carmen Aldunate, Lucia Valenzuela, Sofia Sepúlveda, Gilda Garrido, Ulrike Kemmerling, Gonzalo Cabrera, Norbel Galanti
FLAP endonucleases (FEN) are involved both in DNA replication and repair by processing DNA intermediaries presenting a nucleotide flap using its phosphodiesterase activity. In spite of these important functions in DNA metabolism, this enzyme was not yet studied in Trypanosomatids. Trypanosoma cruzi, the ethiological agent of Chagas disease, presents two dividing cellular forms (epimastigote and amastigote) and one non-proliferative, infective form (trypomastigote). The parasite survives DNA damage produced by reactive species generated in its hosts...
December 9, 2016: Journal of Cellular Biochemistry
Frédéric Lardeux, Claudia Aliaga, Stéphanie Depickère
The study aimed to quantify the bias from parasite detection methods in the estimation of the prevalence of infection of Triatoma infestans by Trypanosoma cruzi, the agent of Chagas disease. Three common protocols that detect T. cruzi in a sample of 640 wild-caught T. infestans were compared: (1) the microscopic observation of insect fecal droplets, (2) a PCR protocol targeting mini-exon genes of T. cruzi (MeM-PCR), and (3) a PCR protocol targeting a satellite repeated unit of the parasite. Agreement among protocols was computed using Krippendorff Kα...
December 2016: Journal of Vector Ecology: Journal of the Society for Vector Ecology
Adriana Ludwig, Marco Aurelio Krieger
Transposable elements are important residents of eukaryotic genomes and eventually the host can domesticate them to serve cellular functions. We reported here a possible domestication event of the vestigial interposed retroelement (VIPER) in trypanosomatids. We found a large gene in a syntenic location in Leishmania braziliensis, L. panamensis, Leptomanas pyrrhocoris, and Crithidia fasciculata whose products share similarity in the C-terminal portion with the third protein of VIPER. No remnants of other VIPER regions surrounding the gene sequence were found...
December 2016: Memórias do Instituto Oswaldo Cruz
Jorge Morales, Sofia Kokkori, Diana Weidauer, Jarrod Chapman, Eugene Goltsman, Daniel Rokhsar, Arthur R Grossman, Eva C M Nowack
BACKGROUND: Bacterial endosymbionts are found across the eukaryotic kingdom and profoundly impacted eukaryote evolution. In many endosymbiotic associations with vertically inherited symbionts, highly complementary metabolic functions encoded by host and endosymbiont genomes indicate integration of metabolic processes between the partner organisms. While endosymbionts were initially expected to exchange only metabolites with their hosts, recent evidence has demonstrated that also host-encoded proteins can be targeted to the bacterial symbionts in various endosymbiotic systems...
November 11, 2016: BMC Evolutionary Biology
Christopher Leija, Filipa Rijo-Ferreira, Lisa N Kinch, Nick V Grishin, Nicole Nischan, Jennifer J Kohler, Zeping Hu, Margaret A Phillips
The human pathogenic parasite Trypanosoma brucei possess both de novo and salvage routes for the biosynthesis of pyrimidine nucleotides. Consequently, they do not require salvageable pyrimidines for growth. Thymidine kinase (TK) catalyzes the formation of dTMP and dUMP and is one of several salvage enzymes that appear redundant to the de novo pathway. Surprisingly, we show through analysis of TK conditional null and RNAi cells that TK is essential for growth and for infectivity in a mouse model, and that a catalytically active enzyme is required for its function...
November 2016: PLoS Pathogens
D G Arias, F E Herrera, A S Garay, D Rodrigues, P S Forastieri, L E Luna, M D L M Bürgi, C Prieto, A A Iglesias, R M Cravero, S A Guerrero
The rational design and synthesis of a series of 5-nitro-2-furoic acid analogues are presented. The trypanocidal activity against epimastigote forms of Trypanosoma cruzi and the toxic effects on human HeLa cells were tested. Between all synthetic compounds, three of thirteen had an IC50 value in the range of Nfx, but compound 13 exhibited an improved effect with an IC50 of 1.0 ± 0.1 μM and a selective index of 70 in its toxicity against HeLa cells. We analyzed the activity of compounds 8, 12 and 13 to interfere in the central redox metabolic pathway in trypanosomatids, which is dependent of reduced trypanothione as the major pivotal thiol...
January 5, 2017: European Journal of Medicinal Chemistry
Zheng Liu, Cristina Gutierrez-Vargas, Jia Wei, Robert A Grassucci, Madhumitha Ramesh, Noel Espina, Ming Sun, Beril Tutuncuoglu, Susan Madison-Antenucci, John L Woolford, Liang Tong, Joachim Frank
Ribosomes of trypanosomatids, a family of protozoan parasites causing debilitating human diseases, possess multiply fragmented rRNAs that together are analogous to 28S rRNA, unusually large rRNA expansion segments, and r-protein variations compared with other eukaryotic ribosomes. To investigate the architecture of the trypanosomatid ribosomes, we determined the 2.5-Å structure of the Trypanosoma cruzi ribosome large subunit by single-particle cryo-EM. Examination of this structure and comparative analysis of the yeast ribosomal assembly pathway allowed us to develop a stepwise assembly model for the eight pieces of the large subunit rRNAs and a number of ancillary "glue" proteins...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
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