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probing trypanosoma brucei glycosylphosphatidylinositol biosynthesis using novel precursor-analogues.glycosylphosphatidylinositol precursor-analogues were synthesized in which the natural diacylglycerol lipid was replaced with either of two steroidal moieties. the ability of the steroidal glycosylphosphatidylinositol precursor-analogues to prime the glycosylphosphatidylinositol biosynthetic pathway was assessed in a trypanosomal cell-free system. the n-acetyl-d-glucosaminylphosphatidylinositol de-n-acetylase was only able to act upon the n-acetylglucosamine form of one of the two analogues. how ...200818637989
in vitro and in vivo trypanocidal effect of lipophilic extracts of medicinal plants from mali and burkina faso.to determine the in vitro and in vivo antitrypanosomal activity of extracts of traditionally used plants.200818638537
glycogen synthase kinase 3 is a potential drug target for african trypanosomiasis therapy.development of a safe, effective, and inexpensive therapy for african trypanosomiasis is an urgent priority. in this study, we evaluated the validity of trypanosoma brucei glycogen synthase kinase 3 (gsk-3) as a potential drug target. interference with the rna of either of two gsk-3 homologues in bloodstream-form t. brucei parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. since the growth arrest after rna interference appeared to b ...200818644955
depletion of dimeric all-alpha dutpase induces dna strand breaks and impairs cell cycle progression in trypanosoma brucei.the enzyme deoxyuridine 5'-triphosphate nucleotidohydrolase (dutpase) is responsible for the control of intracellular levels of dutp thus controlling the incorporation of uracil into dna during replication. trypanosomes and certain eubacteria contain a dimeric dutp-dudpase belonging to the recently described superfamily of all-alpha ntp pyrophosphatases which bears no resemblance with typical eukaryotic trimeric dutpases and presents unique properties regarding substrate specificity and product ...200818656547
ubiquitylation is required for degradation of transmembrane surface proteins in trypanosomes.the surface of trypanosoma brucei is dominated by glycosyl-phosphatidylinositol (gpi)-anchored proteins, and endocytosis is clathrin dependent. the vast majority of internalized gpi-anchored protein is efficiently recycled, while the processes by which transmembrane domain (tmd) proteins are internalized and sorted are unknown. we demonstrate that internalization of invariant surface glycoprotein (isg)65, a trypanosome tmd protein, involves ubiquitylation and also requires clathrin. we find a hi ...200818657071
antigenic variation in trypanosoma brucei: joining the dots. 200818666832
selective and potent in vitro antitrypanosomal activities of ten microbial metabolites.more than 400 compounds isolated from soil microorganisms, and catalogued in the antibiotic library of the kitasato institute for life sciences, were screened against african trypanosomes. ten compounds were found to have selective and potent antitrypanosomal activity in vitro: aureothin, cellocidin, destomycin a, echinomycin, hedamycin, irumamycin, ll-z 1272beta, o-methylnanaomycin a, venturicidin a and virustomycin a. results of the in vitro assays using the gutat 3.1 strain of trypanosomal br ...200818667785
monothiol glutaredoxin-1 is an essential iron-sulfur protein in the mitochondrion of african trypanosomes.african trypanosomes encode three monothiol glutaredoxins (1-c-grx). 1-c-grx1 occurs exclusively in the mitochondrion, and 1-c-grx2 and -3 are predicted to be mitochondrial and cytosolic proteins, respectively. all three 1-c-grx are expressed in both the mammalian bloodstream and the insect procyclic form of trypanosoma brucei, with the highest levels found in stationary phase and starving parasites. in the rudimentary mitochondrion of bloodstream cells, 1-c-grx1 reaches concentrations above 200 ...200818669638
multiple-strain infections of trypanosoma brucei across africa.it is becoming increasingly clear that parasitic infections frequently contain multiple strains of the same parasite species. this may have important consequences for the parasite dynamics in the host and thus alter disease and transmission dynamics. in trypanosoma brucei, the causal agent of human african trypanosomiasis (sleeping sickness), multiple-strain infections have previously been demonstrated to occur. here, we analyzed field isolates of t. b. gambiense, t. b. rhodesiense, and t. b. br ...200818671933
mutual self-defence: the trypanolytic factor story.around 1900 laveran and mesnil discovered that african trypanosomes (prototype: trypanosoma brucei brucei) do not survive in the blood of some primates and humans. the nature of the trypanolytic factor present in these sera has been the focus of a long-standing debate between different groups, but recent developments have allowed the proposal of a coherent model incorporating most seemingly divergent views and providing an interesting example of the complex interplay that continuously occurs bet ...200818675374
kinetoplastid genomics: the thin end of the wedge.the completion of the genome sequencing projects for major pathogens trypanosoma brucei, trypanosoma cruzi and leishmania major has enabled numerous studies that would have been difficult or impossible to perform otherwise. new technologies in sequencing and protein analyses promise further rapid expansion in our capabilities. the keys to successful use of these new tools are recognizing the power and limitations of studies performed thus far, grasping the unrealized potential of new and develop ...200818675383
expression and purification of non-glycosylated trypanosoma brucei transferrin receptor in insect cells.the transferrin receptor of the parasite trypanosoma brucei is a heterodimeric protein complex encoded by the 2 expression site-associated genes (esags) 6 and 7. esag6 is a heterogeneously glycosylated protein of 50-60kda modified by a glycosylphosphatidylinositol anchor at the c-terminus, while esag7 is a 40-42kda glycoprotein carrying an unmodified c-terminus. in order to determine whether glycosylation is necessary for dimer formation and ligand binding, the receptor was expressed in insect c ...200818680745
telomere length in trypanosoma brucei.trypanosoma brucei thwarts the host immune response by replacing its variant surface glycoprotein (vsg). the actively transcribed vsg is located in one of approximately 20 telomeric expression sites (es). antigenic variation can occur by transcriptional switching, reciprocal translocations, or duplicative gene conversion events among es or with the large repertoire of telomeric and non-telomeric vsg. in recently isolated strains, duplicative gene conversion occurs at a high frequency and predomi ...200817910953
differential expression of fat body genes in glossina morsitans morsitans following infection with trypanosoma brucei brucei.to determine which fat body genes were differentially expressed following infection of glossina morsitans morsitans with trypanosoma brucei brucei we generated four suppression subtractive hybridisation (ssh) libraries. we obtained 52 unique gene fragments (ssh clones) of which 30 had a known orthologue at e-05 or less. overall the characteristics of the orthologues suggest: (i) that trypanosome infection has a considerable effect on metabolism in the tsetse fly; (ii) that self-cured flies are m ...200817697681
epimers of bicyclo[2.2.2]octan-2-ol derivatives with antiprotozoal activity.(2sr,6rs,7rs)-4-dialkylaminobicyclo[2.2.2]octan-2-ols and several of their esters have shown promising activity against the causative organisms for malaria and sleeping sickness. the base-catalyzed epimerization of the alcohols was carried out by different methods giving their (2rs,6rs,7rs)-isomers. best results were obtained by the consecutive use of potassium tert-butoxide and sodium. the isomeric alcohols were converted to selected esters. all new compounds were tested for their activity agai ...200817698258
intraflagellar transport and functional analysis of genes required for flagellum formation in trypanosomes.intraflagellar transport (ift) is the bidirectional movement of protein complexes required for cilia and flagella formation. we investigated ift by analyzing nine conventional ift genes and five novel putative ift genes (pift) in trypanosoma brucei that maintain its existing flagellum while assembling a new flagellum. immunostaining against ift172 or expression of tagged ift20 or green fluorescent protein gfp::ift52 revealed the presence of ift proteins along the axoneme and at the basal body an ...200818094047
characterisation of the plasma membrane subproteome of bloodstream form trypanosoma brucei.proteome analysis by conventional approaches is biased against hydrophobic membrane proteins, many of which are also of low abundance. we have isolated plasma membrane sheets from bloodstream forms of trypanosoma brucei by subcellular fractionation, and then applied a battery of complementary protein separation and identification techniques to identify a large number of proteins in this fraction. the results of these analyses have been combined to generate a subproteome for the pellicular plasma ...200818095354
cloning, functional analysis, and mitochondrial localization of trypanosoma brucei monothiol glutaredoxin-1.african trypanosomes encode three monothiol glutaredoxins (1-c-grx1 to 3). 1-c-grx1 has a putative cays active site and cys181 as single additional cysteine. the recombinant protein forms non-covalent homodimers. as observed for other monothiol glutaredoxins, trypanosoma brucei 1-c-grx1 was not active in the glutaredoxin assay with hydroxyethyl disulfide and glutathione nor catalyzed the reduction of insulin disulfide. in addition, it lacked peroxidase activity and did not catalyze protein (de)g ...200818095866
comparative efficacy assessment of pentamidine isethionate and diminazene aceturate in the chemotherapy of trypanosoma brucei brucei infection in dogs.the chemotherapeutic efficacy of diminazene aceturate (berenil)--a standard veterinary trypanocide and pentamidine isethionate (pmi)--a human trypanocide was compared in dogs experimentally infected with trypanosoma brucei brucei. also, the activities of the drugs on some serum liver enzymes were evaluated before and after treatment to ascertain the relative safety of the drugs. fifteen local dogs (mongrels) were used for the study. three of the dogs were uninfected controls, and twelve were inf ...200818155842
trypanosoma evansi: molecular homogeneity as inferred by phenetical analysis of ribosomal internal transcribed spacers dna of an eclectic parasite.the protozoan trypanosoma evansi is described as presenting high morphological and genetic similarities among the isolates despite its biological heterogeneity and wide geographical distribution. pcr amplification of the internal transcribed spacers of the ribosomal gene in combination with the coding region of the 5.8s ribosomal subunit further submitted to restriction enzymes digestion were carried out in dnas extracted from 41 t. evansi strains isolated from horses, dogs, coatis and capybaras ...200818158150
in search of novel agents for therapy of tropical diseases and human immunodeficiency virus.malaria, sleeping sickness, chagas' disease, aleppo boil, and aids are among the tropical diseases causing millions of infections and cases of deaths per year because only inefficient chemotherapy is available. since the targeting of the enzymes of the polyamine pathway may provide novel therapy options, we aimed to inhibit the deoxyhypusine hydroxylase, which is an important step in the biosynthesis of the eukaryotic initiation factor 5a. in order to identify new lead compounds, piperidines wer ...200818159921
acetylation-dependent adp-ribosylation by trypanosoma brucei sir2.sirtuins are a highly conserved family of proteins implicated in diverse cellular processes such as gene silencing, aging, and metabolic regulation. although many sirtuins catalyze a well characterized protein/histone deacetylation reaction, there are a number of reports that suggest protein adp-ribosyltransferase activity. here we explored the mechanisms of adp-ribosylation using the trypanosoma brucei sir2 homologue tbsir2rp1 as a model for sirtuins that reportedly display both activities. ste ...200818165239
adenosine kinase mediates high affinity adenosine salvage in trypanosoma brucei.african sleeping sickness is caused by trypanosoma brucei. this extracellular parasite lacks de novo purine biosynthesis, and it is therefore dependent on exogenous purines such as adenosine that is taken up from the blood and other body fluids by high affinity transporters. the general belief is that adenosine needs to be cleaved to adenine inside the parasites in order to be used for purine nucleotide synthesis. we have found that t. brucei also can salvage this nucleoside by adenosine kinase ...200818167353
development of potent purine-derived nitrile inhibitors of the trypanosomal protease tbcatb.human african trypanosomiasis (hat), a major health concern in sub-saharan africa, is caused by the protozoan parasite trypanosoma brucei. recent studies have shown that a cathepsin b like protease, tbcatb, is essential to the survival of t. brucei in vitro (mackey, z. b.; o'brien, t. c.; greenbaum, d. c.; blank, r. b.; mckerrow, j. h. j. biol. chem. 2004, 279, 48426-48433). herein, we describe the first inhibitors of tbcatb, a series of purine nitriles. the compounds are potent trypanocides, ki ...200818173229
codon usage suggests that translational selection has a major impact on protein expression in trypanosomatids.different proteins are required in widely different quantities to build a living cell. in most organisms, transcription control makes a major contribution to differential expression. this is not the case in trypanosomatids where most genes are transcribed at an equivalent rate within large polycistronic clusters. thus, trypanosomatids must use post-transcriptional control mechanisms to balance gene expression requirements.200818173843
acetylation of histone h4k4 is cell cycle regulated and mediated by hat3 in trypanosoma brucei.post-translational histone modifications have been studied intensively in several eukaryotes. it has been proposed that these modifications constitute a 'histone code' that specifies epigenetic information for transcription regulation. with a limited number of histone-modifying enzymes, implying less redundancy, trypanosoma brucei represents an excellent system in which to investigate the function of individual histone modifications and histone-modifying enzymes. in this study, we characterized ...200818179414
a mitochondrial topoisomerase ia essential for late theta structure resolution in african trypanosomes.trypanosomes and leishmania, protozoans that cause major human diseases, have a topologically intricate mitochondrial dna (kinetoplast or kdna) in the form of a network of thousands of interlocked circles. this unusual system provides a useful reporter for studying topoisomerase functions in vivo. we now find that these organisms have three type ia topoisomerases, one of which is phylogenetically distinctive and which we designate topoisomerase ia(mt). in trypanosoma brucei topoisomerase ia(mt) ...200818179422
protein phosphatase 5 is required for hsp90 function during proteotoxic stresses in trypanosoma brucei.trypanosoma brucei, a parasitic protozoan that causes african trypanosomiasis in human and domestic animals, adapt in various environments during their digenetic life cycle. in this study, we found that hsp90 is crucial for the survival of this parasite. inhibition of hsp90 activity by geldanamycin (ga) reduced cell growth and increased the level of hsp90. both the bloodstream and procyclic forms of t. brucei showed a several-fold greater sensitivity than the mammalian cells to ga and also to 17 ...200818193284
mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in trypanosoma brucei.trypanosoma brucei use microsomal elongases for de novo synthesis of most of its fatty acids. in addition, this parasite utilizes an essential mitochondrial type ii synthase for production of octanoate (a lipoic acid precursor) as well as longer fatty acids such as palmitate. evidence from other organisms suggests that mitochondrially synthesized fatty acids are required for efficient respiration but the exact relationship remains unclear. in procyclic form trypanosomes, we also found that rnai ...200818221265
in vitro trypanocidal activity of the anti-helminthic drug niclosamide.only a few drugs are available for chemotherapy of african trypanosomiasis and there is an urgent need for the development of new anti-trypanosomal agents. in this study, the anti-helminthic drug niclosamide was tested for its trypanocidal activity in vitro using culture-adapted bloodstream forms of trypanosoma brucei brucei and trypanosoma congolense. the concentrations of niclosamide to reduce the growth rate by 50% and to kill all cells were in the low- and mid micromolar ranges for t. b. bru ...200818226810
trypanosoma brucei rna editing: coupled cycles of u deletion reveal processive activity of the editing complex.rna editing in trypanosoma brucei is posttranscriptional uridylate removal/addition, generally at vast numbers of pre-mrna sites, but to date, only single editing cycles have been examined in vitro. we here demonstrate achieving sequential cycles of u deletion in vitro, with editing products confirmed by sequence analysis. notably, the subsequent editing cycle is much more efficient and occurs far more rapidly than single editing cycles; plus, it has different recognition requirements. this indi ...200818227152
sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in trypanosoma brucei.sphingolipids and their metabolites have been thought crucial for cell growth and cell cycle progression, membrane and protein trafficking, signal transduction, and formation of lipid rafts; however, recent studies in trypanosomes point to the dispensability of sphingolipids in some of these processes. in this study, we explore the requirements for de novo sphingolipid biosynthesis in the insect life cycle stage of the african trypanosome trypanosoma brucei by inhibiting the enzyme serine palmit ...200818230649
differential expression of glycosomal and mitochondrial proteins in the two major life-cycle stages of trypanosoma brucei.label-free semi-quantitative differential three-dimensional liquid chromatography coupled to mass spectrometry (3d-lc-ms/ms) was used to compare the glycosomal and mitochondrial proteomes of the bloodstream- and insect-form of trypanosoma brucei. the abundance of glycosomal marker proteins identified in the two life-cycle stages corresponded well with the relative importance of biochemical pathways present in the glycosomes of the two stages and the peptide spectral count ratios of selected enzy ...200818242729
the 3-hydroxyacyl-acp dehydratase of mitochondrial fatty acid synthesis in trypanosoma brucei.the trypanosomatid parasite trypanosoma brucei synthesizes fatty acids in the mitochondrion using the type ii fatty acid synthesis (fas) machinery. when mitochondrial fas was characterized in t. brucei, all of the enzymatic components were identified based on their homology to yeast mitochondrial fas enzymes, except for 3-hydroxyacyl-acp dehydratase. here we describe the characterization of t. brucei mitochondrial 3-hydroxyacyl-acp dehydratase (tbhtd2), which was identified by its similarity to ...200818258193
trypanosome h2bv replaces h2b in nucleosomes enriched for h3 k4 and k76 trimethylation.some inroads have been made into characterizing histone variants and post translational modifications of histones in trypanosoma brucei. histone variant h2bv lysine 129 is homologous to saccharomyces cerevisiae h2b lysine 123, whose ubiquitination is required for methylation of h3 lysines 4 and 79. we show that t. brucei h2bv k129 is not ubiquitinated, but trimethylation of h3 k4 and k76, homologs of h3 k4 and k79 in yeast, was enriched in nucleosomes containing h2bv. mutation of h2bv k129 to al ...200818261990
the anti-trypanosomal agent lonidamine inhibits trypanosoma brucei hexokinase 1.glycolysis is essential to the parasitic protozoan trypanosoma brucei. the first step in this metabolic pathway is mediated by hexokinase, an enzyme that transfers the gamma-phosphate of atp to a hexose. the t. brucei genome (treu927/4 gutat10.1) encodes two hexokinases (tbhk1 and tbhk2) that are 98% identical at the amino acid level. our previous efforts have revealed that tbhk2 is an important regulator of tbhk1 in procyclic form parasites. here, we have found through rnai that tbhk1 is essent ...200818262292
mismatch repair in trypanosoma brucei: heterologous expression of msh2 from trypanosoma cruzi provides new insights into the response to oxidative damage.trypanosomes are unicellular eukaryotes that cause disease in humans and other mammals. trypanosoma cruzi and trypanosoma brucei are the causative agents, respectively, of chagas disease in the americas and sleeping sickness in sub-saharan africa. to better comprehend the interaction of these parasites with their hosts, understanding the mechanisms involved in the generation of genetic variability is critical. one such mechanism is mismatch repair (mmr), which has a crucial, evolutionarily conse ...200818262734
deletion of the tbalg3 gene demonstrates site-specific n-glycosylation and n-glycan processing in trypanosoma brucei.we recently suggested a novel site-specific n-glycosylation mechanism in trypanosoma brucei whereby some protein n-glycosylation sites selectively receive man9glcnac2 from man9glcnac2-pp-dol while others receive man5glcna(2 from man5glcnac2-pp-dol. in this paper, we test this model by creating procyclic and bloodstream form null mutants of tbalg3, the gene that encodes the alpha-mannosyltransferase that converts man5glcnac2-pp-dol to man6glcnac2-pp-dol. the procyclic and bloodstream form tbalg3 ...200818263655
alternative mrna editing in trypanosomes is extensive and may contribute to mitochondrial protein diversity.the editing of trypanosome mitochondrial mrnas produces transcripts necessary for mitochondrial functions including electron transport and oxidative phosphorylation. precursor-mrnas are often extensively edited by specific uridine insertion or deletion that is directed by small guide rnas (grnas). recently, it has been shown that cytochrome c oxidase subunit iii (coxiii) mrnas can be alternatively edited to encode a novel mitochondrial membrane protein composed of a unique hydrophilic n-terminal ...200818270563
design, synthesis, and trypanocidal activity of new aminoadamantane derivatives.to develop functionalized adamantanes for treating african trypanosomiasis, we report on the synthesis of new 1-alkyl-2-aminoadamantanes 1a- i, 1-alkyltricyclo[3.3.1.1 (3,7)]decan-2-guanylhydrazones 2a- g, and their congeneric thiosemicarbazones 3a, b. the potency of these compounds against trypanosoma brucei was compared to that of amantadine and rimantadine and found to be substantially higher. the most active analogues, 1c, 1d, 2c, 2g, and 3b, illustrate the synergistic effect of the lipophil ...200818281929
structure and function of the native and recombinant mitochondrial mrp1/mrp2 complex from trypanosoma brucei.the mitochondrial rna-binding proteins (mrp) 1 and 2 play a regulatory role in rna editing and putative role(s) in rna processing in trypanosoma brucei. here, we report the purification of a high molecular weight protein complex consisting solely of the mrp1 and mrp2 proteins from the mitochondrion of t. brucei. the mrp1/mrp2 complex natively purified from t. brucei and the one reconstituted in escherichia coli in vivo bind guide (g) rnas and pre-mrnas with dissociation constants in the nanomola ...200818295767
key residues of loop 3 in the interaction with the interface residue at position 14 in triosephosphate isomerase from trypanosoma brucei.cysteine 14 is an interface residue that is fundamental for the catalysis and stability of homodimeric triosephosphate isomerase from trypanosoma brucei (tbtim). its side chain is surrounded by a deep pocket of 11 residues that are part of loop 3 of the adjacent monomer. mutation of this residue to serine (producing single mutant c14s) yields a wild-type-like enzyme that is resistant to the action of sulfhydryl reagents methylmethane thiosulfonate (mmts) and 5,5-dithiobis(2-nitrobenzoate) (dtnb) ...200818298085
characterization of trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and rnai studies.nucleotide biosynthesis pathways have been reported to be essential in some protozoan pathogens. hence, we evaluated the essentiality of one enzyme in the pyrimidine biosynthetic pathway, dihydroorotate dehydrogenase (dhodh) from the eukaryotic parasite trypanosoma brucei through gene knockdown studies. rnai knockdown of dhodh expression in bloodstream form t. brucei did not inhibit growth in normal medium, but profoundly retarded growth in pyrimidine-depleted media or in the presence of the kno ...200818312275
the tbmtr1 spliced leader rna cap 1 2'-o-ribose methyltransferase from trypanosoma brucei acts with substrate specificity.in metazoa cap 1 (m(7)gpppnmp-rna) is linked to higher levels of translation; however, the enzyme responsible remains unidentified. we have validated the first eukaryotic encoded cap 1 2'-o-ribose methyltransferase, tbmtr1, a member of a conserved family that modifies the first transcribed nucleotide of spliced leader and u1 small nuclear rnas in the kinetoplastid protozoan trypanosoma brucei. in addition to cap 0 (m(7)gpppnp-rna), mrna in these parasites has ribose methylations on the first fou ...200818048356
p166, a link between the trypanosome mitochondrial dna and flagellum, mediates genome segregation.kinetoplast dna (kdna), the trypanosome mitochondrial genome, is a giant network containing several thousand interlocked dna rings. within the mitochondrion, kdna is condensed into a disk-shaped structure positioned near the flagellar basal body. the disk is linked to the basal body by a remarkable transmembrane filament system named the tripartite attachment complex (tac). following kdna replication, the tac mediates network segregation, pulling the progeny networks into the daughter cells by t ...200818059470
loss of actin does not affect export of newly synthesized proteins to the surface of trypanosoma brucei.vesicle traffic to and from the surface is highly polarized in african trypanosomes. actin is required for polarized endocytic traffic in bloodstream forms of african trypanosomes but its role in other pathways has remained equivocal. a combination of metabolic pulse chase labelling and surface biotinylation during the chase period along with the use of conditional rna interference was employed to demonstrate that substantial loss of actin had no effect on the export of newly synthesized protein ...200818061288
krepa6 is an rna-binding protein essential for editosome integrity and survival of trypanosoma brucei.most mitochondrial mrnas in kinetoplastid protozoa require post-transcriptional rna editing that inserts and deletes uridylates, a process that is catalyzed by multiprotein editosomes. krepa6 is the smallest of six editosome proteins that have predicted oligonucleotide-binding (ob) folds. inactivation of krepa6 expression results in disruption and ultimate loss of approximately 20s editosomes and inhibition of procyclic form cell growth. gel shift studies show that recombinant krepa6 binds rna, ...200818065716
genomic rearrangements and transcriptional analysis of the spliced leader-associated retrotransposon in rna interference-deficient trypanosoma brucei.the trypanosoma brucei genome is colonized by the site-specific non-ltr retrotransposon slacs, or spliced leader-associated conserved sequence, which integrates exclusively into the spliced leader (sl) rna genes. although there is evidence that the rna interference (rnai) machinery regulates slacs transcript levels, we do not know whether rnai deficiency affects the genomic stability of slacs, nor do we understand the mechanism of slacs transcription. here, we report that prolonged culturing of ...200818067542
antiprotozoal and cytotoxic screening of 45 plant extracts from democratic republic of congo.to evaluate in vitro the antiprotozoal and cytotoxic activities of 80% methanol extract from 45 medicinal plants collected in sankuru (democratic republic of congo) against trypanosoma brucei brucei, trypanosoma cruzi and the chloroquine-sensitive ghanaian strain of plasmodium falciparum, and mrc-5 cell lines respectively.200818068320
the direct route: a simplified pathway for protein import into the mitochondrion of trypanosomes.trypanosoma brucei is a unicellular eukaryote that causes the deadly human african trypanosomiasis ('sleeping sickness') in humans. the parasite has a complicated lifestyle, it developmentally changes aspects of its mitochondrial function as it alternates from forms in the tsetse fly to forms adapted for life in the human bloodstream. the single mitochondrion found in each trypanosome has to be duplicated precisely in each round of the cell cycle in order for parasites to replicate, and this dep ...200818068984
conservation of the pro-apoptotic nuclease activity of endonuclease g in unicellular trypanosomatid parasites.endonuclease g is a mitochondrial protein implicated in dna fragmentation during apoptosis in cell types ranging from fungi to mammals. features of programmed cell death have been reported in a number of single-celled organisms, including the human trypanosomatid parasites leishmania and trypanosoma. however, the protozoan cell death pathways and the effector molecules involved in such processes remain to be identified. in this report, we describe the pro-apoptotic function of endonuclease g in ...200818073240
mitochondrial complexes in trypanosoma brucei: a novel complex and a unique oxidoreductase complex.african trypanosomes, early diverged eukaryotes and the agents of sleeping sickness, have several basic cellular processes that are remarkably divergent from those in their mammalian hosts. they have large mitochondria and switch between oxidative phosphorylation and glycolysis as the major pathways for energy generation during their life cycle. we report here the identification and characterization of several multiprotein mitochondrial complexes from procyclic form trypanosoma brucei. these wer ...200818073385
effect of hydroxyurea on procyclic trypanosoma brucei: an unconventional mechanism for achieving synchronous growth.procyclic trypanosoma brucei cells were synchronized with 0.2 mm hydroxyurea. the cells did not arrest at the g(1)/s boundary but proceeded through one round of replication and arrested near the end of s phase. the mitochondrial genome (kinetoplast dna network) replicated, forming two progeny networks, but the repair of minicircle gaps was inhibited.200818083826
a monoclonal antibody that inhibits trypanosoma cruzi growth in vitro and its reaction with intracellular triosephosphate isomerase.in parasites of the order kinetoplastida, such as trypanosoma cruzi and trypanosoma brucei, glycolysis is carried out by glycolytic enzymes in glycosomes. one of the glycolytic enzymes is triosephosphate isomerase (tim), which in t. brucei is localized exclusively in glycosomes, whereas in t. cruzi, the localization of tim has not been fully ascertained. in the present work, we made a monoclonal antibody (mab 6-11g) against recombinant t. cruzi tim (rtctim). incubation of t. cruzi epimastigotes ...200818046577
kinetic and mutational analysis of the trypanosoma brucei nbt1 nucleobase transporter expressed in saccharomyces cerevisiae reveals structural similarities between ent and mfs transporters.parasitic protozoa are unable to synthesise purines de novo and thus depend on the uptake of nucleosides and nucleobases across their plasma membrane through specific transporters. a number of nucleoside and nucleobase transporters from trypanosoma brucei brucei and leishmania major have recently been characterised and shown to belong to the equilibrative nucleoside transporter (ent) family. a number of studies have demonstrated the functional importance of particular transmembrane segments (tms ...200818036529
roles for tbdss-1 in rna surveillance and decay of maturation by-products from the 12s rrna locus.the trypanosoma brucei exoribonuclease, tbdss-1, has been implicated in multiple aspects of mitochondrial rna metabolism. here, we investigate the role of tbdss-1 in rna processing and surveillance by analyzing 12s rrna processing intermediates in tbdss-1 rnai cells. rna fragments corresponding to leader sequence upstream of 12s rrna accumulate upon tbdss-1 depletion. the 5' extremity of 12s rrna is generated by endonucleolytic cleavage, and tbdss-1 degrades resulting upstream maturation by-prod ...200818032430
the gup1 homologue of trypanosoma brucei is a gpi glycosylphosphatidylinositol remodelase.glycosylphosphatidylinositol (gpi) lipids of trypanosoma brucei undergo lipid remodelling, whereby longer fatty acids on the glycerol are replaced by myristate (c14:0). a similar process occurs on gpi proteins of saccharomyces cerevisiae where per1p first deacylates, gup1p subsequently reacylates the anchor lipid, thus replacing a shorter fatty acid by c26:0. heterologous expression of the gup1 homologue of t. brucei in gup1delta yeast cells partially normalizes the gup1delta phenotype and resto ...200818036137
regulation of a transmembrane protein gene family by the small rna-binding proteins tbubp1 and tbubp2.the loci tb927.3.4070, 927.3.4080, tb927.3.4090, 927.3.4100 and 927.3.4110 of trypanosoma brucei encode five similar proteins with 13-14 transmembrane domains. corresponding mrnas are more abundant in bloodstream-form trypanosomes than in procyclics. the 4070, 4090 and 4110 genes have almost identical 3'-intergenic regions and the predicted proteins share a short c-terminal extension; a reporter mrna with the 4110 3'-untranslated region was more abundant in bloodstream forms than procyclic forms ...200818022708
trypanosoma brucei: differential requirement of membrane potential for import of proteins into mitochondria in two developmental stages.trypanosome alternative oxidase (tao) and the cytochrome oxidase (cox) are two developmentally regulated terminal oxidases of the mitochondrial electron transport chain in trypanosoma brucei. here, we have compared the import of tao and cytochrome oxidase subunit iv (coiv), two stage-specific nuclear encoded mitochondrial proteins, into the bloodstream and procyclic form mitochondria of t. brucei to understand the import processes in two different developmental stages. under in vitro conditions ...200818021773
cre recombinase-based positive-negative selection systems for genetic manipulation in trypanosoma brucei.the limited repertoire of drug-resistance markers imposes a serious obstacle to genetic manipulation of trypanosoma brucei. here we describe experiments with a fusion protein that allows positive selection for genome integration followed by cre recombinase-mediated excision of the marker cassette that can be selected by ganciclovir, although the excision event is so efficient that selection is not strictly necessary. we describe two variants of the tetracycline-inducible plew100-based cre-expres ...200818006158
structure of a glycosylphosphatidylinositol-anchored domain from a trypanosome variant surface glycoprotein.the cell surface of african trypanosomes is covered by a densely packed monolayer of a single protein, the variant surface glycoprotein (vsg). the vsg protects the trypanosome cell surface from effector molecules of the host immune system and is the mediator of antigenic variation. the sequence divergence between vsgs that is necessary for antigenic variation can only occur within the constraints imposed by the structural features necessary to form the monolayer barrier. here, the structures of ...200818003615
a novel, high-throughput technique for species identification reveals a new species of tsetse-transmitted trypanosome related to the trypanosoma brucei subgenus, trypanozoon.we describe a novel method of species identification, fluorescent fragment length barcoding, based on length variation in regions of the 18s and 28salpha ribosomal dna. fluorescently tagged primers, designed in conserved regions of the 18s and 28salpha ribosomal dna, were used to amplify fragments with inter-species size variation, and sizes determined accurately using an automated dna sequencer. by using multiple regions and different fluorochromes, a barcode unique to each species was generate ...200817964224
the role of the mitochondrial glycine cleavage complex in the metabolism and virulence of the protozoan parasite leishmania major.for the human pathogen leishmania major, a key metabolic function is the synthesis of thymidylate, which requires 5,10-methylenetetrahydrofolate (5,10-ch(2)-thf). 5,10-ch(2)-thf can be synthesized from glycine by the mitochondrial glycine cleavage complex (gcc). bioinformatic analysis revealed the four subunits of the gcc in the l. major genome, and the role of the gcc in parasite metabolism and virulence was assessed through studies of the p subunit (glycine decarboxylase (gcvp)). first, a tagg ...200817981801
protozoadb: dynamic visualization and exploration of protozoan genomes.protozoadb (http://www.biowebdb.org/protozoadb) is being developed to initially host both genomics and post-genomics data from plasmodium falciparum, entamoeba histolytica, trypanosoma brucei, t. cruzi and leishmania major, but will hopefully host other protozoan species as more genomes are sequenced. it is based on the genomics unified schema and offers a modern web-based interface for user-friendly data visualization and exploration. this database is not intended to duplicate other similar eff ...200817981844
elucidating the role of c/d snorna in rrna processing and modification in trypanosoma brucei.most eukaryotic c/d small nucleolar rnas (snornas) guide 2'-o methylation (nm) on rrna and are also involved in rrna processing. the four core proteins that bind c/d snorna in trypanosoma brucei are fibrillarin (nop1), nop56, nop58, and snu13. silencing of nop1 by rna interference identified rrna-processing and modification defects that caused lethality. systematic mapping of 2'-o-methyls on rrna revealed the existence of hypermethylation at certain positions of the rrna in the bloodstream form ...200817981991
control and regulation of gene expression: quantitative analysis of the expression of phosphoglycerate kinase in bloodstream form trypanosoma brucei.isoenzymes of phosphoglycerate kinase in trypanosoma brucei are differentially expressed in its two main life stages. this study addresses how the organism manages to make sufficient amounts of the isoenzyme with the correct localization, which processes (transcription, splicing, and rna degradation) control the levels of mrnas, and how the organism regulates the switch in isoform expression. for this, we combined new quantitative measurements of phosphoglycerate kinase mrna abundance, rna precu ...200817991737
residues in an atp binding domain influence sugar binding in a trypanosome hexokinase.trypanosoma brucei harbors two hexokinases (tbhk1 and tbhk2) that are 98% identical at the amino acid level. we previously found that recombinant tbhk1 (rtbhk1) has hexokinase activity, while rtbhk2 has not, a finding attributed to differences in the c-termini of the proteins. sequence analysis suggests that the c-termini of tbhks are part of a newly identified conserved motif found in other eukaryotic hexokinases. here, we have explored the role of tail residues in the differences in catalytic ...200817996732
regulation of an amino acid transporter mrna in trypanosoma brucei.trypanosoma brucei regulates gene expression by post-transcriptional mechanisms, such as mrna turnover and translation control. this regulation frequently requires specific sequences located in the 3'-untranslated region. microarray analysis and northern blot hybridization showed that the amino acid transporter 11 mrna is up-regulated in insect stages of the parasite. by rt-pcr and sequencing, the aatp11 polyadenylation site was mapped. we show that this 3'-utr causes higher expression of the ch ...200817996963
rna editing in trypanosoma brucei requires three different editosomes.trypanosoma brucei has three distinct approximately 20s editosomes that catalyze rna editing by the insertion and deletion of uridylates. editosomes with the kren1 or kren2 rnase iii type endonucleases specifically cleave deletion and insertion editing site substrates, respectively. we report here that editosomes with krepb2, which also has an rnase iii motif, specifically cleave cytochrome oxidase ii (coii) pre-mrna insertion editing site substrates in vitro. conditional repression and mutation ...200817954557
novel trypanocidal analogs of 5'-(methylthio)-adenosine.the purine nucleoside 5'-deoxy-5'-(hydroxyethylthio)-adenosine (heta) is an analog of the polyamine pathway metabolite 5'-deoxy-5'-(methylthio)-adenosine (mta). heta is a lead structure for the ongoing development of selectively targeted trypanocidal agents. thirteen novel heta analogs were synthesized and examined for their in vitro trypanocidal activities against bloodstream forms of trypanosoma brucei brucei lab 110 eatro and at least one drug-resistant trypanosoma brucei rhodesiense clinical ...200817954686
wcb is a c2 domain protein defining the plasma membrane - sub-pellicular microtubule corset of kinetoplastid parasites.wcb is a protein that locates between the inner face of the plasma membrane and the sub-pellicular corset of microtubules in trypanosoma brucei. we provide the molecular identity of wcb and bioinformatic analysis suggests that it possesses a c2 domain implicated in membrane/protein interactions and a highly charged region possessing characteristics of a putative tubulin-binding domain. functional analyses via rna interference (rnai) depletion show that wcb is essential for cell morphogenesis. de ...200817951107
a repetitive protein essential for the flagellum attachment zone filament structure and function in trypanosoma brucei.the flagellum is attached along the length of the cell body in the protozoan parasite trypanosoma brucei and is a defining morphological feature of this parasite. the flagellum attachment zone (faz) is a complex structure and has been characterised morphologically as comprising a faz filament structure and the specialised microtubule quartet (mtq) plus the specialised areas of flagellum: plasma membrane attachment. unfortunately, we have no information as to the molecular identity of the faz fil ...200817945531
asymmetric cell division as a route to reduction in cell length and change in cell morphology in trypanosomes.african trypanosomes go through at least five developmental stages during their life cycle. the different cellular forms are classified using morphology, including the order of the nucleus, flagellum and kinetoplast along the anterior-posterior axis of the cell, the predominant cell surface molecules and the location within the host. here, an asymmetrical cell division cycle that is an integral part of the trypanosoma brucei life cycle has been characterised in further detail through the use of ...200817931969
validation of spermidine synthase as a drug target in african trypanosomes.the trypanocidal activity of the odc (ornithine decarboxylase) inhibitor dfmo (difluoromethylornithine) has validated polyamine biosynthesis as a target for chemotherapy. as dfmo is one of only two drugs used to treat patients with late-stage african trypanosomiasis, the requirement for additional drug targets is paramount. here, we report the biochemical properties of tbspsyn (trypanosoma brucei spermidine synthase), the enzyme immediately downstream of odc in this pathway. recombinant tbspsyn ...200817916066
1h, 13c and 15n resonance assignment of urm1 from trypanosoma brucei.urm1 (ubiquitin-related modifier), involved in diverse biological processes in yeast, is proved to be a "molecular fossil" in ubiquitin superfamily. here we report the resonance assignment of urm1 from trypanosoma brucei.200819636925
1h, 13c, and 15n assignment of the oxidized and reduced forms of t. brucei glutathione peroxidase-type tryparedoxin peroxidase.the cysteine-homologues of glutathione peroxidases in trypanosoma brucei catalyze the trypanothione/tryparedoxin-dependent reduction of hydroperoxides. we report the 1h, 13c, and 15n assignment of the oxidized and reduced form of the enzyme by nmr. major changes between these two forms were only observed for residues close to the catalytic site.200819636927
antiplasmodial, beta-haematin inhibition, antitrypanosomal and cytotoxic activity in vitro of novel 4-aminoquinoline 2-imidazolines.a novel series of 4-aminoquinoline-containing 2-imidazolines were synthesized via a one-pot 3-component condensation reaction of amine, aldehyde and isocyanoacetate. the products were obtained in high yield as well as purity and were evaluated directly against two strains of plasmodium falciparum and trypanosoma brucei. compound was the most active across all parasites with ed(50) = 3.3 nm against a chloroquine (cq)-sensitive 3d7 strain, ed(50) = 33 nm against a cq-resistant k1 strain and ed(50) ...200819005606
compartmentation prevents a lethal turbo-explosion of glycolysis in trypanosomes.atp generation by both glycolysis and glycerol catabolism is autocatalytic, because the first kinases of these pathways are fuelled by atp produced downstream. previous modeling studies predicted that either feedback inhibition or compartmentation of glycolysis can protect cells from accumulation of intermediates. the deadly parasite trypanosoma brucei lacks feedback regulation of early steps in glycolysis yet sequesters the relevant enzymes within organelles called glycosomes, leading to the pr ...200819008351
inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids.the link between nucleocytoplasmic transport and apoptosis remains controversial. nucleocytoplasmic exchange of molecules seems indeed essential for the initiation and execution of the apoptotic programme; but inhibition of nuclear transport factors may also represent a powerful apoptotic trigger. the gtpase ran (together with its partners), first discovered to be essential in nucleocytoplasmic transport, has multiple key functions in cell biology, and particularly in spindle assembly, kinetocho ...200819011643
new lycorine-type alkaloid from lycoris traubii and evaluation of antitrypanosomal and antimalarial activities of lycorine derivatives.a new lycorine derivative lt1 (4) was isolated from the aerial part and bulbs of lycoris traubii hayward (amaryllidaceae). its structure including absolute configuration was established by spectroscopic analysis and semi-synthesis to be 1-o-(3's)-hydroxybutanoyllycorine. some lycorine ester derivatives including lt1 were examined for their inhibitory activity against trypanosoma brucei brucei, the parasite associated with sleeping sickness, and against plasmodium falciparum, the causative agent ...200819013823
a new function of trypanosoma brucei mitochondrial topoisomerase ii is to maintain kinetoplast dna network topology.the mitochondrial genome of trypanosoma brucei, called kinetoplast dna, is a network of topologically interlocked dna rings including several thousand minicircles and a few dozen maxicircles. kinetoplast dna synthesis involves release of minicircles from the network, replication of the free minicircles and reattachment of the progeny. here we report a new function of the mitochondrial topoisomerase ii (tbtop2mt). although traditionally thought to reattach minicircle progeny to the network, here ...200819019151
the chromosomal passenger complex and a mitotic kinesin interact with the tousled-like kinase in trypanosomes to regulate mitosis and cytokinesis.aurora b kinase plays essential roles in mitosis and cytokinesis in eukaryotes. in the procyclic form of trypanosoma brucei, the aurora b homolog tbauk1 regulates mitosis and cytokinesis, phosphorylates the tousled-like kinase tbtlk1, interacts with two mitotic kinesins tbkin-a and tbkin-b and forms a novel chromosomal passenger complex (cpc) with two novel proteins tbcpc1 and tbcpc2. here we show with time-lapse video microscopy the time course of cpc trans-localization from the spindle midzone ...200819043568
protective effect of humus extract against trypanosoma brucei infection in mice.humic substances are formed during the decomposition of organic matter in humus, and are found in many natural environments in which organic materials and microorganisms are present. oral administration of humus extract to mice successfully induced effective protection against experimental challenge by the two subspecies, trypanosoma brucei brucei and t. brucei gambiense. mortality was most reduced among mice who received a 3% humus extract for 21 days in drinking water ad libitum. spleen cells ...200819057136
in vitro and in vivo antitrypanosomal activitiy of two microbial metabolites, ks-505a and alazopeptin.our on-going screening program to discover new antitrypanosomal antibiotics has been evaluating compounds isolated from soil microorganisms as well as investigating the antibiotic libraries of the kitasato institute for life sciences and biofrontier laboratories of kyowa hakko kogyo co., ltd. we have now discovered two compounds, ks-505a and alazopeptin, which exhibit moderate antitrypanosomal characteristics. we report here the in vitro and in vivo antitrypanosomal activities and cytotoxicities ...200819168977
role of iron homeostasis in trypanosomiasis-associated anemia.anemia is a well-established infection-associated immunopathological feature of trypanosomiasis and the degree of the anemia is a reliable indicator of the severity of infection. since infections with trypanosomes triggers a strong cytokine production and a type i immune response, the trypanosome-elicited anemia may be type i cytokine driven. this type of anemia termed anemia of chronic disease is characterized by an imbalance between erythrophagocytosis and erythropoiesis that is linked to a pe ...200818926297
diamidine activity against trypanosomes: the state of the art.aromatic diamidines and related compounds are dna minor groove binders that have been screened against a variety of pathogenic microorganisms such as bacteria, fungi and protozoa and show promising results. parasitic infections are widespread in developing countries and are major contributors to human mortality and morbidity, causing considerable economic hardship. trypanosomes are unicellular protozoan organisms that cause serious public health problems in developing countries: african trypanos ...200820021429
a major genetic locus in trypanosoma brucei is a determinant of host pathology.the progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. the influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. we have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a ...200919956590
coordinated gene expression by post-transcriptional regulons in african trypanosomes.the regulation of gene expression in trypanosomes is unique. in the absence of transcriptional control at the level of initiation, a subset of trypanosoma brucei genes form post-transcriptional regulons in which mrnas are co-regulated in response to differentiation signals. see research articles http://www.biomedcentral.com/1471-2164/10/427, http://www.biomedcentral.com/1471-2164/10/482 and http://www.biomedcentral.com/1471-2164/10/495.200920017896
maturation of a trypanosoma brucei infection to the infectious metacyclic stage is enhanced in nutritionally stressed tsetse flies.we report on the effect of tsetse fly starvation on the maturation of an established trypanosoma brucei brucei midgut infection, i.e., the development of procyclic infection into the infectious metacyclic parasites in the tsetse fly salivary glands. glossina morsitans morsitans flies were nutritionally stressed 10 d after the uptake of a t. b. brucei-infected bloodmeal by depriving these flies from feeding for seven consecutive days, whereas the control fly group (nonstarved group) continued to ...200919960695
c-terminal mutants of apolipoprotein l-i efficiently kill both trypanosoma brucei brucei and trypanosoma brucei rhodesiense.apolipoprotein l-i (apol1) is a human-specific serum protein that kills trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. the t. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. in the case of t. b. rhodesiense, resistance to lysis involves interaction of the serum resistance-associated (sra) protein with the c-terminal helix of apol1. we undertook a mutational and deletional analysis of ...200919997494
effect of polyamine-deficient chow on trypanosoma brucei brucei infection in rats.polyamines are essential for proliferation of trypanosoma brucei brucei, and feeding rats polyamine-deficient chow (pdc) decreases their blood polyamine concentrations. proliferation of t. b. brucei (il-tat 1.4 strain) (il) is not restrained within pdc-fed rats. however, symptoms of il-infected rats such as anemia decrease by pdc feeding. we reported cytokine and nitric oxide (no) production of t. b. gambiense (wellcome strain [ws])-infected rats were affected by pdc feeding, and ws proliferatio ...200920049984
uapaca genus (euphorbiaceae), a good source of betulinic acid.betulinic acid, isolated in substantial amounts from stem barks of five distinct species of uapaca could be considered as an important chemotaxomic marker of the uapaca genus. it inhibited trypanosoma brucei gapdh with an ic(50) value of 240 microm and has been shown to be a competitive reversible inhibitor (ki=200+/-10 microm) of this enzyme with respect to its cofactor nad(+).200918926889
development of an alamar blue viability assay in 384-well format for high throughput whole cell screening of trypanosoma brucei brucei bloodstream form strain 427.there is an urgent need for new compounds for the drug development pipeline for treatment of patients with african sleeping sickness. one approach for identifying such compounds is by high throughput screening (hts) of compound collections. for time and cost considerations, there is a need for the development of an assay that uses at least 384-well formats. to our knowledge, there are currently no viability assays for whole cell screening of trypanosomes in the 384-well plate format. we have dev ...200919815884
antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone.here, we describe a series of readily obtainable benzophenone derivatives with antimalarial and antitrypanosomal activity. the most active compounds display submicromolar activity against plasmodium falciparum. micromolar activity is obtained against trypanosoma brucei. main problem of the compounds is low selectivity. however, there are indications that separation of antimalarial and cytotoxic activity might by possible. in addition, some compounds inhibit human abc transporter with nanomolar a ...200919819706
the trypanosome rab-related proteins rabx1 and rabx2 play no role in intracellular trafficking but may be involved in fly infectivity.rab gtpases constitute the largest subgroup of the ras superfamily and are primarily involved in vesicle targeting. the full extent of rab family function is unexplored. several divergent rab-like proteins are known but few have been characterized. in trypanosoma brucei there are sixteen rab genes, but rabx1, rabx2 and rabx3 are divergent within canonical sequence regions. where known, trypanosome rab functions are broadly conserved when orthologous relationships may be robustly established, but ...200919787065
membrane domains and flagellar pocket boundaries are influenced by the cytoskeleton in african trypanosomes.a key feature of immune evasion for african trypanosomes is the functional specialization of their surface membrane in an invagination known as the flagellar pocket (fp), the cell's sole site of endocytosis and exocytosis. the fp membrane is biochemically distinct yet continuous with those of the cell body and the flagellum. the structural features maintaining this individuality are not known, and we lack a clear understanding of how extracellular components gain access to the fp. here, we have ...200919805090
the trypanosome flagellar pocket.trypanosomes are important disease agents and excellent models for the study of evolutionary cell biology. the trypanosome flagellar pocket is a small invagination of the plasma membrane where the flagellum exits the cytoplasm and participates in many cellular processes. it is the only site of exocytosis and endocytosis and part of a multiorganelle complex that is involved in cell polarity and cell division. several flagellar pocket-associated proteins have been identified and found to contribut ...200919806154
predictive computational models of substrate binding by a nucleoside transporter.transporters play a vital role in both the resistance mechanisms of existing drugs and effective targeting of their replacements. melarsoprol and diamidine compounds similar to pentamidine and furamidine are primarily taken up by trypanosomes of the genus trypanosoma brucei through the p2 aminopurine transporter. in standardized competition experiments with [(3)h]adenosine, p2 transporter inhibition constants (k(i)) have been determined for a diverse dataset of adenosine analogs, diamidines, foo ...200919808668
the trypikinome of five human pathogenic trypanosomatids: trypanosoma brucei, trypanosoma cruzi, leishmania major, leishmania braziliensis and leishmania infantum--new tools for designing specific inhibitors.phosphatidylinositol (pi) kinases are at the heart of one of the major pathways of intracellular signal transduction. herein, we present the first report on a survey made by similarity searches against the five human pathogenic trypanosomatids trypanosoma brucei, trypanosoma cruzi, leishmania major, leishmania braziliensis and leishmania infantum genomes available to date for phosphatidylinositol- and related-kinases (trypiks). in addition to generating a panel called "the trypikinome", we propo ...200919852933
blocking variant surface glycoprotein synthesis in trypanosoma brucei triggers a general arrest in translation initiation.the african trypanosome trypanosoma brucei is covered with a dense layer of variant surface glycoprotein (vsg), which protects it from lysis by host complement via the alternative pathway in the mammalian bloodstream. blocking vsg synthesis by the induction of vsg rnai triggers an unusually precise precytokinesis cell-cycle arrest.200919855834
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