| expression and role of cxcl10 during the encephalitic stage of experimental and clinical african trypanosomiasis. | human african trypanosomiasis, caused by trypanosoma brucei, involves an early hemolymphatic stage followed by a late encephalitic stage. | 2009 | 19827943 |
| chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis. | in the search for new therapeutics for the treatment of human african trypanosomiasis, many potential drug targets in trypanosoma brucei have been validated by genetic means, but very few have been chemically validated. trypanothione synthetase (trys; ec 6.3.1.9; spermidine/glutathionylspermidine:glutathione ligase (adp-forming)) is one such target. to identify novel inhibitors of t. brucei trys, we developed an in vitro enzyme assay, which was amenable to high throughput screening. the subseque ... | 2009 | 19828449 |
| protein composition of trypanosoma brucei mitochondrial membranes. | mitochondria consist of four compartments, outer membrane, intermembrane space, inner membrane, and matrix; each harboring specific functions and structures. in this study, we used lc-ms/ms to characterize the protein composition of trypanosoma brucei mitochondrial (mt) membranes, which were enriched by different biochemical fractionation techniques. the analyses identified 202 proteins that contain one or more transmembrane domain(s) and/or positive gravy scores. of these, various criteria were ... | 2009 | 19834910 |
| tide: a software for the systematic scanning of drug targets in kinetic network models. | during the stages of the development of a potent drug candidate compounds can fail for several reasons. one of them, the efficacy of a candidate, can be estimated in silico if an appropriate ordinary differential equation model of the affected pathway is available. with such a model at hand it is also possible to detect reactions having a large effect on a certain variable such as a substance concentration. | 2009 | 19840374 |
| widespread variation in transcript abundance within and across developmental stages of trypanosoma brucei. | trypanosoma brucei, the causative agent of african sleeping sickness, undergoes a complex developmental cycle that takes place in mammalian and insect hosts and is accompanied by changes in metabolism and cellular morphology. while differences in mrna expression have been described for many genes, genome-wide expression analyses have been largely lacking. trypanosomatids represent a unique case in eukaryotes in that they transcribe protein-coding genes as large polycistronic units, and rarely re ... | 2009 | 19840382 |
| reh2 rna helicase in kinetoplastid mitochondria: ribonucleoprotein complexes and essential motifs for unwinding and guide rna (grna) binding. | regulation of gene expression in kinetoplastid mitochondria is largely post-transcriptional and involves the orchestration of polycistronic rna processing, 3'-terminal maturation, rna editing, turnover, and translation; however, these processes remain poorly studied. core editing complexes and their u-insertion/deletion activities are relatively well characterized, and a battery of ancillary factors has recently emerged. this study characterized a novel dexh-box rna helicase, termed here reh2 (r ... | 2010 | 19850921 |
| 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 ... | 2009 | 19852933 |
| 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. | 2009 | 19855834 |
| molecular identification of t. brucei s.l. in tsetse flies after long-term permanence in field traps. | tsetse flies (glossina spp.) are responsible for the transmission of trypanosomes, agents of animal and human african trypanosomiasis (hat). these diseases are associated with considerable animal and human economical loss, morbidity and mortality. the correct identification of trypanosomes species infecting tsetse flies is crucial for adequate control measures. identification presently requires technically difficult, cumbersome and expensive on-site fly dissection. to obviate this difficulty we ... | 2009 | 19858577 |
| trypanocidal drugs: mechanisms, resistance and new targets. | the protozoan parasites trypanosoma brucei and trypanosoma cruzi are the causative agents of african trypanosomiasis and chagas disease, respectively. these are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. here, we review the properties of these drugs and describe new findings on their modes of ac ... | 2009 | 19863838 |
| thiolated trnas of trypanosoma brucei are imported into mitochondria and dethiolated after import. | all mitochondrial trnas in trypanosoma brucei derive from cytosolic trnas that are in part imported into mitochondria. some trypanosomal trnas are thiolated in a compartment-specific manner. we have identified three proteins required for the thio modification of cytosolic trna(gln), trna(glu), and trna(lys). rna interference-mediated ablation of these proteins results in the cytosolic accumulation non-thio-modified trnas but does not increase their import. moreover, in vitro import experiments s ... | 2009 | 19875444 |
| rna interference in trypanosoma brucei: role of the n-terminal rgg domain and the polyribosome association of argonaute. | argonaute proteins (agos) are central to rna interference (rnai) and related silencing pathways. at the core of the rnai pathway in the ancient parasitic eukaryote trypanosoma brucei is a single argonaute protein, tbago1, with an established role in the destruction of potentially harmful retroposon transcripts. one notable feature of tbago1 is that a fraction sediments with polyribosomes, and this association is facilitated by an arginine/glycine-rich domain (rgg domain) at the n terminus of the ... | 2009 | 19880512 |
| a mechanism for functional segregation of mitochondrial and cytosolic genetic codes. | the coexistence of multiple gene translation machineries is a feature of eukaryotic cells and a result of the endosymbiotic events that gave rise to mitochondria, plastids, and other organelles. the conditions required for the integration of these apparatuses within a single cell are not understood, but current evidence indicates that complete ablation of the mitochondrial protein synthesis apparatus and its substitution by its cytosolic equivalent is not possible. why certain mitochondrial comp ... | 2009 | 19880741 |
| propulsion of african trypanosomes is driven by bihelical waves with alternating chirality separated by kinks. | trypanosoma brucei, a parasitic protist with a single flagellum, is the causative agent of african sleeping sickness. propulsion of t. brucei was long believed to be by a drill-like, helical motion. using millisecond differential interference-contrast microscopy and analyzing image sequences of cultured procyclic-form and bloodstream-form parasites, as well as bloodstream-form cells in infected mouse blood, we find that, instead, motility of t. brucei is by the propagation of kinks, separating l ... | 2009 | 19880745 |
| a protein-protein interaction map of the trypanosoma brucei paraflagellar rod. | we have conducted a protein interaction study of components within a specific sub-compartment of a eukaryotic flagellum. the trypanosome flagellum contains a para-crystalline extra-axonemal structure termed the paraflagellar rod (pfr) with around forty identified components. we have used a gateway cloning approach coupled with yeast two-hybrid, rnai and 2d dige to define a protein-protein interaction network taking place in this structure. we define two clusters of interactions; the first being ... | 2009 | 19888464 |
| alanine aminotransferase of trypanosoma brucei--a key role in proline metabolism in procyclic life forms. | african trypanosomes possess high levels of alanine aminotransferase (ec 2.6.1.2), although the function of their activity remains enigmatic, especially in slender bloodstream forms where the metabolism of ketoacids does not occur. therefore, the gene for alanine aminotransferase enzyme in trypanosoma brucei (tbaat) was characterized and its function assessed using a combination of rna interference and gene knockout approaches. surprisingly, as much as 95% or more of the activity appears to be u ... | 2009 | 19895576 |
| side chain specificity of adp-ribosylation by a sirtuin. | endogenous mono-adp-ribosylation in eukaryotes is involved in regulating protein synthesis, signal transduction, cytoskeletal integrity, and cell proliferation, although few cellular adp-ribosyltransferases have been identified. the sirtuins constitute a highly conserved family of protein deacetylases, and several family members have also been reported to perform protein adp-ribosylation. we characterized the adp-ribosylation reaction of the nuclear sirtuin homolog trypanosoma brucei sir2-relate ... | 2009 | 19895577 |
| identification and optimization of inhibitors of trypanosomal cysteine proteases: cruzain, rhodesain, and tbcatb. | trypanosoma cruzi and trypanosoma brucei are parasites that cause chagas' disease and african sleeping sickness, respectively. both parasites rely on essential cysteine proteases for survival: cruzain for t. cruzi and tbcatb/rhodesain for t. brucei. a recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. structural modifications detailed herein, including core scaffold mo ... | 2010 | 19908842 |
| a luciferase based viability assay for atp detection in 384-well format for high throughput whole cell screening of trypanosoma brucei brucei bloodstream form strain 427. | abstract: | 2009 | 19909542 |
| identification of a parasitic immunomodulatory protein triggering the development of suppressive m1 macrophages during african trypanosomiasis. | development of classically activated macrophages (m1 cells) is a prerequisite to controlling parasite growth and therefore resistance to african trypanosomiasis. however, if activation of m1 cells is uncontrolled, including their production of tumor necrosis factor (tnf) and nitric oxide (no), collateral pathogenic damage to tissues ensues. we report the identification of a novel putative trypanosoma brucei m1 cell-triggering protein. the recombinant trypanosome-suppressive immunomodulating fact ... | 2009 | 19911988 |
| nucleosomes are depleted at the vsg expression site transcribed by rna polymerase i in african trypanosomes. | in most eukaryotes, rna polymerase i (pol i) exclusively transcribes long arrays of identical rrna genes (ribosomal dna [rdna]). african trypanosomes have the unique property of using pol i to also transcribe the variant surface glycoprotein vsg genes. vsgs are important virulence factors because their switching allows trypanosomes to escape the host immune system, a mechanism known as antigenic variation. only one vsg is transcribed at a time from one of 15 bloodstream-form expression sites (be ... | 2010 | 19915072 |
| active vsg expression sites in trypanosoma brucei are depleted of nucleosomes. | african trypanosomes regulate transcription differently from other eukaryotes. most of the trypanosome genome is constitutively transcribed by rna polymerase ii (pol ii) as large polycistronic transcription units while the genes encoding the major surface proteins are transcribed by rna polymerase i (pol i). in bloodstream form trypanosoma brucei, the gene encoding the variant surface glycoprotein (vsg) coat is expressed in a monoallelic fashion from one of about 15 vsg bloodstream form expressi ... | 2010 | 19915073 |
| structure-based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases. | pteridine reductase (ptr1) is a target for drug development against trypanosoma and leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. we adopted a structure-based approach to the design of novel ptr1 inhibitors based on three molecular scaffolds. a series of compounds, most newly synthesized, were identified as inhibitors with ptr1-species specific properties explained by structural differences between the t. brucei and l. major enzymes. t ... | 2010 | 19916554 |
| gdp-mannose pyrophosphorylase is essential in the bloodstream form of trypanosoma brucei. | a putative gdp-man pp (guanidine diphosphomannose pyrophosphorylase) gene from trypanosoma brucei (tbgdp-man pp) was identified in the genome and subsequently cloned, sequenced and recombinantly expressed, and shown to be a catalytically active dimer. kinetic analysis revealed a vmax of 0.34 mumol/min per mg of protein and km values of 67 mum and 12 mum for gtp and mannose 1-phosphate respectively. further kinetic studies showed gdp-man was a potent product feedback inhibitor. rnai (rna interfer ... | 2010 | 19919534 |
| crystal structures of trypanosoma brucei sterol 14alpha-demethylase and implications for selective treatment of human infections. | sterol 14alpha-demethylase (14dm, the cyp51 family of cytochrome p450) is an essential enzyme in sterol biosynthesis in eukaryotes. it serves as a major drug target for fungal diseases and can potentially become a target for treatment of human infections with protozoa. here we present 1.9 a resolution crystal structures of 14dm from the protozoan pathogen trypanosoma brucei, ligand-free and complexed with a strong chemically selected inhibitor n-1-(2,4-dichlorophenyl)-2-(1h-imidazol-1-yl)ethyl)- ... | 2010 | 19923211 |
| investigation of trypanothione reductase as a drug target in trypanosoma brucei. | there is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human african trypanosomiasis, which is caused by trypanosoma brucei. the enzyme trypanothione reductase (tryr) is a potential drug target within these organisms. herein we report the screening of a 62,000 compound library against t. brucei tryr. further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammali ... | 2009 | 19924760 |
| depletion of 14-3-3 proteins in bloodstream-form trypanosoma brucei inhibits variant surface glycoprotein recycling. | bloodstream-form trypanosoma brucei have two 14-3-3 proteins, which are required for parasite multiplication. we here describe the effects of 14-3-3 depletion on vesicular transport of variant surface glycoprotein (vsg). 14-3-3 depletion had no detectable effect on de novo synthesis and trafficking of vsg to the cell surface, or on vsg endocytosis. despite strong inhibition of cell division, the flagellar pocket was not enlarged and the ultrastructure of internal organelles appeared normal. the ... | 2010 | 19925803 |
| improved models of mini anion exchange centrifugation technique (maect) and modified single centrifugation (msc) for sleeping sickness diagnosis and staging. | | 2009 | 19936296 |
| loss-of-function mutations in the human ortholog of chlamydomonas reinhardtii oda7 disrupt dynein arm assembly and cause primary ciliary dyskinesia. | cilia and flagella are evolutionarily conserved structures that play various physiological roles in diverse cell types. defects in motile cilia result in primary ciliary dyskinesia (pcd), the most prominent ciliopathy, characterized by the association of respiratory symptoms, male infertility, and, in nearly 50% of cases, situs inversus. so far, most identified disease-causing mutations involve genes encoding various ciliary components, such those belonging to the dynein arms that are essential ... | 2009 | 19944405 |
| trypanosoma brucei brucei: thymine 7-hydroxylase-like proteins. | two genes from trypanosoma brucei brucei are predicted to encode fe(ii)- and alpha-ketoglutarate-dependent enzymes related to fungal thymine 7-hydroxylase. transcription of the thymine hydroxylase-like genes is up-regulated in the bloodstream form of the parasite over the insect form, whereas western blot analysis indicates more cross-reactive protein in the latter life stage. the genes were cloned, the proteins purified from escherichia coli, and both proteins were shown to bind fe(ii) and alph ... | 2010 | 19945457 |
| kinesin 9 family members perform separate functions in the trypanosome flagellum. | numerous eukaryote genome projects have uncovered a variety of kinesins of unknown function. the kinesin 9 family is limited to flagellated species. our phylogenetic experiments revealed two subfamilies: kif9a (including chlamydomonas reinhardtii klp1) and kif9b (including human kif6). the function of kif9a and kif9b was investigated in the protist trypanosoma brucei that possesses a single motile flagellum. kif9a and kif9b are strongly associated with the cytoskeleton and are required for motil ... | 2009 | 19948486 |
| trypanothione efficiently intercepts nitric oxide as a harmless iron complex in trypanosomatid parasites. | trypanosomatids are protozoan organisms that cause serious diseases, including african sleeping sickness, chagas' disease, and leishmaniasis, affecting about 30 million people in the world. these parasites contain the unusual dithiol trypanothione [t(sh)(2)] instead of glutathione (gsh) as the main intracellular reductant, and they have replaced the otherwise ubiquitous gsh/glutathione reductase redox couple with a t(sh)(2)/trypanothione reductase (tr) system. the reason for the existence of t(s ... | 2010 | 19952282 |
| flow cytometry-based methods for assessing soluble scfv activities and detecting antigens in solution. | novel methods are reported for evaluating and utilizing single chain fragment variable (scfv) antibodies derived from yeast-display libraries. yeast-display was used to select scfv specific to invariant surface glycoproteins (isg) of trypanosoma brucei. a limiting step in the isolation of scfv from non-immune libraries is the conversion of highly active yeast-displayed scfv into soluble antibodies that can be used in standard immunoassays. challenges include limited solubility or activity follow ... | 2010 | 19953671 |
| new oxapolycyclic cage amines with nmda receptor antagonist and trypanocidal activities. | the synthesis of several (1,2,3,5,6,7-hexahydro-1,5:3,7-dimethano-4-benzoxonin-3-yl)amines and related compounds is reported. several of them display very similar activity to memantine as nmda receptor antagonists. several derivatives showed a significant level of trypanocidal activity. | 2010 | 19954985 |
| 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 ... | 2009 | 19956590 |
| screening of some tanzanian medicinal plants for their trypanocidal and cytotoxic activities. | the objective of the present study was to evaluate in vitro antitrypanosomal and cytotoxic activities of crude extracts of 20 traditionally used medicinal plants of tanzania. a total of 40 extracts (dichloromethane and methanol) were screened for antiproliferative activity of bloodstream form of t. b. brucei and human leukaemia hl-60 cell. inhibition of cell proliferation was assessed using resazurin as vital stain. of the 40 extracts tested, the dichloromethane extract from bark of warburgia sa ... | 2010 | 19957246 |
| 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 ... | 2009 | 19960695 |
| discovery of halo-nitrobenzamides with potential application against human african trypanosomiasis. | a series of halo-nitrobenzamide were synthesized and evaluated for their ability to block proliferation of trypanosoma brucei brucei. a number of these compounds had significant activity against the parasite, particularly 2-chloro-n-(4-chlorophenyl)-5-nitrobenzamide 17 which exhibited low micromolar inhibitory potency against t. brucei and selectivity towards both malaria and mammalian cells. | 2010 | 19963377 |
| multiple genetic mechanisms lead to loss of functional tbat1 expression in drug-resistant trypanosomes. | the p2 aminopurine transporter, encoded by tbat1 in african trypanosomes in the trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. loss of this transporter contributes to drug resistance. we identified the genomic location of tbat1 to be in the subtelomeric region of chromosome 5 and determined the status of the tbat1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (cymelarsan), and ... | 2010 | 19966032 |
| functions and cellular localization of cysteine desulfurase and selenocysteine lyase in trypanosoma brucei. | nfs-like proteins have cysteine desulfurase (cysd) activity, which removes sulfur (s) from cysteine, and provides s for iron-sulfur cluster assembly and the thiolation of trnas. these proteins also have selenocysteine lyase activity in vitro, and cleave selenocysteine into alanine and elemental selenium (se). it was shown previously that the nfs-like protein called nfs from the parasitic protist trypanosoma brucei is a genuine cysd. a second nfs-like protein is encoded in the nuclear genome of t ... | 2010 | 19968861 |
| investigations into human serum sensitivity expressed by stocks of trypanosoma brucei evansi. | trypanosoma brucei evansi, a widely distributed species of trypanosome infecting different livestock species in many countries in africa, asia and south america, has recently been reported as a pathogen causing a case of human trypanosomiasis in india. to date, there is little information regarding the natural resistance of animal-infective stocks of t. b. evansi to normal human serum (nhs). in this study, we investigated the degree of sensitivity to nhs of 15 stocks of t. b. evansi from differe ... | 2010 | 19968993 |
| 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 ... | 2009 | 19997494 |
| curcuminoid analogs with potent activity against trypanosoma and leishmania species. | the natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the trypanosoma and leishmania species. the parent curcuminoids exhibited low antitrypanosomal activity (ec(50) for our drug-sensitive trypanosoma brucei brucei line (wt) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7 microm, respe ... | 2010 | 20004045 |
| newly identified antibacterial compounds are topoisomerase poisons in african trypanosomes. | human african trypanosomiasis, caused by the trypanosoma brucei protozoan parasite, is fatal when left untreated. current therapies are antiquated, and there is a need for new pharmacologic agents against t. brucei targets that have no human ortholog. trypanosomes have a single mitochondrion with a unique mitochondrial dna, known as kinetoplast dna (kdna), a topologically complex network that contains thousands of interlocking circular dnas, termed minicircles (approximately 1 kb) and maxicircle ... | 2010 | 20008775 |
| excreted/secreted proteins from trypanosome procyclic strains. | trypanosoma secretome was shown to be involved in parasite virulence and is suspected of interfering in parasite life-cycle steps such as establishment in the glossina midgut, metacyclogenesis. therefore, we attempted to identify the proteins secreted by procyclic strains of t. brucei gambiense and t. brucei brucei, responsible for human and animal trypanosomiasis, respectively. using mass spectrometry, 427 and 483 nonredundant proteins were characterized in t. brucei brucei and t. brucei gambie ... | 2010 | 20011064 |
| discovery of functional motifs in h-regions of trypanosome signal sequences. | n-terminal signal peptides direct secretory proteins into the er (endoplasmic reticulum) of eukaryotes or the periplasmic space of prokaryotes. a hydrophobic core (h-region) is important for signal sequence function; however, the mechanism of h-region action is not resolved. to gain new insight into signal sequences, bioinformatic analysis of h-regions from humans, saccharomyces cerevisiae, trypanosoma brucei and escherichia coli was performed. each species contains a unique set of peptide motif ... | 2010 | 20017734 |
| 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. | 2009 | 20017896 |
| a protein-protein interaction map of trypanosome ~20s editosomes. | mitochondrial mrna editing in trypanosomatid parasites involves several multiprotein assemblies, including three very similar complexes that contain the key enzymatic editing activities and sediment at ~20s on glycerol gradients. these ~20s editosomes have a common set of 12 proteins, including enzymes for uridylyl (u) removal and addition, 2 rna ligases, 2 proteins with rnase iii-like domains, and 6 proteins with predicted oligonucleotide binding (ob) folds. in addition, each of the 3 distinct ... | 2010 | 20018860 |
| 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 ... | 2008 | 20021429 |
| exploiting the drug-activating properties of a novel trypanosomal nitroreductase. | nitroheterocyclic prodrugs have been used to treat trypanosomal diseases for more than 40 years. recently, the key step involved in the activation of these compounds has been elucidated and shown to be catalyzed by a type i nitroreductase (ntr). this class of enzyme is normally associated with bacteria and is absent from most eukaryotes, with trypanosomes being a major exception. here we exploit this difference by evaluating the trypanocidal activity of a library of nitrobenzylphosphoramide must ... | 2010 | 20028822 |
| towards the synthesis of bisubstrate inhibitors of protein farnesyltransferase: synthesis and biological evaluation of new farnesylpyrophosphate analogues. | protein farnesyltransferase (ftase) has recently appeared as a new target of parasitic diseases, a field poor in drugs in development. with the aim of creating new bisubstrate inhibitors of ftase, new farnesyl pyrophosphate analogues have been studied. farnesyl analogues with a malonic acid function exhibited the best inhibitory activity on ftase. this group was introduced into our imidazole-containing model leading to new compounds with submicromolar activities. kinetic experiments have been re ... | 2010 | 20036564 |
| tbpif1, a trypanosoma brucei mitochondrial dna helicase, is essential for kinetoplast minicircle replication. | kinetoplast dna, the trypanosome mitochondrial genome, is a network of interlocked dna rings including several thousand minicircles and a few dozen maxicircles. minicircles replicate after release from the network, and their progeny reattach. remarkably, trypanosomes have six mitochondrial dna helicases related to yeast pif1 helicase. here we report that one of the six, tbpif1, functions in minicircle replication. rna interference (rnai) of tbpif1 causes a growth defect and kinetoplast dna loss. ... | 2010 | 20042610 |
| structure of trypanosoma brucei glutathione synthetase: domain and loop alterations in the catalytic cycle of a highly conserved enzyme. | glutathione synthetase catalyses the synthesis of the low molecular mass thiol glutathione from l-gamma-glutamyl-l-cysteine and glycine. we report the crystal structure of the dimeric enzyme from trypanosoma brucei in complex with the product glutathione. the enzyme belongs to the atp-grasp family, a group of enzymes known to undergo conformational changes upon ligand binding. the t. brucei enzyme crystal structure presents two dimers in the asymmetric unit. the structure reveals variability in ... | 2010 | 20045436 |
| the small ubiquitin-like modifier (sumo) is essential in cell cycle regulation in trypanosoma brucei. | sumo, a reversible post-translational protein modifier, plays important roles in many processes of higher eukaryotic cell life. although sumo has been identified in many eukaryotes, sumo and sumo system are still unknown in some eukaryotic unicellular organisms, such as trypanosoma brucei (t. brucei). in this study, only one sumo homologue (tbsumo) was identified in t. brucei. expression of tbsumo was knocked down by using rna interference technique in procyclic-form t. brucei. the growth of tbs ... | 2010 | 20045687 |
| 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 ... | 2009 | 20049984 |
| chaperone requirements for biosynthesis of the trypanosome variant surface glycoprotein. | trypanosoma brucei does not respond transcriptionally to several endoplasmic reticulum (er) stress conditions, including tunicamycin or dithiothreitol, indicating the absence of a conventional unfolded protein response. this suggests divergent mechanisms for quality control (qc) of er protein folding and export may be present in trypanosomes. as the variant surface glycoprotein (vsg) represents approximately 90% of trypanosome plasma membrane protein, it is possible that vsg has evolved to fold ... | 2010 | 20052285 |
| active vsg expression sites of african trypanosomes are depleted of nucleosomes. | | 2010 | 20054065 |
| purification and kinetic characterization of recombinant alternative oxidase from trypanosoma brucei brucei. | the trypanosome alternative oxidase (tao) functions in the african trypanosomes as a cytochrome-independent terminal oxidase, which is essential for their survival in the mammalian host and as it does not exist in the mammalian host is considered to be a promising drug target for the treatment of trypanosomiasis. in the present study, recombinant tao (rtao) overexpressed in a haem-deficient escherichia coli strain has been solubilized from e. coli membranes and purified to homogeneity in a stabl ... | 2010 | 20056101 |
| no gold standard estimation of the sensitivity and specificity of two molecular diagnostic protocols for trypanosoma brucei spp. in western kenya. | african animal trypanosomiasis is caused by a range of tsetse transmitted protozoan parasites includingtrypanosoma vivax, trypanosoma congolense and trypansoma brucei. in western kenya and other parts of east africa two subspecies of t. brucei, t.b. brucei and the zoonotict.b. rhodesiense, co-circulate in livestock. a range of polymerase chain reactions (pcr) have been developed as important molecular diagnostic tools for epidemiological investigations of t. brucei s.l. in the animal reservoir a ... | 2010 | 20062795 |
| a mitochondrial dna primase is essential for cell growth and kinetoplast dna replication in trypanosoma brucei. | kinetoplast dna in african trypanosomes contains a novel form of mitochondrial dna consisting of thousands of minicircles and dozens of maxicircles topologically interlocked to form a two-dimensional sheet. the replication of this unusual form of mitochondrial dna has been studied for more than 30 years, and although a large number of kinetoplast replication genes and proteins have been identified, in vitro replication of these dnas has not been possible since a kinetoplast dna primase has not b ... | 2010 | 20065037 |
| the crystal structure and activity of a putative trypanosomal nucleoside phosphorylase reveal it to be a homodimeric uridine phosphorylase. | purine nucleoside phosphorylases (pnps) and uridine phosphorylases (ups) are closely related enzymes involved in purine and pyrimidine salvage, respectively, which catalyze the removal of the ribosyl moiety from nucleosides so that the nucleotide base may be recycled. parasitic protozoa generally are incapable of de novo purine biosynthesis; hence, the purine salvage pathway is of potential therapeutic interest. information about pyrimidine biosynthesis in these organisms is much more limited. t ... | 2010 | 20070944 |
| toxicity and potential anti-trypanosomal activity of ethanolic extract of azadirachta indica (maliacea) stem bark: an in vivo and in vitro approach using trypanosoma brucei. | to determine the toxicity and anti-trypanosomal activity of the ethanolic extract of azadirachta indica (maliacea) stem bark, through in vivo and in vitro approach using trypanosoma brucei brucei. | 2010 | 20079420 |
| essential role of a trypanosome u4-specific sm core protein in small nuclear ribonucleoprotein assembly and splicing. | spliceosomal small nuclear ribonucleoproteins (snrnps) in trypanosomes contain either the canonical heptameric sm ring or variant sm cores with snrna-specific sm subunits. here we show biochemically by a combination of rnase h cleavage and tandem affinity purification that the u4 snrnp contains a variant sm heteroheptamer core in which only smd3 is replaced by ssm4. this u4-specific, nuclear-localized sm core protein is essential for growth and splicing. as shown by rna interference (rnai) knock ... | 2010 | 20081062 |
| optimization of a non-radioactive high-throughput assay for decarboxylase enzymes. | herein, we describe the optimization of a linked enzyme assay suitable for high-throughput screening of decarboxylases, a target family whose activity has historically been difficult to quantify. our approach uses a commercially available bicarbonate detection reagent to measure decarboxylase activity. the assay is performed in a fully enclosed automated screening system under inert nitrogen atmosphere to minimize perturbation by exogenous co2. receiver operating characteristic (roc) analysis fo ... | 2010 | 20085486 |
| role for parasite genetic diversity in differential host responses to trypanosoma brucei infection. | the postgenomic era has revolutionized approaches to defining host-pathogen interactions and the investigation of the influence of genetic variation in either protagonist upon infection outcome. we analyzed pathology induced by infection with two genetically distinct trypanosoma brucei strains and found that pathogenesis is partly strain specific, involving distinct host mechanisms. infections of balb/c mice with one strain (927) resulted in more severe anemia and greater erythropoietin producti ... | 2010 | 20086091 |
| ret1-catalyzed uridylylation shapes the mitochondrial transcriptome in trypanosoma brucei. | rna uridylylation is critical for the expression of the mitochondrial genome in trypanosomes. short u tails are added to guide rnas and rrnas, while long a/u heteropolymers mark 3' ends of most mrnas. three divergent mitochondrial terminal uridylyl transferases (tutases) are known: ret1 catalyzes guide rna (grna) uridylylation, ret2 executes u insertion mrna editing, and meat1 associates with the editosome-like complex. however, the activities responsible for 3' uridylylation of rrnas and mrnas, ... | 2010 | 20086102 |
| integrated cytokine and metabolic analysis of pathological responses to parasite exposure in rodents. | parasitic infections cause a myriad of responses in their mammalian hosts, on immune as well as on metabolic level. a multiplex panel of cytokines and metabolites derived from four parasite-rodent models, namely, plasmodium berghei-mouse, trypanosoma brucei brucei-mouse, schistosoma mansoni-mouse, and fasciola hepatica-rat were statistically coanalyzed. (1)h nmr spectroscopy and multivariate statistical analysis were used to characterize the urine and plasma metabolite profiles in infected and n ... | 2010 | 20092362 |
| application of electrospray mass spectrometry to the structural determination of glycosylphosphatidylinositol membrane anchors. | the addition of glycosylphosphatidylinositol (gpi) anchors to proteins is an important posttranslational modification in eukaryotic cells. the complete structural elucidation of gpi anchors is a complex process that requires relatively large amounts of starting material. in this paper, we assess the degree of structural information that can be obtained by applying electrospray mass spectrometry and tandem mass spectrometry to permethylated gpi glycans prepared from a well-characterized gpi-ancho ... | 2010 | 20100693 |
| additional insights on the bastadins: isolation of analogues from the sponge ianthella cf. reticulata and exploration of the oxime configurations. | the focus of this study is on the bastadin class of bromotyrosine derivatives, commonly isolated from ianthella marine sponges, and is the first report on the secondary metabolites from ianthella cf. reticulata. two new bastadins were isolated, (e,z)-bastadin 19 (1a), a diastereoisomer of the known (e,e)-bastadin 19 (1b), and dioxepine bastadin 3 (2), an unusual dibenzo-1,3-dioxepine. a bastadin nmr database was created and assisted in the structure determination of 1b and 2 and the rapid derepl ... | 2010 | 20102170 |
| persistent er stress induces the spliced leader rna silencing pathway (sls), leading to programmed cell death in trypanosoma brucei. | trypanosomes are parasites that cycle between the insect host (procyclic form) and mammalian host (bloodstream form). these parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (upr). however, they possess a stress response mechanism, the spliced leader rna silencing (sls) pathway. sls elicits shut-off of spliced leader rna (sl rna) transcription by perturbing the binding of the transcription factor tsnap42 to its cognate promoter, thu ... | 2010 | 20107599 |
| trypanosoma brucei: reduction of gpi-phospholipase c protein during differentiation is dependent on replication of newly transformed cells. | the protozoan parasite trypanosoma brucei lives in the bloodstream of vertebrates or in a tsetse fly. expression of a gpi-phospholipase c polypeptide (gpi-plcp) in the parasite is restricted to the bloodstream form. events controlling the amount of gpi-plcp expressed during differentiation are not completely understood. our metabolic "pulse-chase" analysis reveals that gpi-plcp is stable in bloodstream form. however, during differentiation of bloodstream to insect stage (procyclic) t. brucei, tr ... | 2010 | 20109448 |
| trypanosoma brucei: trypanosome-specific endoplasmic reticulum proteins involved in variant surface glycoprotein expression. | in trypanosoma brucei the gpi-anchored variant surface glycoprotein (vsg) represents approximately 90% of cell surface protein and a major proportion of endoplasmic reticulum (er) biosynthetic output. we identified four trypanosomatid-specific genes encoding candidate er-resident proteins; all were required for normal proliferation. for tb11.01.2640 and tb11.01.8120, an increase in vsg abundance was found on silencing, while the protein products localized to the er; we designated these erap32 an ... | 2010 | 20109450 |
| the zinc-fingers of krepa3 are essential for the complete editing of mitochondrial mrnas in trypanosoma brucei. | most mitochondrial mrnas in trypanosomes undergo uridine insertion/deletion editing that is catalyzed by approximately 20s editosomes. the editosome component krepa3 is essential for editosome structural integrity and its two zinc finger (zf) motifs are essential for editing in vivo but not in vitro. krepa3 function was further explored by examining the consequence of mutation of its n- and c-terminal zfs (zf1 and zf2, respectively). exclusively expressed myc-tagged krepa3 with zf2 mutation resu ... | 2010 | 20111718 |
| intraspecific competition between co-infecting parasite strains enhances host survival in african trypanosomes. | it is becoming increasingly clear that under natural conditions parasitic infections commonly consist of co-infections with multiple conspecific strains. multiple-strain infections lead to intraspecific interactions and may have important ecological and evolutionary effects on both hosts and parasites. however, experimental evidence on intraspecific competition or facilitation in infections has been scarce because of the technical challenges of distinguishing and tracking individual co-infecting ... | 2009 | 20120806 |
| quiescin sulfhydryl oxidase from trypanosoma brucei: catalytic activity and mechanism of a qsox family member with a single thioredoxin domain. | quiescin sulfhydryl oxidase (qsox) flavoenzymes catalyze the direct, facile, insertion of disulfide bonds into reduced unfolded proteins with the reduction of oxygen to hydrogen peroxide. to date, only qsoxs from vertebrates have been characterized enzymatically. these metazoan sulfhydryl oxidases have four recognizable domains: a redox-active thioredoxin (trx) domain containing the first of three cxxc motifs (c(i)-c(ii)), a second trx domain with no obvious redox-active disulfide, a helix-rich ... | 2010 | 20121244 |
| the rna helicase dhh1 is central to the correct expression of many developmentally regulated mrnas in trypanosomes. | in trypanosomes, the predominant mechanisms of regulation of gene expression are post-transcriptional. the dead-box rna helicase dhh1 was identified in a screen for gene products that are necessary for the instability of the gpi-plc mrna in insect-stage trypanosomes. expression of an atpase-deficient dhh1 mutant caused a rapid growth arrest associated with a decrease in polysomes, an increase in p-bodies and a slight decrease in average mrna levels. however, the effect of dhh1 mutant expression ... | 2010 | 20124414 |
| in vitro activities of plant extracts from saudi arabia against malaria, leishmaniasis, sleeping sickness and chagas disease. | the in vitro activity of the methanol extracts of 51 plants randomly collected from the kingdom of saudi arabia and some of their fractions (petroleum ether, chloroform, ethyl acetate and aqueous) were evaluated against plasmodium falciparum, trypanosoma brucei brucei, t. cruzi and leishmania infantum, as well as toxicity against mrc-5 fibroblast cells. ten crude methanolic extracts that demonstrated potent and adequately selective antiprotozoal activity were subjected to solvent fractionation u ... | 2010 | 20127723 |
| podophyllotoxin analogues active versus trypanosoma brucei. | in an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (nsaids) has been synthesized and evaluated for activity versus trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. it was discovered that coupling of nsaids to podophyllotoxin increased the potencies of both compounds over 1300-fold. the compounds were shown to be cytostatic in nature and seem to act ... | 2010 | 20129783 |
| michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids. | new peptidic michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing asn, gln, or phe. as target enzymes, falcipain-2 and -3 from p. falciparum and rhodesain from t. b. rhodesiense were used. in the case of the asn/gln containing compounds, the trityl-protected, diastereomeric e-configured vinylogous dipeptide esters 16 (boc-(s)-phg-(r/s)-vgln(trt)-oet) were discovered as most active inhi ... | 2010 | 20131843 |
| mitochondrial dna polymerase polib is essential for minicircle dna replication in african trypanosomes. | the unique mitochondrial dna of trypanosomes is a catenated network of minicircles and maxicircles called kinetoplast dna (kdna). the network is essential for survival, and requires an elaborate topoisomerase-mediated release and reattachment mechanism for minicircle theta structure replication. at least seven dna polymerases (pols) are involved in kdna transactions, including three essential proteins related to bacterial dna pol i (polib, polic and polid). how trypanosoma brucei utilizes multip ... | 2010 | 20132449 |
| crystal structures of trypanosomal histidyl-trna synthetase illuminate differences between eukaryotic and prokaryotic homologs. | crystal structures of histidyl-trna synthetase (hisrs) from the eukaryotic parasites trypanosoma brucei and trypanosoma cruzi provide a first structural view of a eukaryotic form of this enzyme and reveal differences from bacterial homologs. hisrss in general contain an extra domain inserted between conserved motifs 2 and 3 of the class ii aminoacyl-trna synthetase catalytic core. the current structures show that the three-dimensional topology of this domain is very different in bacterial and ar ... | 2010 | 20132829 |
| sirtuin chemical mechanisms. | sirtuins are ancient proteins widely distributed in all lifeforms of earth. these proteins are universally able to bind nad(+), and activate it to effect adp-ribosylation of cellular nucleophiles. the most commonly observed sirtuin reaction is the adp-ribosylation of acetyllysine, which leads to nad(+)-dependent deacetylation. other types of adp-ribosylation have also been observed, including protein adp-ribosylation, nad(+) solvolysis and adp-ribosyltransfer to 5,6-dimethylbenzimidazole, a reac ... | 2010 | 20132909 |
| an internal sequence targets trypanosoma brucei triosephosphate isomerase to glycosomes. | in kinetoplastid protists, glycolysis is compartmentalized in glycosomes, organelles belonging to the peroxisome family. the trypanosoma brucei glycosomal enzyme triosephosphate isomerase (tpi) does not contain either of the two established peroxisome-targeting signals, but we identified a 22 amino acids long fragment, present at an internal position of the polypeptide, that has the capacity to route a reporter protein to glycosomes in transfected trypanosomes, as demonstrated by cell-fractionat ... | 2010 | 20138091 |
| a cross-sectional study of trypanosomosis and its vectors in donkeys and mules in northwest ethiopia. | a preliminary study was conducted in january 2009 in four peasant associations (pas) selected from two districts in benishangul gumuz regional state, northwest ethiopia to investigate the prevalence and species of trypanosomes infecting donkeys and mules and identify the fly vectors playing a role in the transmission of trypanosomosis. blood samples were collected from a total of 334 donkeys and 52 mules and examined by dark ground/phase contrast buffy coat technique and giemsa-stained blood sme ... | 2010 | 20143093 |
| mitochondrial membrane potential-based genome-wide rnai screen of trypanosoma brucei. | we have screened the trypanosoma brucei genome-wide rnai library by staining the procyclics with the dye jc-1 followed by sorting the differentially stained cells by flow cytometry. this allowed us to highly enrich for cells in which mitochondrial membrane potential was decreased. we have further validated a subset of selected clones by a reverse approach in which we showed that cloning the selected genomic regions into another rnai vector also results in a drop in mitochondrial membrane potenti ... | 2010 | 20143094 |
| in vitro activity and preliminary toxicity of various diamidine compounds against trypanosoma evansi. | trypanosoma evansi is an animal pathogenic protozoan, causing a wasting disease called surra, which is broadly distributed in a wide range of mammalian hosts. chemotherapy is the most efficient control method, which depends on four drugs. unfortunately, with the appearance of resistance to these drugs, their effective use is threatened, emphasising a need to find new drugs. diamidines bind to the minor groove of dna at at-rich sites and exert their anti-trypanosomal activity by inhibiting one or ... | 2010 | 20149544 |
| the trypanosome pumilio-domain protein puf7 associates with a nuclear cyclophilin and is involved in ribosomal rna maturation. | proteins with pumilio rna binding domains (puf proteins) are ubiquitous in eukaryotes. some puf proteins bind to the 3'-untranslated regions of mrnas, acting to repress translation and promote degradation; others are involved in ribosomal rna maturation. the genome of trypanosoma brucei encodes eleven puf proteins whose function cannot be predicted by sequence analysis. we show here that epitope-tagged tbpuf7 is located in the nucleolus, and associated with a nuclear cyclophilin-like protein, tb ... | 2010 | 20153321 |
| interactions of antimicrobial peptides with leishmania and trypanosomes and their functional role in host parasitism. | antimicrobial peptides (amps) are multifunctional components of the innate systems of both insect and mammalian hosts of the pathogenic trypanosomatids leishmania and trypanosoma species. structurally diverse amps from a wide range of organisms have in vitro activity against these parasites acting mainly to disrupt surface-membranes. in some cases amps also localize intracellularly to affect calcium levels, mitochondrial function and induce autophagy, necrosis and apoptosis. in this review we di ... | 2010 | 20159013 |
| establishment of an in vitro trans-splicing system in trypanosoma brucei that requires endogenous spliced leader rna. | in trypanosomes a 39 nucleotide exon, the spliced leader (sl) is donated to all mrnas from a small rna, the sl rna, by trans-splicing. since the discovery of trans-splicing in trypanosomes two decades ago, numerous attempts failed to reconstitute the reaction in vitro. in this study, a crude whole-cell extract utilizing the endogenous sl rna and synthetic tubulin pre-mrna were used to reconstitute the trans-splicing reaction. an rnase protection assay was used to detect the trans-spliced product ... | 2010 | 20159996 |
| design and evaluation of trypanosoma brucei metacaspase inhibitors. | metacaspase (mca) is an important enzyme in trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. therefore mca constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. a first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. in this letter we prese ... | 2010 | 20167486 |
| cerebral and peripheral changes occurring in nitric oxide (no) synthesis in a rat model of sleeping sickness: identification of brain inos expressing cells. | the implication of nitric oxide (no) in the development of human african trypanosomiasis (hat) using an animal model, was examined. the manner by which the trypanocidal activity of no is impaired in the periphery and in the brain of rats infected with trypanosoma brucei brucei (t. b. brucei) was analyzed through: (i) the changes occurring in no concentration in both peripheral (blood) and cerebral compartments; (ii) the activity of nnos and inos enzymes; (iii) identification of the brain cell ty ... | 2010 | 20169057 |
| prolyl oligopeptidase of trypanosoma brucei hydrolyzes native collagen, peptide hormones and is active in the plasma of infected mice. | proteases play important roles in many biological processes of parasites, including their host interactions. in sleeping sickness, trypanosoma brucei proteases released into the host bloodstream could hydrolyze host factors, such as hormones, contributing to the development of the disease's symptoms. in this study, we present the identification of the t. brucei prolyl oligopeptidase gene (poptb) and the characterization of its corresponding enzyme, pop tb. secondary structure predictions of pop ... | 2010 | 20188209 |
| a trk/hkt-type k+ transporter from trypanosoma brucei. | the molecular mechanisms of k(+) homeostasis are only poorly understood for protozoan parasites. trypanosoma brucei subsp. parasites, the causative agents of human sleeping sickness and nagana, are strictly extracellular and need to actively concentrate k(+) from their hosts' body fluids. the t. brucei genome contains two putative k(+) channel genes, yet the trypanosomes are insensitive to k(+) antagonists and k(+) channel-blocking agents, and they do not spontaneously depolarize in response to ... | 2010 | 20190075 |
| evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis. | in this paper, we present the biochemical and biological evaluation of n-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of trypanosoma vivax inosine-adenosine-guanosine nucleoside hydrolase (iag-nh). however, when the compounds were tested against bloodstream-form trypanosoma brucei brucei, only one inhibitor, n-(9-deaza-adenin-9-yl) ... | 2010 | 20194690 |
| scrutinizing the mechanisms underlying the induction of anemia of inflammation through gpi-mediated modulation of macrophage activation in a model of african trypanosomiasis. | in animal trypanosomiasis the severity of infection is reflected by the degree of anemia which resembles anemia of inflammation, involving a skewed iron homeostasis leading to iron accumulation within the reticuloendothelial system. myeloid cells (m cells) have been implicated in the induction and maintenance of this type of anemia and modulation of m cells through the main trypanosome-derived glycosylphosphatidylinositol (gpi)-anchor could attenuate both anemia and trypano-susceptibility in try ... | 2010 | 20197106 |
| crystallization and preliminary crystallographic analysis of cyanide-insensitive alternative oxidase from trypanosoma brucei brucei. | cyanide-insensitive alternative oxidase (aox) is a mitochondrial membrane protein and a non-proton-pumping ubiquinol oxidase that catalyzes the four-electron reduction of dioxygen to water. in the african trypanosomes, trypanosome alternative oxidase (tao) functions as a cytochrome-independent terminal oxidase that is essential for survival in the mammalian host; hence, the enzyme is considered to be a promising drug target for the treatment of trypanosomiasis. in the present study, recombinant ... | 2010 | 20208159 |
| a structural domain mediates attachment of ethanolamine phosphoglycerol to eukaryotic elongation factor 1a in trypanosoma brucei. | ethanolamine phosphoglycerol (epg) represents a protein modification that so far has only been found in eukaryotic elongation factor 1a (eef1a). in mammals and plants, epg is covalently attached to two conserved glutamate residues located in domains ii and iii of eef1a. in contrast, trypanosoma brucei eef1a contains a single epg attached to glu362 in domain iii. the sequence and/or structural requirements for covalent linkage of epg to eef1a have not been determined for any organism. using a com ... | 2010 | 20209157 |
| two thymidine hydroxylases differentially regulate the formation of glucosylated dna at regions flanking polymerase ii polycistronic transcription units throughout the genome of trypanosoma brucei. | base j is a hypermodified dna base localized primarily to telomeric regions of the genome of trypanosoma brucei. we have previously characterized two thymidine-hydroxylases (th), jbp1 and jbp2, which regulate j-biosynthesis. jbp2 is a chromatin re-modeling protein that induces de novo j-synthesis, allowing jbp1, a j-dna binding protein, to stimulate additional j-synthesis. here, we show that both jbp2 and jbp1 are capable of stimulating de novo j-synthesis. we localized the jbp1- and jbp2-stimul ... | 2010 | 20215442 |
| discovery of potent and selective inhibitors of trypanosoma brucei ornithine decarboxylase. | human african trypanosomiasis, caused by the eukaryotic parasite trypanosoma brucei, is a serious health problem in much of central africa. the only validated molecular target for treatment of human african trypanosomiasis is ornithine decarboxylase (odc), which catalyzes the first step in polyamine metabolism. here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of odc. this screen identified four novel families ... | 2010 | 20220141 |
| rna editing in kinetoplastids. | rna editing in kinetoplastid protozoa is a post-transcriptional process of uridine insertion or deletion in mitochondrial mrnas. the process involves two rna species, the pre-edited mrna and in most cases a trans-acting guide rna (grna). sequences within grnas define the position and extend of mrna editing. both mrnas and grnas are encoded by mitochondrial genes in the kinetoplast dna (kdna), which consists of thousands of small circular dna molecules, called minicircles, encoding thousands of g ... | 2010 | 20220308 |