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Sent on Tuesday, 2011 May 24Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Enzyme Res. 2011;2011:873230. Epub 2011 Apr 10.Role of heme and heme-proteins in trypanosomatid essential metabolic pathways.Tripodi KE, Menendez Bravo SM, Cricco JA.SourceDepartamento de Química Biológica and Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina. AbstractAround the world, trypanosomatids are known for being etiological agents of several highly disabling and often fatal diseases like Chagas disease (Trypanosoma cruzi), leishmaniasis (Leishmania spp.), and African trypanosomiasis (Trypanosoma brucei). Throughout their life cycle, they must cope with diverse environmental conditions, and the mechanisms involved in these processes are crucial for their survival. In this review, we describe the role of heme in several essential metabolic pathways of these protozoans. Notwithstanding trypanosomatids lack of the complete heme biosynthetic pathway, we focus our discussion in the metabolic role played for important heme-proteins, like cytochromes. Although several genes for different types of cytochromes, involved in mitochondrial respiration, polyunsaturated fatty acid metabolism, and sterol biosynthesis, are annotated at the Tritryp Genome Project, the encoded proteins have not yet been deeply studied. We pointed our attention into relevant aspects of these protein functions that are amenable to be considered for rational design of trypanocidal agents. |
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| 2. | Enzyme Res. 2011;2011:576483. Epub 2011 Apr 4.Singular features of trypanosomatids' phosphotransferases involved i n cell energy management.Pereira CA, Bouvier LA, Cámara Mde L, Miranda MR.SourceLaboratorio de Biología Molecular de Trypanosoma cruzi (LBMTC), Instituto de Investigaciones Médicas "Alfredo Lanari", Universidad de Buenos Aires and CONICET, Combatientes de Malvinas 3150, 1427 Buenos Aires, Argentina. AbstractTrypanosomatids are responsible for economically important veterinary affections and severe human diseases. In Africa, Trypanosoma brucei causes sleeping sickness or African trypanosomiasis, while in America, Trypanosoma cruzi is the etiological agent of Chagas disease. These parasites have complex life cycles which involve a wide variety of environments with very different compositions, physicochemical properties, and availability of metabolites. As the environment changes there is a need to maintain the nucleoside homeostasis, requiring a quick and regulated response. Most of the enzymes required for energy management are phosphotransferases. These enzymes present a nitrogenous group or a phosphate as acceptors, and the most clear examples are arginine kinase, nucleoside diphosphate kinase, and adenylate kinase. Trypanosoma and Leishmania have the largest number of phosphotransferase isoforms ever found in a single cell; some of them are absent in mammals, suggesting that these enzymes are required in many cellular compartments associated to different biological processes. The presence of such number of phosphotransferases support the hypothesis of the existence of an intracellular enzymatic phosphotransfer network that communicates the spatially separated intracellular ATP consumption and production processes. All these unique features make phosphotransferases a promising start point for rational drug design for the treatment of human trypanosomiasis. |
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| 3. | Enzyme Res. 2011;2011:392082. Epub 2011 Apr 5.Phospholipases a in trypanosomatids.Belaunzarán ML, Lammel EM, de Isola EL.SourceDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 13, C1121ABG Buenos Aires, Argentina. AbstractPhospholipases are a complex and important group of enzymes widespread in nature, that play crucial roles in diverse biochemical processes and are classified as A(1), A(2), C, and D. Phospholipases A(1) and A(2) activities have been linked to pathogenesis in various microorganisms, and particularly in pathogenic protozoa they have been implicated in cell invasion. Kinetoplastids are a group of flagellated protozoa, including extra- and intracellular parasites that cause severe disease in humans and animals. In the present paper, we will mainly focus on the three most important kinetoplastid human pathogens, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., giving a perspective of the research done up to now regarding biochemical, biological, and molecular characteristics of Phospholipases A(1) and A(2) and their contribution to pathogenesis. |
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| 4. | Enzyme Res. 2011;2011:932549. Epub 2011 Apr 7.Enolase: a key player in the metabolism and a probable virulence factor of trypanosomatid parasites-perspectives for its use as a therapeutic target.Avilán L, Gualdrón-López M, Quiñones W, González-González L, Hannaert V, Michels PA, Concepción JL.SourceLaboratorio de Fisiología, Facultad de Ciencias, Universidad de los Andes, 5101 Mérida, Venezuela. AbstractGlycolysis and glyconeogenesis play crucial roles in the ATP supply and synthesis of glycoconjugates, important for the viability and virulence, respectively, of the human-pathogenic stages of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. These pathways are, therefore, candidate targets for antiparasite drugs. The glycolytic/gluconeogenic enzyme enolase is generally highly conserved, with similar overall fold and identical catalytic residues in all organisms. Nonetheless, potentially important differences exist between the trypanosomatid and host enzymes, with three unique, reactive residues close to the active site of the former that might be exploited for the development of new drugs. In addition, enolase is found both in the secretome and in association with the surface of Leishmania spp. where it probably functions as plasminogen receptor, playing a role in the parasite's invasiveness and virulence, a function possibly also present in the other trypanosomatids. This location and possible function of enolase offer additional perspectives for both drug discovery and vaccination. |
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| 5. | RNA. 2011 May 20. [Epub ahead of print]The C-terminal end of the Trypanosoma brucei editing deaminase plays a critical role in tRNA binding.Ragone FL, Spears JL, Wohlgamuth-Benedum JM, Kreel N, Papavasiliou FN, Alfonzo JD.SourceOhio State Biochemistry Program, Ohio State University, Columbus, Ohio 43210, USA. AbstractAdenosine to inosine editing at the wobble position allows decoding of multiple codons by a single tRNA. This reaction is catalyzed by adenosine deaminases acting on tRNA (ADATs) and is essential for viability. In bacteria, the anticodon-specific enzyme is a homodimer that recognizes a single tRNA substrate (tRNA(Arg)(ACG)) and can efficiently deaminate short anticodon stem-loop mimics of this tRNA in vitro. The eukaryal enzyme is composed of two nonidentical subunits, ADAT2 and ADAT3, which upon heterodimerization, recognize seven to eight different tRNAs as substrates, depending on the organism, and require a full-length tRNA for activity. Although crystallographic data have provided clues to why the bacterial deaminase can utilize short substrates, residues that provide substrate binding and recognition with the eukaryotic enzymes are not currently known. In the present study, we have used a combination of mutagenesis, binding studies, and kinetic analysis to explore the contribution of individual residues in Trypanosoma brucei ADAT2 (TbADAT2) to tRNA recognition. We show that deletion of the last 10 amino acids at the C terminus of TbADAT2 abolishes tRNA binding. In addition, single alanine replacements of a string of positively charged amino acids (KRKRK) lead to binding defects that correlate with losses in enzyme activity. This region, which we have termed the KR-domain, provides a first glance at key residues involved in tRNA binding by eukaryotic tRNA editing deaminases. |
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| 6. | Biomed Pharmacother. 2011 May 4. [Epub ahead of print]Synthesis of 4-aminoquinoline analogues and their platinum(II) complexes as new antileishmanial and antitubercular agents.Carmo AM, Silva FM, Machado PA, Fontes AP, Pavan FR, Leite CQ, Leite SR, Coimbra ES, Da Silva AD.SourceDepartamento de Química, ICE, Universidade Federal de Juiz de Fora, Campus Universitário, Juiz de Fora, MG 36036-900, Brazil. AbstractA series of 4-amino-7-chloroquinoline derivatives were synthesized by the reaction of 4,7-dichloro-quinoline with the corresponding diamine and then with propargyl bromide. In addition, platinum(II) complexes were obtained by reacting some of the organic derivatives with K(2)PtCl(4). Several of the synthesized compounds displayed antituberculosis activities. Compound 3 was 47.5 times more active than amphotericin B against Leishmania chagasi (IC(50)=0.04μg/mL). Compounds 5, 6, 7, 9, 10, 11 and 13 presented promising results against Mycobacterium tuberculosis, with MIC values ranging from 12.5 to 15.6μg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Copyright © 2011 Elsevier Masson SAS. All rights reserved. |
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| 7. | Theriogenology. 2011 May 20. [Epub ahead of print]Genital lesions in male red fronted gazelles (Gazella rufifrons) experimentally infected with Trypanosoma brucei and the effect of melarsamine hydrochloride (Cymelarsan(®)) and diminazene aceturate (Berenil(®)) in its treatment.Mbaya AW, Nwosu CO, Kumshe HA.SourceDepartment of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine, University of Maiduguri, Nigeria. AbstractThirty red fronted gazelles (Gazella rufifrons) were used to assess the genital lesions associated with trypanosomosis and the efficacy of melarsamine hydrochloride (Cymelarsan(®)) and diminazene aceturate (Berenil(®)) in the treatment of the condition. The animals were divided into 6 equal groups (A-F). Animals in groups A-E were infected with Trypanosoma brucei, and later treated on day 8 post infection (p.i.) with either melarsamine hydrochloride (Cymelarsan(®)) at 0.3 mg/kg (Group A) and 0.6 mg/kg (Group B) or diminazene aceturate (Berenil(®)) at 3.5 mg/kg (Group C) and 7.0 mg/kg (Group D). Animals in group E remained untreated while group F served as healthy controls. Parasitaemia was established by day 8 p.i. in all infected groups and eliminated by day 16 following treatment on day 8 p.i. with melarsamine hydrochloride (Cymelarsan(®)) (Groups A and B) or diminazene aceturate (Berenil(®)) (Group D). On the other hand, diminazene aceturate treatment (Berenil(®)) on day 8 p.i. at 3.5 mg/kg (Group C) caused a temporary disappearance of parasites from the circulation by day 16 p.i. but there was a relapse parasitaemia on day 44 with a peak count of 500 ± 2.79 × 10(3) parasites/μL of blood by day 52 p.i. In the infected/untreated group (E), parasitaemia fluctuated but attained the same peak as Group C by day 52 p.i. Increase in body temperatures (40.5 ± 3.16 - 42.8 ± 3.25 °C) occurred during the first wave of parasitaemia but declined to pre-infection values from day 28 p.i. in Groups A, B and D. In Groups C and E, there was a second wave of parasitaemia (P < 0.05) with peak counts of 42.4 ± 0.81 × 10(3)/μL and 41.8 ± 0.80 × 10(3)/μL respectively by day 52 p.i. A significant (P < 0.05) decline in packed cell volume was also noted by day 52 p.i. The major clinical signs observed in Groups C and E were pyrexia, inappetance, emaciation, anaemia, dullness, starry hair coat, pallor of buccal and ocular mucous membranes. Similarly, in Groups C and E, the testicles appeared oedematous and painful to touch with degenerative changes, morphological sperm abnormalities and oligospermia with 2.0% and 0% sperm reserves respectively. Sperm reserve was 100% in Groups A, B and D. It is therefore, concluded that trypanosomosis can cause serious infertility in male red fronted gazelles and that early treatments with melarsamine hydrochloride (Cymelarsan(®) ) at 0.3 and 0.6 mg/kg body weight or diminazene aceturate (Berenil(®)) at 7.0 mg/kg body weight may prevent such effects. Copyright © 2011 Elsevier Inc. All rights reserved. |
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| 8. | Phytochemistry. 2011 May 20. [Epub ahead of print]Antiprotozoal and antiangiogenic saponins from Apodytes dimidiata.Foubert K, Cuyckens F, Matheeussen A, Vlietinck A, Apers S, Maes L, Pieters L.SourceLaboratory of Pharmacognosy and Pharmaceutical Analysis, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. AbstractBioassay-guided isolation was performed on the leaves of Apodytes dimidiata E. Mey. Ex Arn. (Icacinaceae), based on previously demonstrated activity against Leishmania. Six saponins never isolated from nature before were elucidated with LC-MS/MS, GC-MS and 1D and 2D NMR. The compounds apodytine A-F are responsible at least in part for the antiprotozoal activity, but also possess haemolytic activity and display antiangiogenic activity in the rat aorta ring assay, an effect which may be due to a non-selective toxicity. Copyright © 2011 Elsevier Ltd. All rights reserved. |
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| 9. | Toxicon. 2011 May 12. [Epub ahead of print]A comparative study of the effects of venoms from five rear-fanged snake species on the growth of Leishmania major: Identification of a protein with in hibitory activity against the parasite.Peichoto ME, Tavares FL, Dekrey G, Mackessy SP.SourceCátedra de Farmacología, Facultad de Ciencias Veterinarias, Universidad Nacional del Nordeste, Sargento Cabral 2139, 3400 Corrientes, Argentina; School of Biological Sciences, University of Northern Colorado, 501 20th St., CB 92, Greeley, CO 80639-0017, USA. AbstractLeishmania parasites of several species cause cutaneous and visceral disease to millions of people worldwide, and treatment for this vector-borne protozoan parasite typically involves administration of highly toxic antimonial drugs. Snake venoms are one of the most concentrated enzyme sources in nature, displaying a broad range of biological effects, and several drugs now used in humans were derived from venoms. In this study, we compared the effects of the venoms of the South American rear-fanged snakes Philodryas baroni (PbV), Philodryas olfersii olfersii (PooV) and Philodryas patagoniensis (PpV), and the North American rear-fanged snakes Hypsiglena torquata texana (HttV) and Trimorphodon biscutatus lambda (TblV), on the growth of Leishmania major, a causative agent of cutaneous leishmaniasis. Different concentrations of each venom were incubated with the log-phase promastigote stage of L. major. TblV showed significant anti-leishmanial activity (IC(50) of 108.6 μg/mL) at its highest concentrations; however, it induced parasite proliferation at intermediate concentrations. PpV was not very active in decreasing the parasitic growth, and a high final concentration (1.7 mg/mL) was necessary to inhibit proliferation by only 51.5% ± 3.6%. PbV, PooV and HttV, at final concentrations of 562, 524 and 438 μg/mL respectively, had no significant effect on L. major growth. The phospholipase A(2) of TblV (trimorphin) was isolated and assayed as for crude venom, and it also exhibited dose-dependent biphasic effects on the parasite culture, with potent cytotoxicity at higher concentrations (IC(50) of 0.25 μM; 3.6 μg/mL) and stimulation of proliferation at very low concentrations. Antil-eishmanial activity of TblV appears to be solely due to the action of trimorphin. This is the first report of anti-leishmanial activity of rear-fanged snake venoms, and these results suggest novel possibilities for discovering new protein-based drugs that might be used as possible agents against leishmaniasis as well as tools to study the biology of Leishmania parasites. Copyright © 2011 Elsevier Ltd. All rights reserved. |
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| 10. | Acta Trop. 2011 May 13. [Epub ahead of print]The pharmacological inhibition of sterol biosynthesis in Leishmania is counteracted by enhancement of LDL endocytosis.de Andrade-Neto VV, Cicco NN, da Cunha-Junior EF, do Canto-Cavalheiro MM, Atella GC, Torres-Santos EC.SourceLaboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Av Brasil, 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil. AbstractLeishmania parasites, despite being able to synthesize their own sterols, acquire and accumulate significant amounts of cholesterol through low density lipoprotein (LDL) particle endocytosis. The role of this system in Leishmania amazonensis promastigotes under pharmacological pressure by sterol biosynthesis inhibitors (SBIs) was investigated. First, thin layer chromatography demonstrated that L. amazonensis promastigotes, in response to ergosterol biosynthesis inhibition by treatment with 4.0 and 6.0μM ketoconazole or miconazole, accumulate up to two times more cholesterol than controls. The treatment of promastigotes with ketoconazole and simvastatin, two SBIs with non-related mechanisms of action, showed that both drugs induce increases in (125)I-LDL endocytosis in a dose-dependent manner, indicating that the accumulation of exogenous cholesterol is due to the enhancement of LDL uptake. Finally, it was demonstrated that L. amazonensis promastigotes were rendered more susceptible to treatment with SBIs (ketoconazole, miconazole, simvastatin and terbinafine) in the absence of exogenous cholesterol sources, with a reduction of the IC50s of about 50% in three of the four tested drugs. These results show that the exogenous cholesterol uptake system in L. amazonensis plays a role as a compensatory mechanism in response to the presence of SBIs, suggesting that it may be a potential pharmacological target. Copyright © 2011. Published by Elsevier B.V. |
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