What's new for 'Trypanosomatids' in PubMed

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Sent on Thursday, 2010 Jun 17
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 4 of 4

1.	Rapid Commun Mass Spectrom. 2010 Jun 15;24(14):2074-2082. [Epub ahead of print] Profiling of lipids in Leishmania donovani using hydrophilic interaction chromatography in combination with Fourier transform mass spectrometry. Zheng L, T'kind R, Decuypere S, von Freyend SJ, Coombs GH, Watson DG. Strathclyde Institute of Pharmacy and Biomedical and Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK. Abstract There is evidence from our current research on resistance to stibigluconate and from some previous observations that lipid composition may be altered in resistant Leishmania donovani and in order to explore this we required a comprehensive lipidomics method. Phospholipids can be analysed by direct infusion into a mass spectrometer and such methods can work very well. However, chromatographic methods can also be very effective and are extensively used. They potentially avoid ion suppression effects, associate lipid classes with a retention time range and deliver good quantitative accuracy. In the current study three chromatography columns were compared for their ability to separate different classes of lipid. Butylsilane (C-4), Zic-HILIC and a silica gel column were compared. The best results were obtained with a silica gel column used in hydrophilic interaction chromatography (HILIC) mode with a mobile phase gradient consisting of (A) 20% isopropyl alcohol (IPA) in acetonitrile (v/v) and (B) 20% IPA in 0.02 M ammonium formate. Using these conditions separate peaks were obtained for triglycerides (TG), phosphoinositols (PI), inositol phosphoceramides (IPC), phosphatidylethanolamines (PE), phosphatidylserines (PS), phosphatidylcholines (PC), sphingosines (SG), lysophosphatidyethanolamines (LPE) and lysophosphatidylcholines (LPC). The methodology was applied to the analysis of lipid extracts from Leishmania donovani and by coupling the chromatography with an LTQ Orbitrap mass spectrometer. It was possible to detect 188 lipid species in the extracts with the following breakdown: PC 59, PE 38, TG 35, PI 20, CPI 13, LPC 11, LPE 2 and SG 10. The fatty acid composition of the more abundant lipids was characterised by MS(2) and MS(3) experiments carried out by using an LCQ Deca low-resolution ion trap instrument coupled with the silica gel column. The separation of lipids into well-defined groups gives extra confidence in their identification and minimises the risk of ion suppression effects. High-resolution mass spectrometry was necessary in order to be able to differentiate between acyl- and acyl-alkyl-lipids. Copyright (c) 2010 John Wiley & Sons, Ltd.
	PMID: 20552712 [PubMed - as supplied by publisher]

2.	Proc Natl Acad Sci U S A. 2010 Jun 15. [Epub ahead of print] Expansion of the target of rapamycin (TOR) kinase family and function in Leishmania shows that TOR3 is required for acidocalcisome biogenesis and animal infectivity. Madeira da Silva L, Beverley SM. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110. Abstract Target of rapamycin (TOR) kinases are key regulators of cell growth, proliferation, and structure in eukaryotes, processes that are highly coordinated during the infectious cycle of eukaryotic pathogens. Database mining revealed three TOR kinases in the trypanosomatid parasite Leishmania major, as defined by homology to the phosphoinositide 3-kinase-related kinase (PIKK) family and a signature conserved FKBP12/rapamycin-binding domain. Consistent with the essential roles of TOR complexes in other organisms, we were unable to generate null TOR1 or TOR2 mutants in cultured L. major promastigotes. In contrast, tor3(-) null mutants were readily obtained; while exhibiting somewhat slower growth, tor3(-) maintained normal morphology, rapamycin sensitivity, and differentiation into the animal-infective metacyclic stage. Significantly, tor3(-) mutants were unable to survive or replicate in macrophages in vitro, or to induce pathology or establish infections in mice in vivo. The loss of virulence was associated with a defect in acidocalcisome formation, as this unique organelle was grossly altered in tor3- mutants and no longer accumulated polyphosphates. Correspondingly, tor3- mutants showed defects in osmoregulation and were sensitive to starvation for glucose but not amino acids, glucose being a limiting nutrient in the parasitophorous vacuole. Thus, in Leishmania, the TOR kinase family has expanded to encompass a unique role in AC function and biology, one that is essential for parasite survival in the mammalian infective stage. Given their important roles in cell survival and virulence, inhibition of TOR kinase function in trypanosomatids offers an attractive target for chemotherapy.
	PMID: 20551225 [PubMed - as supplied by publisher]

3.	Genes Dev. 2010 Jun 15;24(12):1306-16. A novel phosphatase cascade regulates differentiation in Trypanosoma brucei via a glycosomal signaling pathway. Szöor B, Ruberto I, Burchmore R, Matthews KR. Centre for Immunity, Infection, and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT; United Kingdom; Abstract In the mammalian bloodstream, the sleeping sickness parasite Trypanosoma brucei is held poised for transmission by the activity of a tyrosine phosphatase, TbPTP1. This prevents differentiation of the transmissible "stumpy forms" until entry into the tsetse fly, whereupon TbPTP1 is inactivated and major changes in parasite physiology are initiated to allow colonization of the arthropod vector. Using a substrate-trapping approach, we identified the downstream step in this developmental signaling pathway as a DxDxT phosphatase, TbPIP39, which is activated upon tyrosine phosphorylation, and hence is negatively regulated by TbPTP1. In vitro, TbPIP39 promotes the activity of TbPTP1, thereby reinforcing its own repression, this being alleviated by the trypanosome differentiation triggers citrate and cis-aconitate, generating a potentially bistable regulatory switch. Supporting a role in signal transduction, TbPIP39 becomes rapidly tyrosine-phosphorylated during differentiation, and RNAi-mediated transcript ablation in stumpy forms inhibits parasite development. Interestingly, TbPIP39 localizes in glycosomes, peroxisome-like organelles that compartmentalize the trypanosome glycolytic reactions among other enzymatic activities. Our results invoke a phosphatase signaling cascade in which the developmental signal is trafficked to a unique metabolic organelle in the parasite: the glycosome. This is the first characterized environmental signaling pathway targeted directly to a peroxisome-like organelle in any eukaryotic cell.
	PMID: 20551176 [PubMed - in process]

4.	J Phys Chem A. 2010 Jun 15. [Epub ahead of print] Assignment of UV-vis Spectrum of (3,3')-Diindolylmethane, a Leishmania donovani Topoisomerase IB Inhibitor and a Candidate DNA Minor Groove Binder. Coletta A, Morozzo Della Rocca B, Jaisankar P, Majumder HK, Chillemi G, Sanna N, Desideri A. Dipartimento di Biologia, Universita degli Studi di Roma "Tor Vergata", Via della Ricerca Scientifica, 00133 Roma, Italy, Departments of Medicinal Chemistry and Parasitology, Indian Institut of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata-700032, India, and CASPUR Interuniversities Consortium for Supercomputing Applications, Via dei Tizii 6b, 00185 Roma, Italy. Abstract The geometrical optimization of (3,3')-diindolylmethane (DIM), an inhibitor of the bisubunit enzyme topoisomerase I from Leishmania donovani, a pathogenic protozoan parasite, mostly diffused in developing countries, has been carried out through quantum mechanical calculation. Using first-principle DFT restrained geometrical optimization, a potential energy surface has been constructed to identify a set of local minimum energy conformations of DIM. Starting from these conformations, the experimental UV-vis absorption spectrum in aqueous solution has been reproduced through TD-DFT calculations. A molecular mechanics classical force-field has been also parametrized and tested, verifying the correct coherence between the canonical ensemble obtained from molecular dynamics simulation and the potential energy surface calculation. The force field has been used to elucidate the interaction of DIM with a 22 bp DNA double strand. The best docked DIM-DNA complexes display a binding energy pretty similar to the experimental energy and are all located in the DNA minor groove, strongly suggesting that DIM is a minor groove binder.
	PMID: 20550156 [PubMed - as supplied by publisher]