Thursday, April 23, 2009

What's new for 'Trypanosomatids' in PubMed

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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 -5 of 5

1: Proteins. 2009 Mar 3. [Epub ahead of print]

Systematic structural studies of iron superoxide dismutases from human parasites and a statistical coupling analysis of metal binding specificity.

Bachega JF, Navarro MV, Bleicher L, Bortoleto-Bugs RK, Dive D, Hoffmann P, Viscogliosi E, Garratt RC.

Institute of Physics of São Carlos, University of São Paulo, CEP 13560-970, São Carlos, SP, Brazil.

Superoxide dismutases (SODs) are a crucial class of enzymes in the combat against intracellular free radical damage. They eliminate superoxide radicals by converting them into hydrogen peroxide and oxygen. In spite of their very different life cycles and infection strategies, the human parasites Plasmodium falciparum, Trypanosoma cruzi and Trypanosoma brucei are known to be sensitive to oxidative stress. Thus the parasite Fe-SODs have become attractive targets for novel drug development. Here we report the crystal structures of FeSODs from the trypanosomes T. brucei at 2.0 A and T. cruzi at 1.9 A resolution, and that from P. falciparum at a higher resolution (2.0 A) to that previously reported. The homodimeric enzymes are compared to the related human MnSOD with particular attention to structural aspects which are relevant for drug design. Although the structures possess a very similar overall fold, differences between the enzymes at the entrance to the channel which leads to the active site could be identified. These lead to a slightly broader and more positively charged cavity in the parasite enzymes. Furthermore, a statistical coupling analysis (SCA) for the whole Fe/MnSOD family reveals different patterns of residue coupling for Mn and Fe SODs, as well as for the dimeric and tetrameric states. In both cases, the statistically coupled residues lie adjacent to the conserved core surrounding the metal center and may be expected to be responsible for its fine tuning, leading to metal ion specificity. Proteins 2009. (c) 2009 Wiley-Liss, Inc.

PMID: 19384994 [PubMed - as supplied by publisher]

2: Molecules. 2009 Apr 14;14(4):1513-36.

Comparative molecular docking of antitrypanosomal natural products into multiple Trypanosoma brucei drug targets.

Ogungbe IV, Setzer WN.

Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA. dayovictor2000@yahoo.com

Antitrypanosomal natural products with different structural motifs previously shown to have growth inhibitory activity against Trypanosoma brucei were docked into validated drug targets of the parasite, which include trypanothione reductase, rhodesain, farnesyl diphosphate synthase, and triosephosphate isomerase. The in-silico calculations predicted that lowest energy docked poses of a number of the compounds can interact with catalysis-dependent residues, thus making them possible catalytic inhibitors and of course physiologically active. Compounds that possess a number of hydrogen-bond-accepting and/or -donating groups like phenolics and quinones show extensive interactions with the targets. Compounds like cissampeloflavone, 3-geranylemodin and ningpogenin thus offer profound promise.

PMID: 19384282 [PubMed - in process]

3: Proc Natl Acad Sci U S A. 2009 Apr 21. [Epub ahead of print]

Regulated expression of the Leishmania major surface virulence factor lipophosphoglycan using conditionally destabilized fusion proteins.

Madeira da Silva L, Owens KL, Murta SM, Beverley SM.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.

Surface glycoconjugates play important roles in the infectious cycle of Leishmania major, including the abundant lipophosphoglycan (LPG) implicated in parasite survival in the sand fly vector and the initial stages of establishment in the mammalian host macrophage. We describe a system for inducible expression of LPG, applying a novel protein-based system that allows controlled degradation of a key LPG biosynthetic enzyme, UDP-galactopyranose mutase (UGM). This methodology relies on a mutated FK506-binding protein (FKBP) destabilizing domain (dd) fused to the protein of interest; in the absence of rapamycin analogs, such as Shld1, the dd domain is destabilized, leading to proteasomal degradation, whereas drug treatment confers stabilization. Tests in L. major using dd fusions to a panel of reporters and cellular proteins confirmed its functionality, with a high degree of regulation and low background, and we established the kinetics of protein activation and/or loss. Two inexpensive and widely available ligands, FK506 and rapamycin, functioned similarly to Shld1, without effect on Leishmania growth or differentiation. We generated parasites lacking UGM through deletion of the GLF gene and substitution with a ddGLF fusion construct, either as chromosomal knockins or through episomal complementation; these showed little or no LPG expression in the absence of inducer, whereas in its presence, high levels of LPG were attained rapidly. Complement lysis tests confirmed the correct integrity of the Leishmania LPG coat. These data suggest that the dd approach has great promise in the study of LPG and other pathways relevant to parasite survival and virulence.

PMID: 19383793 [PubMed - as supplied by publisher]

4: Microbiology. 2009 Apr 21. [Epub ahead of print]

Strategies for acquiring the phospholipid metabolite inositol in pathogenic bacteria, fungi, and protozoa: making it and taking it.

Reynolds TB.

University of Tennessee, Knoxville.

Myo-inositol (inositol) is an essential nutrient that is used for building phosphatidylinositol and its derivatives in eukaryotes and even in some eubacteria such as the mycobacteria. As a consequence, fungal, protozoan, and mycobacterial pathogens must be able to acquire inositol in order to proliferate and cause infection in their hosts. There are two primary mechanisms for acquiring inositol. One is to synthesize inositol from glucose-6-phosphate using two sequentially acting enzymes. The enzyme inositol-3-phosphate synthase (Ino1p) converts glucose-6-phosphate to inositol-3-phosphate, and then the inositol monophosphatase enzyme (IMPase) dephosphorylates inositol-3-phosphate to generate inositol. The other mechanism is to import inositol from the environment via inositol transporters. Inositol is readily abundant in the bloodstream of mammalian hosts providing a source from which many pathogens could potentially import inositol. However, despite this abundance of inositol in the host, some pathogens such as the bacterium Mycobacterium tuberculosis and the parasite Trypanosoma brucei must be able to make inositol de novo in order to cause disease (M. tuberculosis) or even grow (T. brucei). Other pathogens such as the fungus Candida albicans are equally adept at causing disease by importing inositol or by making it de novo. The role of inositol acquisition in the biology and pathogenesis of the parasite Leishmania and the fungus Cryptococcus are being explored as well. The specific strategies used by these pathogens to acquire inositol while in the host are discussed in relationship to each pathogen's unique metabolic requirements.

PMID: 19383710 [PubMed - as supplied by publisher]

5: New Microbiol. 2009 Jan;32(1):93-100.

Serological and entomological survey of zoonotic visceral leishmaniasis in Denizli Province, Aegean Region, Turkey.

Ozensoy Töz S, Sakru N, Ertabaklar H, Demir S, Sengul M, Ozbel Y.

Ege University Medical School Department of Parasitology Bornova, Izmir, Turkey. seray.ozensoy.toz@ege.edu.tr

A cross-sectional seroepidemiological survey of leishmaniasis was carried out among children and adults from four villages and one district of Denizli province located in the Southern Aegean Region of Turkey where 14 human visceral leishmaniasis (HVL) cases including 4 adults were reported between 1993 and 2000. Blood samples were taken from 329 children, 217 adults and 140 dogs and a physical examination was also done. Indirect fluorescent antibody test and enzyme linked immunosorbent assay were performed for all sera. All 329 sera collected from children were found to be negative while 2 (0.09%) out of 217 adult sera were found to be seropositive. One seropositive adult patient was confirmed parasitologically as HVL after bone marrow aspiration and treated with AmBisome while the other was followed only serologically because of the absence of symptoms. The overall canine leishmaniasis seroprevalence was found to be 20.7%. Sand flies were collected using CDC light traps in three out of five study sites and midguts of females were checked for promastigotes after dissection/identification. Eight Phlebotomus species were found in the region. Phlebotomus neglectus and P. papatasi were determined as dominant species with the ratio of 43.52% and 37.35%, respectively. No promastigotes were found in the midgut specimens. In addition, the results showed the presence of vector sand fly species, as well as a high seroprevalence of anti-Leishmania antibodies among dogs from rural and a suburban area of Denizli province with a large proportion of asymptomatic seropositive dogs.

PMID: 19382674 [PubMed - in process]

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