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91.
Alistair J. Standish Angela A. Salim Robert J. Capon Renato Morona 《Biochemical and biophysical research communications》2013,430(1):167-172
Increasing antibiotic resistance is making the identification of novel antimicrobial targets critical. Recently, we discovered an inhibitor of protein tyrosine phosphatase CpsB, fascioquinol E (FQE), which unexpectedly inhibited the growth of Gram-positive pathogens. CpsB is a member of the polymerase and histidinol phosphate phosphatase (PHP) domain family. Another member of this family found in a variety of Gram-positive pathogens is DNA polymerase PolC. We purified the PHP domain from PolC (PolCPHP), and showed that this competes away FQE inhibition of CpsB phosphatase activity. Furthermore, we showed that this domain hydrolyses the 5′-p-nitrophenyl ester of thymidine-5′-monophosphate (pNP-TMP), which has been used as a measure of exonuclease activity. Finally, we showed that FQE not only inhibits the phosphatase activity of CpsB, but also ability of PolCPHP to catalyse the hydrolysis of pNP-TMP. This suggests that PolC may be the essential target of FQE, and that the PHP domain may represent an as yet untapped target for the development of novel antibiotics. 相似文献
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93.
Alistair J. Fielding Kristian Parey Ulrich Ermler Silvan Scheller Bernhard Jaun Marina Bennati 《Journal of biological inorganic chemistry》2013,18(8):905-915
Heterodisulfide reductase (Hdr) is a key enzyme in the energy metabolism of methanogenic archaea. The enzyme catalyzes the reversible reduction of the heterodisulfide (CoM-S-S-CoB) to the thiol coenzymes M (CoM-SH) and B (CoB-SH). Cleavage of CoM-S-S-CoB at an unusual FeS cluster reveals unique substrate chemistry. The cluster is fixed by cysteines of two cysteine-rich CCG domain sequence motifs (CX31–39CCX35–36CXXC) of subunit HdrB of the Methanothermobacter marburgensis HdrABC complex. We report on Q-band (34 GHz) 57Fe electron-nuclear double resonance (ENDOR) spectroscopic measurements on the oxidized form of the cluster found in HdrABC and in two other CCG-domain-containing proteins, recombinant HdrB of Hdr from M. marburgensis and recombinant SdhE of succinate: quinone reductase from Sulfolobus solfataricus P2. The spectra at 34 GHz show clearly improved resolution arising from the absence of proton resonances and polarization effects. Systematic spectral simulations of 34 GHz data combined with previous 9 GHz data allowed the unambiguous assignment of four 57Fe hyperfine couplings to the cluster in all three proteins. 13C Mims ENDOR spectra of labelled CoM-SH were consistent with the attachment of the substrate to the cluster in HdrABC, whereas in the other two proteins no substrate is present. 57Fe resonances in all three systems revealed unusually large 57Fe ENDOR hyperfine splitting as compared to known systems. The results infer that the cluster’s unique magnetic properties arise from the CCG binding motif. 相似文献
94.
Robert L. Jones Wan A.N. Wan Ahmad David F. Woodward Jenny Wang 《Prostaglandins, leukotrienes, and essential fatty acids》2013,88(4):321-330
The remarkably slow onset/offset of relaxation of guinea-pig isolated trachea induced by a ‘non-prostanoid’ EP2 receptor agonist, (o-(o-benzyloxy)-cinnamyl)-cinnamic acid (coded (L)-9), was investigated. (L)-9 kinetics was slightly faster on mouse trachea and considerably faster on rabbit vena cava. In each case, reversal of (L)-9 relaxation by the selective EP2 antagonist ACA-23 was rapid and similar to other EP2 agonists (e.g. ONO-AE1-259). On guinea-pig aorta, in the presence of extensive EP2 receptor blockade, (L)-9 inhibited TP agonist-induced contraction more slowly than TP antagonists of similar affinity. The slower kinetics of (L)-9 appear to correlate with greater adventitial/submucosal barriers and thicker smooth muscle layers in the tissues examined. It is proposed that interactions of (L)-9 with EP2 and TP receptors are not rate-limiting, rather diffusion to and from the centre of the muscle mass is retarded by the high lipophilicity of (L)-9 (logP=6.69; ONO-AE1-259=3.95). 相似文献
95.
G. Michael Taylor Katie Tucker Rachel Butler Alistair W. G. Pike Jamie Lewis Simon Roffey Philip Marter Oona Y-C Lee Houdini H. T. Wu David E. Minnikin Gurdyal S. Besra Pushpendra Singh Stewart T. Cole Graham R. Stewart 《PloS one》2013,8(4)
Nine burials excavated from the Magdalen Hill Archaeological Research Project (MHARP) in Winchester, UK, showing skeletal signs of lepromatous leprosy (LL) have been studied using a multidisciplinary approach including osteological, geochemical and biomolecular techniques. DNA from Mycobacterium leprae was amplified from all nine skeletons but not from control skeletons devoid of indicative pathology. In several specimens we corroborated the identification of M. leprae with detection of mycolic acids specific to the cell wall of M. leprae and persistent in the skeletal samples. In five cases, the preservation of the material allowed detailed genotyping using single-nucleotide polymorphism (SNP) and multiple locus variable number tandem repeat analysis (MLVA). Three of the five cases proved to be infected with SNP type 3I-1, ancestral to contemporary M. leprae isolates found in southern states of America and likely carried by European migrants. From the remaining two burials we identified, for the first time in the British Isles, the occurrence of SNP type 2F. Stable isotope analysis conducted on tooth enamel taken from two of the type 3I-1 and one of the type 2F remains revealed that all three individuals had probably spent their formative years in the Winchester area. Previously, type 2F has been implicated as the precursor strain that migrated from the Middle East to India and South-East Asia, subsequently evolving to type 1 strains. Thus we show that type 2F had also spread westwards to Britain by the early medieval period. 相似文献
96.
Menno J. Oudhoff Frann Antignano Alistair L. Chenery Kyle Burrows Stephen A. Redpath Mitchell J. Braam Georgia Perona-Wright Colby Zaph 《PLoS pathogens》2016,12(9)
The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7
-/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection. 相似文献
97.
Sanjeev Rajakulendran Robert D. S. Pitceathly Jan-Willem Taanman Harry Costello Mary G. Sweeney Cathy E. Woodward Zane Jaunmuktane Janice L. Holton Thomas S. Jacques Brian N. Harding Carl Fratter Michael G. Hanna Shamima Rahman 《PloS one》2016,11(1)
Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors. 相似文献
98.
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100.
Manuel J. Steinbauer Richard Field John‐Arvid Grytnes Panayiotis Trigas Claudine Ah‐Peng Fabio Attorre H. John B. Birks Paulo A. V. Borges Pedro Cardoso Chang‐Hung Chou Michele De Sanctis Miguel M. de Sequeira Maria C. Duarte Rui B. Elias José María Fernández‐Palacios Rosalina Gabriel Roy E. Gereau Rosemary G. Gillespie Josef Greimler David E. V. Harter Tsurng‐Juhn Huang Severin D. H. Irl Daniel Jeanmonod Anke Jentsch Alistair S. Jump Christoph Kueffer Sandra Nogué Rüdiger Otto Jonathan Price Maria M. Romeiras Dominique Strasberg Tod Stuessy Jens‐Christian Svenning Ole R. Vetaas Carl Beierkuhnlein 《Global Ecology and Biogeography》2016,25(9):1097-1107