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71.
Mulji A Haslam C Brown F Randle R Karamshi B Smith J Eagle R Munoz-Muriedas J Taylor J Sheikh A Bridges A Gill K Jepras R Smee P Barker M Woodrow M Liddle J Thomas P Jones E Gordon L Tanner R Leveridge M Hutchinson S Martin M Brown M Kruidenier L Katso R 《Journal of biomolecular screening》2012,17(1):108-120
The biological complexity associated with the regulation of histone demethylases makes it desirable to configure a cellular mechanistic assay format that simultaneously encompasses as many of the relevant cellular processes as possible. In this report, the authors describe the configuration of a JMJD3 high-content cellular mechanistic imaging assay that uses single-cell multiparameter measurements to accurately assess cellular viability and the enzyme-dependent demethylation of the H3K27(Me)3 mark by exogenously expressed JMJD3. This approach couples robust statistical analyses with the spatial resolving power of cellular imaging. This enables segregation of expressing and nonexpressing cells into discrete subpopulations and consequently pharmacological quantification of compounds of interest in the expressing population at varying JMJD3 expression levels. Moreover, the authors demonstrate the utility of this hit identification strategy through the successful prosecution of a medium-throughput focused campaign of an 87 500-compound file, which has enabled the identification of JMJD3 cellular-active chemotypes. This study represents the first report of a demethylase high-content imaging assay with the ability to capture a repertoire of pharmacological tools, which are likely both to inform our mechanistic understanding of how JMJD3 is modulated and, more important, to contribute to the identification of novel therapeutic modalities for this demethylase enzyme. 相似文献
72.
Parsons JB Dinesh SD Deery E Leech HK Brindley AA Heldt D Frank S Smales CM Lünsdorf H Rambach A Gass MH Bleloch A McClean KJ Munro AW Rigby SE Warren MJ Prentice MB 《The Journal of biological chemistry》2008,283(21):14366-14375
Many heterotrophic bacteria have the ability to make polyhedral structures containing metabolic enzymes that are bounded by a unilamellar protein shell (metabolosomes or enterosomes). These bacterial organelles contain enzymes associated with a specific metabolic process (e.g. 1,2-propanediol or ethanolamine utilization). We show that the 21 gene regulon specifying the pdu organelle and propanediol utilization enzymes from Citrobacter freundii is fully functional when cloned in Escherichia coli, both producing metabolosomes and allowing propanediol utilization. Genetic manipulation of the level of specific shell proteins resulted in the formation of aberrantly shaped metabolosomes, providing evidence for their involvement as delimiting entities in the organelle. This is the first demonstration of complete recombinant metabolosome activity transferred in a single step and supports phylogenetic evidence that the pdu genes are readily horizontally transmissible. One of the predicted shell proteins (PduT) was found to have a novel Fe-S center formed between four protein subunits. The recombinant model will facilitate future experiments establishing the structure and assembly of these multiprotein assemblages and their fate when the specific metabolic function is no longer required. 相似文献
73.
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75.
Kenneth B. Raper Ann C. Worley Terrence A. Kurzynski 《American journal of botany》1978,65(9):1011-1026
A new genus of cellular slime molds, Copromyxella, is described together with four species that comprise it. Since it resembles Zopf's Copromyxa more than any genus presently recognized, but differs from it in important characteristics such as the smaller dimensions of its cellular elements and the delicacy of its fructifications, the name Copromyxella is chosen for the new taxon. Four species are included: C. silvatica, C. filamentosa, C. spicata, and C. coralloides. All are characterized by small myxamoebae with lobose and potentially “explosive” pseudopodia and may assume limax forms in liquid media; all possess nuclei with centrally positioned nucleoli; all lack true contractile vacuoles (with a single possible exception); all aggregate without stream formation; and all form fructifications with no demarcation into stalks and sori. Taxonomically the genus belongs in the Acrasidae with Copromyxa, Guttulinopsis and Acrasis rosea rather than in the better known Dictyostelidae that includes Dictyostelium and Polysphondylium. 相似文献
76.
77.
A series of eight novel, highly modified mono-, di- and trisaccharide derivatives, each containing an iminoalditol moiety, has been synthesized in the quest for potential heparanase inhibitors. 相似文献
78.
Helen M. Cockerton Robert J. Vickerstaff Amanda Karlström Fiona Wilson Maria Sobczyk Joe Q. He Daniel J. Sargent Andy J. Passey Kirsty J. McLeary Katalin Pakozdi Nicola Harrison Maria Lumbreras-Martinez Laima Antanaviciute David W. Simpson Richard J. Harrison 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2018,131(9):1995-2007
79.
Hend A.A. Abd El-wahab Mauro Accietto Leonardo B. Marino Kirsty J. McLean Colin W. Levy Hamdy M. Abdel-Rahman Mahmoud A. El-Gendy Andrew W. Munro Ahmed S. Aboraia Claire Simons 《Bioorganic & medicinal chemistry》2018,26(1):161-176
Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC?=?12.5?μg/mL, 17a 50?μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2?Å. A model generated from a 1.5?Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target. 相似文献