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Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform

dc.contributor.authorTheron, A.en_ZA
dc.contributor.authorRoth, R. L.en_ZA
dc.contributor.authorHoppe, H.en_ZA
dc.contributor.authorParkinson, C.en_ZA
dc.contributor.authorVan Der Westhuyzen, C. W.en_ZA
dc.contributor.authorStoychev, S.en_ZA
dc.contributor.authorWiid, I.en_ZA
dc.contributor.authorPietersen, R. D.en_ZA
dc.contributor.authorBaker, B.en_ZA
dc.contributor.authorKenyon, C. P.en_ZA
dc.date.accessioned2018-11-13T10:04:30Z
dc.date.available2018-11-13T10:04:30Z
dc.date.issued2017-03-29
dc.identifier.citationTheron, A., et al. 2017. Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform. PLoS ONE, 12(10):e0185068, doi:10.1371/ journal.pone.0185068
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0185068
dc.identifier.urihttp://hdl.handle.net/10019.1/104680
dc.descriptionCITATION: Theron, A., et al. 2017. Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform. PLoS ONE, 12(10):e0185068, doi:10.1371/journal.pone.0185068.
dc.descriptionThe original publication is available at https://journals.plos.org/plosone
dc.description.abstractENGLISH ABSTRACT: Glutamine synthetase is a ubiquitous central enzyme in nitrogen metabolism that is controlled by up to four regulatory mechanisms, including adenylylation of some or all of the twelve subunits by adenylyl transferase. It is considered a potential therapeutic target for the treatment of tuberculosis, being essential for the growth of Mycobacterium tuberculosis, and is found extracellularly only in the pathogenic Mycobacterium strains. Human glutamine synthetase is not regulated by the adenylylation mechanism, so the adenylylated form of bacterial glutamine synthetase is of particular interest. Previously published reports show that, when M. tuberculosis glutamine synthetase is expressed in Escherichia coli, the E. coli adenylyl transferase does not optimally adenylylate the M. tuberculosis glutamine synthetase. Here, we demonstrate the production of soluble adenylylated M. tuberulosis glutamine synthetase in E. coli by the co-expression of M. tuberculosis glutamine synthetase and M. tuberculosis adenylyl transferase. The differential inhibition of adenylylated M. tuberulosis glutamine synthetase and deadenylylated M. tuberulosis glutamine synthetase by ATP based scaffold inhibitors are reported. Compounds selected on the basis of their enzyme inhibition were also shown to inhibit M. tuberculosis in the BACTEC 460TB™ assay as well as the intracellular inhibition of M. tuberculosis in a mouse bone-marrow derived macrophage assay.en_ZA
dc.description.urihttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185068
dc.format.extent22 pages : illustrationsen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.subjectTuberculosisen_ZA
dc.subjectGlutamine synthetaseen_ZA
dc.subjectMycobacterium tuberculosisen_ZA
dc.subjectTuberculosis -- Chemotherapyen_ZA
dc.subjectMultidrug resistanceen_ZA
dc.titleDifferential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platformen_ZA
dc.typeArticleen_ZA
dc.description.versionPublisher's version
dc.rights.holderAuthors retain copyrighten_ZA


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