Quaternary structure is an essential component that contributes to the sophisticated allosteric regulation mechanism in a key enzyme from Mycobacterium tuberculosis

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dc.contributor.authorJiao W
dc.contributor.authorBlackmore NJ
dc.contributor.authorNazmi AR
dc.contributor.authorParker EJ
dc.contributor.editorHofmann A
dc.date.accessioned2017-12-05T00:55:40Z
dc.date.available2017-12-05T00:55:40Z
dc.date.issued2017en
dc.date.updated2017-07-27T04:19:26Z
dc.description.abstractThe first enzyme of the shikimate pathway, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS), adopts a range of distinct allosteric regulation mechanisms in different organisms, related to different quaternary assemblies. DAH7PS from Mycobacterium tuberculosis (MtuDAH7PS) is a homotetramer, with the allosteric sites in close proximity to the interfaces. Here we examine the importance of the quaternary structure on catalysis and regulation, by amino acid substitution targeting the tetramer interface of MtuDAH7PS. Using only single amino acid substitutions either in, or remote from the interface, two dimeric variants of MtuDAH7PS (MtuDAH7PS F227D and MtuDAH7PS G232P ) were successfully generated. Both dimeric variants maintained activity due to the distance between the sites of amino acid substitution and the active sites, but attenuated catalytic efficiency was observed. Both dimeric variants showed significantly disrupted allosteric regulation with greatly impaired binding affinity for one of the allosteric ligands. Molecular dynamics simulations revealed changes in protein dynamics and average conformations in the dimeric variant caused by amino acid substitution remote to the tetramer interface (MtuDAH7PS G232P ), which are consistent with the observed reduction in catalytic efficiency and loss of allosteric response.en
dc.identifier.citationJiao W, Blackmore NJ, Nazmi AR, Parker EJ (2017). Quaternary structure is an essential component that contributes to the sophisticated allosteric regulation mechanism in a key enzyme from Mycobacterium tuberculosis. PLoS ONE. 12(6). e0180052-.en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0180052
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10092/14686
dc.languageEnglish
dc.language.isoen
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subject.anzsrcFields of Research::31 - Biological sciences::3101 - Biochemistry and cell biology::310106 - Enzymesen
dc.subject.anzsrcField of Research::03 - Chemical Sciences::0304 - Medicinal and Biomolecular Chemistryen
dc.titleQuaternary structure is an essential component that contributes to the sophisticated allosteric regulation mechanism in a key enzyme from Mycobacterium tuberculosisen
dc.typeJournal Articleen
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