Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/151959
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dc.contributor.authorZhong, Wenheen_US
dc.contributor.authorGuo, Jingjingen_US
dc.contributor.authorCui, Liangen_US
dc.contributor.authorChionh, Yok Hianen_US
dc.contributor.authorLi, Kuohanen_US
dc.contributor.authorEl Sahili, Abbasen_US
dc.contributor.authorCai, Qixuen_US
dc.contributor.authorYuan, Mengen_US
dc.contributor.authorMichels, Paul A. M.en_US
dc.contributor.authorFothergill-Gilmore, Linda A.en_US
dc.contributor.authorWalkinshaw, Malcolm D.en_US
dc.contributor.authorMu, Yuguangen_US
dc.contributor.authorLescar, Julienen_US
dc.contributor.authorDedon, Peter C.en_US
dc.date.accessioned2021-07-08T02:06:48Z-
dc.date.available2021-07-08T02:06:48Z-
dc.date.issued2019-
dc.identifier.citationZhong, W., Guo, J., Cui, L., Chionh, Y. H., Li, K., El Sahili, A., Cai, Q., Yuan, M., Michels, P. A. M., Fothergill-Gilmore, L. A., Walkinshaw, M. D., Mu, Y., Lescar, J. & Dedon, P. C. (2019). Pyruvate kinase regulates the pentose-phosphate pathway in response to hypoxia in mycobacterium tuberculosis. Journal of Molecular Biology, 431(19), 3690-3705. https://dx.doi.org/10.1016/j.jmb.2019.07.033en_US
dc.identifier.issn0022-2836en_US
dc.identifier.urihttps://hdl.handle.net/10356/151959-
dc.description.abstractIn response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate-pyruvate-oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose monophosphate inhibitors or the activator glucose 6-phosphate (G6P) to MtbPYK tightly regulates the metabolic flux. Intriguingly, pentose monophosphates were found to share the same binding site with G6P. The determination of a crystal structure of MtbPYK with bound ribose 5-phosphate (R5P), combined with biochemical analyses and molecular dynamic simulations, revealed that the allosteric inhibitor pentose monophosphate increases PYK structural dynamics, weakens the structural network communication, and impairs substrate binding. G6P, on the other hand, primes and activates the tetramer by decreasing protein flexibility and strengthening allosteric coupling. Therefore, we propose that MtbPYK uses these differences in conformational dynamics to up- and down-regulate enzymic activity. Importantly, metabolome profiling in mycobacteria reveals a significant increase in the levels of pentose monophosphate during hypoxia, which provides insights into how PYK uses dynamics of the tetramer as a competitive allosteric mechanism to retard glycolysis and facilitate metabolic reprogramming toward the pentose-phosphate pathway for achieving redox balance and an anticipatory metabolic response in Mtb.en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.description.sponsorshipNational Research Foundation (NRF)en_US
dc.language.isoenen_US
dc.relationNMRC/CBRG/ 0073/2014en_US
dc.relationRG146/17en_US
dc.relation.ispartofJournal of Molecular Biologyen_US
dc.rights© 2019 Elsevier Ltd. All rights reserved. This paper was published in Journal of Molecular Biology and is made available with permission of Elsevier Ltd.en_US
dc.subjectScience::Biological sciencesen_US
dc.titlePyruvate kinase regulates the pentose-phosphate pathway in response to hypoxia in mycobacterium tuberculosisen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.researchInstitute of Structural Biologyen_US
dc.contributor.researchSingapore Centre for Environmental Life Sciences and Engineering (SCELSE)en_US
dc.contributor.researchSingapore-MIT Alliance for Research and Technologyen_US
dc.identifier.doi10.1016/j.jmb.2019.07.033-
dc.description.versionAccepted versionen_US
dc.identifier.pmid31381898-
dc.identifier.scopus2-s2.0-85070557671-
dc.identifier.issue19en_US
dc.identifier.volume431en_US
dc.identifier.spage3690en_US
dc.identifier.epage3705en_US
dc.subject.keywordsAllosteric Regulationen_US
dc.subject.keywordsStructural Dynamicsen_US
dc.description.acknowledgementThis research was supported by the National Research Foundation of Singapore through the Singapore–MIT Alliance for Research and Technology Antimicrobial Resistance research program, and a Singapore–MIT Alliance for Research and Technology Postdoctoral Fellowship (W.Z.). During the course of this study, the J.L. laboratory was supported by grant NMRC/CBRG/ 0073/2014. The Y. M. laboratory was supported by the grant of MOE Tier 1 RG146/17 from Ministry of Education Singapore.en_US
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