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dc.contributor.authorBello, Davide
dc.contributor.authorRubanu, Maria Grazia
dc.contributor.authorBandaranayaka, Nouchali
dc.contributor.authorGötze, Jan. P.
dc.contributor.authorBühl, Michael
dc.contributor.authorO'Hagan, David
dc.date.accessioned2020-03-29T00:32:00Z
dc.date.available2020-03-29T00:32:00Z
dc.date.issued2019-05-02
dc.identifier.citationBello , D , Rubanu , M G , Bandaranayaka , N , Götze , J P , Bühl , M & O'Hagan , D 2019 , ' Acetyl coenzyme A analogues as rationally designed inhibitors of citrate synthase ' , ChemBioChem , vol. 20 , no. 9 , pp. 1174-1182 . https://doi.org/10.1002/cbic.201800700en
dc.identifier.issn1439-4227
dc.identifier.otherPURE: 257337674
dc.identifier.otherPURE UUID: 5e244294-a820-4889-9a15-0fdf758c8b60
dc.identifier.otherRIS: urn:F49DA2F0A70BE27DA6A2078040DD5C18
dc.identifier.otherScopus: 85063648758
dc.identifier.otherORCID: /0000-0002-1095-7143/work/56184269
dc.identifier.otherWOS: 000471317500013
dc.identifier.otherORCID: /0000-0002-0510-5552/work/68281230
dc.identifier.urihttp://hdl.handle.net/10023/19724
dc.descriptionAuthors thank the EPSRC (Grant EP/N03001X/1) for financial support.en
dc.description.abstractIn this study, we probed the inhibition of pig heart citrate synthase (E.C. 4.1.3.7) by synthesising seven analogues either designed to mimic the proposed enolate intermediate in this enzyme reaction or developed from historical inhibitors. The most potent inhibitor was fluorovinyl thioether 9 (Ki=4.3 μm), in which a fluorine replaces the oxygen atom of the enolate. A comparison of the potency of 9 with that of its non‐fluorinated vinyl thioether analogue 10 (Ki=68.3 μm) revealed a clear “fluorine effect” favouring 9 by an order of magnitude. The dethia analogues of 9 and 10 proved to be poor inhibitors. A methyl sulfoxide analogue was a moderate inhibitor (Ki=11.1 μm), thus suggesting hydrogen bonding interactions in the enolate site. Finally, E and Z propenoate thioether isomers were explored as conformationally constrained carboxylates, but these were not inhibitors. All compounds were prepared by the synthesis of the appropriate pantetheinyl diol and then assembly of the coenzyme A structure according to a three‐enzyme biotransformation protocol. A quantum mechanical study, modelling both inhibitors 9 and 10 into the active site indicated short CF ⋅⋅⋅ H contacts of ≈2.0 Å, consistent with fluorine making two stabilising hydrogen bonds, and mimicking an enolate rather than an enol intermediate. Computation also indicated that binding of 9 to citrate synthase increases the basicity of a key aspartic acid carboxylate, which becomes protonated.
dc.language.isoeng
dc.relation.ispartofChemBioChemen
dc.rightsCopyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1002/cbic.201800700en
dc.subjectCitrate synthaseen
dc.subjectMechanismen
dc.subjectEnzyme inhibitionen
dc.subjectOrgano-fluorine chemistryen
dc.subjectCoenzyme A analoguesen
dc.subjectQD Chemistryen
dc.subjectNDASen
dc.subject.lccQDen
dc.titleAcetyl coenzyme A analogues as rationally designed inhibitors of citrate synthaseen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Chemistryen
dc.contributor.institutionUniversity of St Andrews.EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1002/cbic.201800700
dc.description.statusPeer revieweden
dc.date.embargoedUntil2020-03-29


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