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dc.contributor.authorThompson, Stephen
dc.contributor.authorMcMahon, Stephen
dc.contributor.authorNaismith, Jim
dc.contributor.authorO'Hagan, David
dc.identifier.citationThompson , S , McMahon , S , Naismith , J & O'Hagan , D 2015 , ' Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme ' , Bioorganic Chemistry , vol. In press .
dc.identifier.otherPURE: 232407985
dc.identifier.otherPURE UUID: 1e308e7c-0979-45a3-93fa-46ab5de5bd9d
dc.identifier.otherRIS: urn:2699CDD888A23CB8016995DFDDB5067E
dc.identifier.otherScopus: 84948674967
dc.identifier.otherORCID: /0000-0002-0510-5552/work/68281264
dc.identifier.otherWOS: 000368533200005
dc.descriptionThe authors thank EPSRC and the Scottish Imaging Network (SINAPSE) for grants. DO’H thanks the Royal Society for a Wolfson Research Merit Award and ST is grateful to the John and Kathleen Watson Scholarship for financial support.en
dc.description.abstractThe investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5’,5’–Difluoro-5’-deoxyadenosine 7 (F2DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5’–fluoro-5’-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F2DA 7 was found, however, not to undergo the enzyme catalysed reaction with l–selenomethionine, unlike FDA 2, which undergoes reaction with l-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F2DA 7 and tartrate was solved to 1.8 Å, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of fluoride for reaction. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C–F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.
dc.relation.ispartofBioorganic Chemistryen
dc.rightsCopyright © 2015 Published by Elsevier Inc. This work is 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:
dc.subjectIsothermal titration calorimetryen
dc.subjectProtein crystallographyen
dc.subjectQD Chemistryen
dc.titleExploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzymeen
dc.typeJournal articleen
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.description.statusPeer revieweden

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