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dc.contributor.authorAlbreht, Alen
dc.contributor.authorVovk, Irena
dc.contributor.authorMavri, Janez
dc.contributor.authorMarco-Contelles, Jose
dc.contributor.authorRamsay, Rona R.
dc.identifier.citationAlbreht , A , Vovk , I , Mavri , J , Marco-Contelles , J & Ramsay , R R 2018 , ' Evidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanism ' , Frontiers in Chemistry , vol. 6 , 169 .
dc.identifier.otherPURE: 253086779
dc.identifier.otherPURE UUID: ae51e775-56ee-48d8-992b-062770712e83
dc.identifier.otherScopus: 85048241260
dc.identifier.otherORCID: /0000-0003-1535-4904/work/45366199
dc.identifier.otherWOS: 000433176600001
dc.descriptionThe authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P1-0005 and P1-0012). We thank COST CA15135 for facilitating collaboration on multi-target compounds and providing support for publication. Part of this work was also supported by the bilateral cooperation between the Royal Society of Edinburgh and the Slovenian Academy of Sciences and Arts and by COST Action CM1103 which facilitated short research visits in Ljubljana and St Andrews, respectively.en
dc.description.abstractSuccessful propargylamine drugs such as deprenyl inactivate monoamine oxidase (MAO), a target in multi-faceted approaches to prevent neurodegeneration in the aging population, but the chemical structure and mechanism of the irreversible inhibition are still debated. We characterized the covalent cyanine structure linking the multi-target propargylamine inhibitor ASS234 and the flavin adenine dinucleotide in MAO-A using a combination of ultra-high performance liquid chromatography, spectroscopy, mass spectrometry, and computational methods. The partial double bond character of the cyanine chain gives rise to 4 interconverting geometric isomers of the adduct which were chromatographically separated at low temperatures. The configuration of the cyanine linker governs adduct stability with segments of much higher flexibility and rigidity than previously hypothesized. The findings indicate the importance of intramolecular electrostatic interactions in the MAO binding site and provide key information relevant to incorporation of the propargyl moiety into novel multi-target drugs. Based on the structure, we propose a mechanism of MAO inactivation applicable to all propargylamine inhibitors.
dc.relation.ispartofFrontiers in Chemistryen
dc.rightsCopyright © 2018 Albreht, Vovk, Mavri, Marco-Contelles and Ramsay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en
dc.subjectMonoamine oxidaseen
dc.subjectInhibition mechanismen
dc.subjectElectrostatic interactionsen
dc.subjectQuantum chemical calculationsen
dc.subjectQD Chemistryen
dc.subjectRM Therapeutics. Pharmacologyen
dc.titleEvidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanismen
dc.typeJournal articleen
dc.contributor.sponsorThe Royal Society of Edinburghen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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