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dc.contributor.authorMalcomson, Thomas
dc.contributor.authorKelekci, Kemal
dc.contributor.authorBorrello, Maria T.
dc.contributor.authorGanesan, A.
dc.contributor.authorSemina, Elena
dc.contributor.authorDe Kimpe, Norbert
dc.contributor.authorMangelinckx, Sven
dc.contributor.authorRamsay, Rona R.
dc.date.accessioned2016-03-28T11:02:59Z
dc.date.available2016-03-28T11:02:59Z
dc.date.issued2015-08
dc.identifier.citationMalcomson , T , Kelekci , K , Borrello , M T , Ganesan , A , Semina , E , De Kimpe , N , Mangelinckx , S & Ramsay , R R 2015 , ' cis-Cyclopropylamines as mechanism-based inhibitors of Monoamine Oxidases ' , FEBS Journal , vol. 282 , no. 16 , pp. 3190-3198 . https://doi.org/10.1111/febs.13260en
dc.identifier.issn1742-464X
dc.identifier.otherPURE: 172755561
dc.identifier.otherPURE UUID: 38678590-7018-4999-b45f-41bf7e31e689
dc.identifier.otherScopus: 84939250541
dc.identifier.otherORCID: /0000-0003-1535-4904/work/34907346
dc.identifier.otherWOS: 000360016700015
dc.identifier.urihttp://hdl.handle.net/10023/8496
dc.descriptionWe thank our funding sources: COST Action CM1103 STSM14325 and the School of Biology at the University of St Andrews to TM; Ghent University (BOF) and the Research Foundation - Flanders (FWO - Vlaanderen) to SM; and the University of East Anglia (AG).en
dc.description.abstractCyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for the therapy of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity from docking revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. The reversible inhibition of MAO A gave high IC50 values for most compounds but sub-micromolar values with MAO B. After pre-incubation with the enzyme, the inhibition was irreversible in both MAO A and MAO B and the activity was not restored by dilution. Spectral changes during inactivation of MAO A showed bleaching at 456 nm and an increase at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective mechanism-based inhibitors without inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nM for MAO B and 170 nM for MAO A after 30 min preincubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine so could be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.
dc.language.isoeng
dc.relation.ispartofFEBS Journalen
dc.rightsCopyright 2015 FEBS. This is the peer reviewed version of the following article: cis-Cyclopropylamines as mechanism-based inhibitors of Monoamine Oxidases Malcomson, T., Kelekci, K., Borrello, M. T., Ganesan, A., Semina, E., De Kimpe, N., Mangelinckx, S. & Ramsay, R. R. Aug 2015 In : FEBS Journal. 282, 16, p. 3190-3198, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/febs.13260/abstract. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archivingen
dc.subjectFlavin adducten
dc.subjectDockingen
dc.subjectMonoamine oxidaseen
dc.subjectMechanism-based inhibitoren
dc.subjectCyclopropylamineen
dc.subjectQH301 Biologyen
dc.subjectBiochemistry, Genetics and Molecular Biology(all)en
dc.subject.lccQH301en
dc.titlecis-Cyclopropylamines as mechanism-based inhibitors of Monoamine Oxidasesen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1111/febs.13260
dc.description.statusPeer revieweden
dc.date.embargoedUntil2016-03-27


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