Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism
Successful 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 cya...
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| Format: | Article |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2018.00169/full |
| _version_ | 1817977544674115584 |
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| author | Alen Albreht Irena Vovk Janez Mavri Jose Marco-Contelles Rona R. Ramsay |
| author_facet | Alen Albreht Irena Vovk Janez Mavri Jose Marco-Contelles Rona R. Ramsay |
| author_sort | Alen Albreht |
| collection | DOAJ |
| description | Successful 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. |
| first_indexed | 2024-04-13T22:17:50Z |
| format | Article |
| id | doaj.art-e83048c9959646f28a08618a7e7135f7 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-13T22:17:50Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-e83048c9959646f28a08618a7e7135f72022-12-22T02:27:25ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-05-01610.3389/fchem.2018.00169365827Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation MechanismAlen Albreht0Irena Vovk1Janez Mavri2Jose Marco-Contelles3Rona R. Ramsay4Department of Food Chemistry, National Institute of Chemistry, Ljubljana, SloveniaDepartment of Food Chemistry, National Institute of Chemistry, Ljubljana, SloveniaLaboratory of Computational Biochemistry and Drug Design, Theory Department, National Institute of Chemistry, Ljubljana, SloveniaLaboratorio de Química Médica, Instituto de Química Orgánica General (CSIC), Madrid, SpainBiomedical Sciences Research Complex, University of St Andrews, St Andrews, United KingdomSuccessful 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.https://www.frontiersin.org/article/10.3389/fchem.2018.00169/fullmonoamine oxidasepropargylamineinhibition mechanismstructureelectrostatic interactionsquantum chemical calculations |
| spellingShingle | Alen Albreht Irena Vovk Janez Mavri Jose Marco-Contelles Rona R. Ramsay Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism Frontiers in Chemistry monoamine oxidase propargylamine inhibition mechanism structure electrostatic interactions quantum chemical calculations |
| title | Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism |
| title_full | Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism |
| title_fullStr | Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism |
| title_full_unstemmed | Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism |
| title_short | Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism |
| title_sort | evidence for a cyanine link between propargylamine drugs and monoamine oxidase clarifies the inactivation mechanism |
| topic | monoamine oxidase propargylamine inhibition mechanism structure electrostatic interactions quantum chemical calculations |
| url | https://www.frontiersin.org/article/10.3389/fchem.2018.00169/full |
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