The Action of Acetylenic Inhibitors on Mitochondrial Monoamine Oxidase: Structure of the Flavin Site in the Inhibited Enzyme

Maycock, Alan L.; Abeles, Robert H.; Salach, James I.; Singer, Thomas P.; M, Bernheim

doi:10.1002/9780470720219.ch3

Cited by 7 publications

(1 citation statement)

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“…Plausible covalent adduct structures and inhibition mechanisms of MAO by propargylamines were proposed by Maycock et al in 1975 (Maycock, 1975 ; Maycock et al, 1976a , b ). Proposed mechanisms without experimental evidence included: (i) an enzymatic abstraction of the propargylic proton from the inhibitor and its subsequent attack on oxidized FAD, (ii) a mechanism proceeding through radical intermediates which then collapse to form the cyanine adduct, (iii) a reduced FAD moiety reacting with an oxidized inhibitor into the covalent adduct.…”

Section: Introductionmentioning

confidence: 96%

Evidence for a Cyanine Link Between Propargylamine Drugs and Monoamine Oxidase Clarifies the Inactivation Mechanism

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 96%