Inhibitors alter the spectrum and redox properties of monoamine oxidase A.
Monoamine oxidase A (MAO A) catalyses the oxidation of both neurotransmitter and ingested amines. The mechanism of catalysis involves the covalently bound FAD cofactor. Although substrates and inhibitors alter the thermodynamic and kinetic properties of the flavin, how the ligands interact with the flavin is unknown. This work characterises the spectral changes that occur on inhibitor binding to MAO A and examines how the binding influences the flavin. The inhibitors, D-amphetamine, harmine, tetrindole, and befloxatone all induce similar (but not identical) changes in the spectrum of MAO A, consistent with stacking of inhibitor with the flavin in the active site. D-Amphetamine, harmine, and tetrindole stabilise the semiquinone form of FAD during reduction of MAO A by dithionite and no further reduction of these inhibitor-MAO A complexes has been observed. In contrast, semiquinone is never observed during reduction of the befloxatone-MAO A complex. Instead, partial reduction directly to the FADH(2) form occurs extremely slowly. Thus, inhibitor binding has a strong, structure-dependent influence on the environment of the flavin that alters its electronic properties.
Ramsay
Rona R
RR
Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9AL, UK. rrr@st-andrews.ac.uk
Hunter
Dominic J B
DJ
D002227:Carbazoles / Q000494:pharmacology; D003001:Cloning, Molecular; D003913:Dextroamphetamine / Q000494:pharmacology; D004227:Dithionite; D006247:Harmine / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013053:Spectrophotometry
D002227:Carbazoles; D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D011994:Recombinant Proteins; C082644:tetrindole; D004227:Dithionite; D006247:Harmine; C090014:befloxatone; D008995:Monoamine Oxidase; D003913:Dextroamphetamine