title: Structural and mechanistic studies of mofegiline inhibition of recombinant human monoamine oxidase B.
abstract: Mechanistic and structural studies have been carried out to investigate the molecular basis for the irreversible inhibition of human MAO-B by mofegiline. Competitive inhibition with substrate shows an apparent K(i) of 28 nM. Irreversible inhibition of MAO-B occurs with a 1:1 molar stoichiometry with no observable catalytic turnover. The absorption spectral properties of mofegiline inhibited MAO-B show features (lambda(max) approximately 450 nm) unlike those of traditional flavin N(5) or C(4a) adducts. Visible and near-UV circular dichroism spectra of the mofegiline-MAO-B adduct shows a negative peak at 340 nm with an intensity similar to that of N(5) flavocyanine adducts. The X-ray crystal structure of the mofegiline-MAO-B adduct shows a covalent bond between the flavin cofactor N(5) with the distal allylamine carbon atom as well as the absence of the fluorine atom. A mechanism to explain these structural and spectral data is proposed.
authors.affiliation: Department of Chemistry, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Milczek
authors.forename: Daniele
authors.initials: D
authors.lastname: Bonivento
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.forename: Ian A
authors.initials: IA
authors.lastname: McDonald
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson
mesh_terms: D000498:Allyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002082:Butylamines / Q000737:chemistry* / Q000494:pharmacology*; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry*
chemical_list: D000498:Allyl Compounds; D002082:Butylamines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C058000:mofegiline; D002244:Carbon; D008995:Monoamine Oxidase