Structural and mechanistic studies of mofegiline inhibition of recombinant human monoamine oxidase B.
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.
Milczek
Erika M
EM
Department of Chemistry, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
Bonivento
Daniele
D
Binda
Claudia
C
Mattevi
Andrea
A
McDonald
Ian A
IA
Edmondson
Dale E
DE
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*
D000498:Allyl Compounds; D002082:Butylamines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C058000:mofegiline; D002244:Carbon; D008995:Monoamine Oxidase