Download MendeleyStructural and mechanistic studies of mofegiline inhibition of recombinant human monoamine oxidase B.
Milczek, E.M., Bonivento, D., Binda, C., Mattevi, A., McDonald, I.A., Edmondson, D.E.(2008) J Med Chem 51: 8019-8026
- PubMed: 19053775
- DOI: https://doi.org/10.1021/jm8011867
- Primary Citation of Related Structures:
2VZ2 - PubMed 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.
Organizational Affiliation:
Department of Chemistry, Emory University, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
