Identification of amino acid residues associated with modulation of flavin-containing monooxygenase (FMO) activity by imipramine: structure/function studies with FMO1 from pig and rabbit

Biochemistry
M K WyattR M Philpot

Abstract

The activity of the flavin-containing monooxygenase (FMO) can be modulated by a number of nitrogen-containing compounds in a manner that is both isoform and modulator-dependent. We now show that the direction (activation or inhibition) and extent of modulation can also be dependent on substrate concentration. Imipramine activates methimazole metabolism catalyzed by rabbit FMO1 or FMO2 at methimazole concentrations greater than 50 or 100 microM, respectively, and inhibits at lower methimazole concentrations. The extent of the activation increases as the substrate concentration increases, and the extent of inhibition increases as the substrate concentration decreases. With either inhibition or activation, the magnitude of the effect shows a similar, direct dependency on imipramine concentration. In contrast, imipramine inhibits the metabolism of methimazole catalyzed by pig FMO1 at all substrate concentrations. The structural basis for this unique ortholog difference between the responses of rabbit and pig FMO1 to imipramine was studied by random chimeragenesis and site-directed mutagenesis. Results with chimeras indicated that modulation of FMO1 activity by imipramine is controlled to a great extent by two areas of the FMO prima...Continue Reading

Citations

Jan 6, 2000·Archives of Biochemistry and Biophysics·B J Brock, M R Waterman
Aug 13, 1999·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·O AdaliR M Philpot
Jul 22, 2010·Journal of Veterinary Pharmacology and Therapeutics·F CapolongoC Montesissa
Jan 16, 2003·Molecular Pharmacology·Jeffrey C StevensLeslie C Engel
Sep 21, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tímea BorbásJohn R Cashman
Dec 18, 2001·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sharon K KruegerDavid E Williams

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