The effect of arginine-428 mutation on modulation of activity of human liver flavin monooxygenase 3 (FMO3) by imipramine and chlorpromazine

Adali O., Carver G., Philpot R.

EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY, cilt.51, ss.271-276, 1999 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 51
  • Basım Tarihi: 1999
  • Doi Numarası: 10.1016/s0940-2993(99)80004-9
  • Dergi Adı: EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.271-276
  • Anahtar Kelimeler: flavin-containing monooxygenases, FMO3, liver, human, imipramine, chlorpromazine, KIDNEY MICROSOMES, N-OXIDATION, GENE FAMILY, METABOLISM, RABBIT, METHIONINE, FORM
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

This study was carried out to investigate the molecular basis for modulation of recombinant FMO3-catalyzed activity by the tricyclicantidepressants, imipramine and chlorpromazine. A mutant of human liver FMO3 (T428R) was formed by site-directed mutagenesis and characterized along with the native enzyme in order to elucidate a possible structure-function relationship. Functional properties of native and T428R human FMO3s were studied with methimazole as substrate. Both enzymes catalyzed the S-oxidation of methimazole with the same Km value. Imipramine modulated the activities of the native and T428R human FMO3s differently; the activity of the native FMO3 was increased at all concentrations, whereas the activity of the mutant enzyme was inhibited at concentrations above 300 mu M. Chlorpromazine activated the native enzyme at all concentrations of methimazole but activated the mutant enzyme only at high substrate concentrations. The direction (activation or inhibition) and extend of modulation of FMO3 activity is not only dependent on the concentration of the modulator, it is also dependent on the substrate concentration. This study confirms our previous findings with FMO1 that position 428 is important in the interaction of the FMO with modulators.