Flavin-containing monooxygenase (FMO)-dependent metabolism of methionine and evidence for FMO3 being the major FMO involved in methionine sulfoxidation in rabbit liver and kidney microsomes

Abstract

Methionine was a substrate for cDNA-expressed rabbit flavin-containing monooxygenase (FMO) 1, FMO2, and FMO3, while incubations with membrane fractions containing cDNA-expressed FMO5 did not lead to the detection of methionine sulfoxide; Km values with FMO1, FMO2, and FMO3 were about 48.0, 30.0, and 6.5 mM, respectively. With FMO3 methionine d-sulfoxide was formed in nearly 8-fold higher concentrations than the l-diastereomer, whereas with FMO1 and FMO2, the d:l diastereomeric ratios were approximately 1.5:1 and 0.7:1, respectively. These results provide evidence for methionine being the first identified endogenous compound metabolized to diastereomeric sulfoxides by flavin-containing monooxygenases. The Km values for methionine sulfoxidation in rabbit liver and kidney microsomes (3.7 and 6.0 mM, respectively) were more comparable to the Km value obtained with FMO3 than FMO1 or FMO2. This result provides evidence that FMO3 is the major FMO isoform involved in methionine sulfoxidation in rabbit liver and kidney microsomes. Further evidence for this hypothesis is provided by the finding that methionine d-sulfoxide was also the preferred product in rabbit liver and kidney microsomes by nearly 8:1 and 6:1 over the l-diastereomer, respectively.