Flavin-Containing Monooxygenases Mediate Resistance to Nereistoxin Insecticides in Lepidopteran Pests: Insights into Conserved Tertiary Amine Oxidation Mechanisms

This study elucidates the molecular mechanism by which flavin-containing monooxygenase (FMO) mediates metabolic resistance to nereistoxin insecticides in lepidopteran pests. A field population of <i>Spodoptera exigua</i> exhibited 50-fold resistance with upregulated SeFMO expression. Using FMO-specific inhibitors, recombinant protein expression, and mass spectrometry, we confirmed that FMO catalyzes <i>N</i>-oxidation of nereistoxin insecticide at the tertiary amine nitrogen. Molecular docking revealed that insect FMO's catalytic mechanism resembles that of human FMO. Transgenic <i>Drosophila</i> models demonstrated that the FMO-mediated <i>N</i>-oxidation enhances insecticide resistance, indicating evolutionary conservation. This highlights FMO's role in insecticide detoxification and its conserved function across species, providing new insights into pest resistance mechanisms.