Environmental biotransformation mechanisms by flavin-dependent monooxygenase: A computational study

The enzyme-catalyzed metabolic biotransformation of xenobiotics plays a significant role in toxicology evolution and subsequently environmental health risk assessment. Recent studies noted that the phase I human flavin-dependent monooxygenase (e.g., FMO3) can catalyze xenobiotics into more toxic metabolites. However, de-tails of the metabolic mechanisms are insufficient. To fill the mechanism in the gaps, the systemic density functional theory calculations were performed to elucidate diverse FMO-catalyzed oxidation reactions toward environmental pollutants, including denitrification (e.g., nitrophenol), N-oxidation (e.g., nicotine), desulfuriza-tion (e.g., fonofos), and dehalogenation (e.g., pentachlorophenol). Similar to the active center compound 0 of cytochrome P450, FMO mainly catalyzed reactions with the structure of the tricyclic isoalloxazine C-4a-hy-droperoxide (FADHOOH). As will be shown, FMO-catalyzed pathways are more favorable with a concerted than stepwise mechanism; Deprotonation is necessary to initiate the oxidation reactions for phenolic substrates; The regioselectivity of nicotine by FMO prefers the N-oxidation other than N-demethylation pathway; Formation of the P-S-O triangle ring is the key step for desulfurization of fonofos by FMO. We envision that these fundamental mechanisms catalyzed by FMO with a computational method can be extended to other xenobiotics of similar structures, which may aid the high-throughput screening and provide theoretical predictions in the future.

Automated summary

The enzyme-catalyzed metabolic biotransformation of xenobiotics is crucial in toxicology evolution and environmental health risk assessment. Recent research focuses on the role of human flavin-dependent monooxygenase (FMO3) in catalyzing xenobiotics to more toxic metabolites, but details of the metabolic mechanisms are lacking. This study elucidates the diverse FMO-catalyzed oxidation reactions of environmental pollutants through systematic density functional theory calculations, providing insights into the regioselectivity and key steps of these reactions. The findings can be extended to aid the screening and prediction of similar xenobiotics in the future.