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

Area of Science:

• Biochemistry
• Environmental Toxicology
• Computational Chemistry

Background:

• Enzyme-catalyzed xenobiotic metabolism is crucial for toxicology and environmental health risk assessment.
• Phase I human flavin-dependent monooxygenase (FMO) enzymes, like FMO3, can convert xenobiotics into more toxic metabolites.
• Detailed mechanisms of FMO-catalyzed xenobiotic metabolism remain incompletely understood.

Purpose of the Study:

• To elucidate the diverse FMO-catalyzed oxidation reaction mechanisms of environmental pollutants using computational methods.
• To provide fundamental mechanistic insights into FMO activity toward xenobiotics.
• To aid in the high-throughput screening and theoretical prediction of FMO-mediated xenobiotic metabolism.

Main Methods:

• Systematic density functional theory (DFT) calculations were employed.
• Diverse FMO-catalyzed oxidation reactions were investigated, including denitrification, N-oxidation, desulfurization, and dehalogenation.
• Reaction mechanisms, including concerted vs. stepwise pathways and substrate-specific requirements, were analyzed.

Main Results:

• FMO primarily catalyzes reactions via the tricyclic isoalloxazine C-4a-hydroperoxide (FADHOOH) intermediate.
• FMO-catalyzed pathways are generally more favorable through concerted mechanisms.
• Deprotonation is essential for initiating oxidation of phenolic substrates, and FMO regioselectively prefers N-oxidation over N-demethylation for nicotine.
• The formation of a P-S-O triangle ring is a key step in the desulfurization of fonofos by FMO.

Conclusions:

• The study provides fundamental computational insights into FMO-catalyzed xenobiotic metabolism.
• These mechanisms can be extended to similar xenobiotic structures for improved toxicological assessment.
• The findings support the use of computational methods for high-throughput screening and theoretical predictions in environmental toxicology.