Quantum chemical exploration on the metabolic mechanisms of caffeine by flavin-containing monooxygenase

Caffeine, a ubiquitous natural product, is widely consumed by humans. The metabolic mechanisms of caffeine by flavin-containing monooxygenase (FMO) were systematically investigated in this study by quantum mechanics calculations. Four main metabolic pathways were characterized, including N-demethylations at N1-, N3-, and N7- sites (paths I-III) and C-8 oxidation (path IV). N-demethylation proceeds via the concerted homolytic cleavages of C-H and O-O bonds, while C-8 oxidation is an oxygen atom transfer mechanism. It shows that C-8 oxidation predominates over N-demethylations and trimethyluric acid is therefore the optimum metabolite of caffeine by FMO. Additionally, N3-demethylation is more favorable than N1 and N7-demethylations. This study can offer important clues for the bio-decaffeination techniques.