Caffeine is a natural compound found in plant seeds that after consumption by humans effects the central nervous system as well as the cardiovascular system. In general, the cytochrome P450 enzymes in the liver are involved in the biodegradation of caffeine, which gives paraxanthine, theobromine and theophylline products. There has been debate for many years why multiple products are obtained and how their distributions are determined. To this end we performed a high-level computational study using a combination of molecular dynamics and quantum mechanical approaches. A series of quantum chemical cluster models on the mechanism of caffeine activation by P450 model complexes give hydrogen atom abstraction barriers that predicts the correct ordering and statistical distribution of products. Our studies highlight that second-coordination sphere effects and thermochemical properties of the substrate determine the product distributions.
Keywords: density functional theory; enzyme catalysis; heme enzymes; hydroxylation; inorganic reaction mechanisms.
© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.