Caffeine Biodegradation by Cytochrome P450 1A2. What Determines the Product Distributions?

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.

Automated summary

Caffeine, a natural compound found in plant seeds, affects the central nervous system and cardiovascular system when consumed by humans. The biodegradation of caffeine in the liver involves cytochrome P450 enzymes, resulting in the production of paraxanthine, theobromine, and theophylline. Through a combination of molecular dynamics and quantum mechanical approaches, our computational study provides insights into the mechanism of caffeine activation by P450 model complexes, including the hydrogen atom abstraction barriers and the statistical distribution of products. Our findings highlight the importance of second-coordination sphere effects and thermochemical properties of the substrate in determining the product distributions.