Lignin biodegradation by a cytochrome P450 enzyme: A computational study into syringol activation by GcoA

A recently characterized cytochrome P450 isozyme GcoA activates lignin components through a selective O‐demethylation or alternatively an acetal formation reaction. These are important reactions in biotechnology and since lignin is the main component in plant cell walls it is readily available. In this work we present a density functional theory study on a large active site model of GcoA to investigate syringol activation by an iron(IV)‐oxo heme cation radical oxidant (Compound I) leading to hemiacetal and acetal products. Several substrate‐binding positions were tested and full energy landscapes calculated. The study shows that substrate positioning determines the product distributions. Thus, with the phenol group pointing away from the heme, an O‐demethylation is predicted, whereas an initial hydrogen‐atom abstraction of the weak phenolic O‒H group would trigger a pathway leading to ring‐closure to form acetal products. Predictions on how to engineer P450 GcoA to get more selective product distributions are given.