Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase

The reaction mechanism of human O⁶-alkylguanine-DNA alkyltransferase (AGT) is studied using density functional theory. AGT repairs alkylated DNA by directly removing the alkyl group from the O6 position of the guanine. A quantum chemical model of the active site was devised based on the recent crystal structure of the AGT–DNA complex. The potential energy curve is calculated and the stationary points are characterized. It is concluded that the previously proposed reaction mechanism is energetically plausible. In this mechanism, His146 first acts as a water-mediated general base to activate Cys145, which then performs a nucleophilic attack to dealkylate the guanine base.