AlkB is the title protein of a family of enzymes that catalyze the direct oxidative de-alkylation of several substrates including DNA and RNA. AlkB repairs damaged single--stranded DNA, with preference for 1-methyl adenine (1meA) and 3-methyl cytosine (3meC). The proposed mechanism for repair involves the formation of an Fe(IV)-oxo intermediate, which abstracts an H atom from the methyl moiety, followed by rebound of the OH and dissociation of the resulting methoxide to obtain the repaired adenine base and formaldehyde. We will present results based on <i>ab initio</i> QM/MM, quantum topological and orbital analysis calculations, which support an alternative mechanism. The proposed pathway involves a hydroxide bound to the Fe atom. The mechanisms for both the originally proposed pathway and the new pathway will be discussed and compared to available experimental data. Our results also provide a possible explanation for the substrate preference of AlkB.

Ab initio QM/MM simulations point to an alternative mechanism for the AlkB catalyzed repair of 1-methyl adenine

249th National Meeting (2015)

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