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The Journal of Physical Chemistry
Oxidative dealkylation is a unique mechanistic pathway found in the α-ketoglutarate-Fe(II)-dependent AlkB family of enzymes to remove the alkylation damage to DNA bases and regenerate nucleobases to their native state. The B3LYP density functional combined with a self-consistent reaction field was used to explore the triplet, quintet, and septet spin-state potential energy surfaces of the multistep catalytic mechanism of AlkB. The mechanism was found to consist of four stages. First, binding of dioxygen to iron in the active-site complex occurs concerted with electron transfer, thereby yielding a ferric-superoxido species. Second, competing initiation for the activation of oxygen to generate the high-valent iron−oxygen intermediates (ferryl-oxo FeIV═O and ferric-oxyl FeIII—O• species) was found to occur on the quintet and septet surfaces. Then, conformational reorientation of the activated iron−oxygen ligand was found to be nearly thermoneutral with a barrier of ca. 50 kJ mol−1. The final stage is the oxidative dealkylation of the damaged nucleobase with the rate-controlling step being the abstraction of a hydrogen atom from the damaging methyl group by the ferryl-oxo ligand. For this step, the calculated barrier of 87.4 kJ mol−1 is in good agreement with the experimental activation energy of ca. 83 kJ mol−1for the enzyme-catalyzed reaction.
Liu, Haining and Gauld, James. (2009). A DFT Study of Nucleobase Dealkylation by the DNA Repair Enzyme AlkB. The Journal of Physical Chemistry, 113 (14), 4887-4898.
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