DFT study of a model system for the dealkylation step catalyzed by AlkB

Interdisciplinary Sciences, Computational Life Sciences
G Andrés Cisneros

Abstract

E. coli AlkB is a DNA repair enzyme that catalyzes the de-methylation of DNA by means of a non-heme iron and alpha-keto glutarate as a co-factor. The proposed reaction mechanism can be separated in four stages. The first stage involves the binding of the co-factor and molecular oxygen to the Fe in the active site. This is followed by the formation of a ferryl intermediate in a high-spin state, along with CO(2) and succinate. Subsequently, the O atom on the Fe center is reoriented. The last stage comprises the oxidative de-methylation of the base to produce the native DNA base and formaldehyde. This stage also includes the rate limiting step in the reaction. Here, the last stage of the proposed reaction mechanism of AlkB has been studied for a model of the active site with DFT methods. Minimum structures have been calculated for all intermediates along the path in triplet and quintet spin states. Our results point to the quintet states as more stable, in agreement with previously reported calculations. Potential energy barriers have been obtained for all the steps along this last stage in the quintet state. In the first step the oxygen bound to the Fe center of the ferryl intermediate abstracts a hydrogen atom from the methyl mo...Continue Reading

References

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Citations

Mar 4, 2014·Chemical Reviews·Guanqun ZhengChuan He
Sep 29, 2015·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Allan LohPhilip C Andrews
Jul 15, 2015·The Journal of Biological Chemistry·Bogdan I FedelesJohn M Essigmann
Sep 30, 2021·Physical Chemistry Chemical Physics : PCCP·Madison B BergerG Andrés Cisneros

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