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RESEARCH PRODUCT

Molecular Mechanism of Inhibition of DNA Methylation by Zebularine

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In this work, we have analyzed the molecular mechanism of inhibition of a C5-DNA methyltransferase by zebularine using classical and QM/MM simulations. We found that the reaction proceeds with the addition of an unprotonated cysteine to the C6 position of the ring followed by methyl transfer to the C5 position. However, while the first step is reversible and presents a moderate free-energy barrier, the second step presents a large free-energy barrier, preventing the formation of the methylated complex. This mechanistic proposal agrees with recent experimental observations that point to the formation of a reversible covalent complex between DNA containing zebularine and methyltransferases. The absence of the exocyclic amino group in zebularine, as compared to the natural substrate cytosine, makes it more difficult to reach an optimal orientation of the substrate both for cysteine addition and methyl transfer and decreases the nucleophilicity of the carbon atom to be methylated, making this step unaffordabl...