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pH-Dependent Equilibrium between 5-Guanidinohydantoin and Iminoallantoin Affects Nucleotide Insertion Opposite the DNA Lesion

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Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States
Center for High Performance Computing, University of Utah, Salt Lake City, Utah 84112-0190, United States
*Phone: (801) 585-7290. E-mail: [email protected]
Cite this: J. Org. Chem. 2016, 81, 2, 351–359
Publication Date (Web):November 19, 2015
Copyright © 2015 American Chemical Society

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    Four-electron oxidation of 2′-deoxyguanosine (dG) yields 5-guanidinohydantoin (dGh) as a product. Previously, we hypothesized that dGh could isomerize to iminoallantoin (dIa) via a mechanism similar to the isomerization of allantoin. The isomerization reaction was monitored by HPLC and found to be pH dependent with a transition pH = 10.1 in which dGh was favored at low pH and dIa was favored at high pH. The structures for these isomers were confirmed by UV–vis, MS, and 1H and 13C NMR. Additionally, the UV–vis and NMR experimental results are supported by density functional theory calculations. A mechanism is proposed to support the pH dependency of the isomerization reaction. Next, we noted the hydantoin ring of dGh mimics thymine, while the iminohydantoin ring of dIa mimics cytosine; consequently, a dGh/dIa site was synthesized in a DNA template strand, and standing start primer extension studies were conducted with Klenow fragment exo. The dATP/dGTP insertion ratio opposite the dGh/dIa site as a function of pH was evaluated from pH 6.5–9.0. At pH 6.5, only dATP was inserted, but as the pH increased to 9.0, the amount of dGTP insertion steadily increased. This observation supports dGh to dIa isomerization in DNA with a transition pH of ∼8.2.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.5b02180.

    • LC-ESI+-MS, HRMS, 1H and 13C NMR, and PAGE analysis for the polymerase studies, dihedral scan energies, and coordinates for DFT-optimized structures (PDF)

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