Hydrophobicity, shape, and π-electron contributions during translesion DNA synthesis

被引：0
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作者：
Zhang, Xuemei [2 ]
Lee, Irene [2 ]
Zhou, Xiang [3 ]
Berdis, Anthony J. [1 ]
机构：
[1] Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States
[2] Department of Chemistry, 2121 Euclid Avenue, Cleveland, OH 44115, United States
[3] Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, United States
来源：
Journal of the American Chemical Society | 2006年 / 128卷 / 01期
关键词：
Translesion DNA synthesis; the ability of a DNA polymerase to misinsert a nucleotide opposite a damaged DNA template; represents a common route toward mutagenesis and possibly disease development. To further define the mechanism of this promutagenic process; we synthesized and tested the enzymatic incorporation of two isosteric 5-substituted indolyl-2′deoxyriboside triphosphates opposite an abasic site. The catalytic efficiency for the incorporation of the 5-cyclohexene-indole derivative opposite an abasic site is 75-fold greater than that for the 5-cyclohexyl-indole derivative. The higher efficiency reflects a substantial increase in the kpol value (compare 25 versus 0.5 s-1; respectively) as opposed to an influence on ground-state binding of either non-natural nucleotide. The faster k pol value for the 5-cyclohexene-indole derivative indicates that π-electron density enhances the rate of the enzymatic conformational change step required for insertion opposite the abasic site. However; the kinetic dissociation constants for the non-natural nucleotides are identical and indicate that π-electron density does not directly influence ground-state binding opposite the DNA lesion. Surprisingly; each non-natural nucleotide can be incorporated opposite natural templating bases; albeit with a greatly reduced catalytic efficiency. In this instance; the lower catalytic efficiency is caused by a substantial decrease in the kpol value rather than perturbations in ground-state binding. Collectively; these data indicate that the rate of the conformational change during translesion DNA synthesis depends on π-electron density; while the enhancement in ground-state binding appears related to the size and shape of the non-natural nucleotide. © 2006 American Chemical Society;
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页码：143 / 149
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