Reactivity of damaged pyrimidines: DNA cleavage via hemiaminal formation at the C4 positions of the saturated thymine of spore photoproduct and dihydrouridine.
Reactivity of damaged pyrimidines: DNA cleavage via hemiaminal formation at the C4 positions of the saturated thymine of spore photoproduct and dihydrouridine.
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DOI：
10.1021/ja505407p
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发表时间：
2014-09-17
影响因子：
15
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Lin G;Jian Y;Dria KJ;Long EC;Li L
本文描述了两个修饰/饱和嘧啶残基的化学反应性的机理细节，这两个修饰/饱和嘧啶残基代表了天然存在的DNA损伤形式：5-胸腺嘧啶-5，6-二氢胸腺嘧啶，通常称为“孢子光产物”（SP），和5，6-二氢-2 ′-脱氧尿苷（dHdU），在缺氧条件下通过电离辐射损伤胞嘧啶而形成，并且也用作饱和嘧啶残基的一般模型。结果表明，由于嘧啶C5-C6双键的损失和随之而来的环芳香性的损失，这两种饱和嘧啶的C4位易于通过水加成形成半缩醛胺中间体。碱性条件有利于加水;然而，在生理pH下也会以较慢的速度加水。如此形成的半缩醛胺物质随后通过嘧啶N3-C4键的裂解转化为开环水解产物。该开环产物在生理pH以上的进一步分解导致DNA链断裂形成。综上所述，这些结果表明，一旦嘧啶残基的芳香性丧失，C4位置就成为形成四面体中间体的“热点”，四面体中间体的衰变引发了消除反应的级联反应，在某些条件下可以将简单的核碱基修饰转化为DNA链断裂。
Described here are mechanistic details of the chemical reactivities of two modified/saturated pyrimidine residues that represent naturally occurring forms of DNA damage: 5-thyminyl-5,6-dihydrothymine, commonly referred to as the “spore photoproduct” (SP), and 5,6-dihydro-2′-deoxyuridine (dHdU), formed via ionizing radiation damage to cytosine under anoxic conditions and also serving as a general model of saturated pyrimidine residues. It is shown that due to the loss of the pyrimidine C5–C6 double bond and consequent loss of ring aromaticity, the C4 position of both these saturated pyrimidines is prone to the formation of a hemiaminal intermediate via water addition. Water addition is facilitated by basic conditions; however, it also occurs at physiological pH at a slower rate. The hemiaminal species so-formed subsequently converts to a ring-opened hydrolysis product through cleavage of the pyrimidine N3–C4 bond. Further decomposition of this ring-opened product above physiological pH leads to DNA strand break formation. Taken together, these results suggest that once the aromaticity of a pyrimidine residue is lost, the C4 position becomes a “hot spot” for the formation of a tetrahedral intermediate, the decay of which triggers a cascade of elimination reactions that can under certain conditions convert a simple nucleobase modification into a DNA strand break.