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首页> 外文期刊>Biochemistry >Enzymatic Mechanism of Human Apurinic/Apyrimidinic Endonuclease against a THF AP Site Model Substrate
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Enzymatic Mechanism of Human Apurinic/Apyrimidinic Endonuclease against a THF AP Site Model Substrate

机译：人尖锐的/嘧啶核糖核酸内切酶对THF AP位点模型底物的酶促机制。

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摘要

The endonucleolytic activity of human apurinic/apyrimidinic endonuclease (AP endo) is a major factor in the maintenance of the integrity of the human genome. There are estimates that this enzyme is responsible for eliminating as many as 105 potentially mutagenic and genotoxic lesions from the genome of each cell every day. Furthermore, inhibition of AP endonuclease may be effective in decreasing the dose requirements of chemotherapeutics used in the treatment of cancer as well as other diseases. Therefore, it is essential to accurately and directly characterize the enzymatic mechanism of AP endo. Here we describe specifically designed double-stranded DNA oligomers containing tetrahydrofuran (THF) with a 5′-phosphorothioate linkage as the abasic site substrate. Using H218O during the cleavage reaction and leveraging the stereochemical preferences of AP endo and T4 DNA ligase for phosphorothioate substrates, we show that AP endo acts by a one-step associative phosphoryl transfer mechanism on a THF-containing substrate.
机译：人嘌呤/嘧啶核糖核酸内切酶（AP内切酶）的内切核酸酶活性是维持人类基因组完整性的主要因素。据估计，该酶每天可从每个细胞的基因组中消除多达105个潜在的诱变和遗传毒性损伤。此外，抑制AP核酸内切酶可有效降低用于治疗癌症以及其他疾病的化学治疗剂的剂量需求。因此，准确，直接表征AP内切酶的机制至关重要。在这里，我们描述了专门设计的双链DNA寡聚体，其中包含具有5'-硫代磷酸酯键的四氢呋喃（THF）作为无碱基位点底物。在裂解反应中使用H218O并利用AP内含物和T4 DNA连接酶对硫代磷酸酯底物的立体化学偏好，我们显示AP内含物通过一步关联的磷酸基转移机制作用于含THF的底物。

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