Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System.
Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System.
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DNA中脱嘌呤/脱嘧啶位点的胺催化链裂解产生的产物：来自仿生核苷模型系统的新见解。
DOI：
10.1021/acs.chemrestox.1c00408
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发表时间：
2022-02-21
影响因子：
4.1
通讯作者：
Gates, Kent S.
中科院分区：
文献类型：
--
作者：
Jha, Jay S.;Nel, Christopher;Haldar, Tuhin;Peters, Daniel;Housh, Kurt;Gates, Kent S.
非碱性位点在细胞和合成DNA中很常见。因此，重要的是表征这些病变的化学命运。在DNA中的脱碱基位点处的胺催化的链切割是一个重要的过程，其中少量开环的脱碱基醛残基转化为亚胺离子促进3'-磷酰基的β-消除。该反应在链断裂的3'-末端产生反式-α，β-不饱和亚胺鎓离子作为专性中间体。预期在AP位点处胺催化裂解的典型产物是由该亚胺离子水解产生的相应的反式-α，β-不饱和醛糖残基。有趣的是，少数研究报道了胺催化的链裂解产生的非经典3'-糖残留物，但这些产物的形成和性质还没有很好的理解。为了解决这一知识缺口，开发了一种核苷系统，该系统能够对2-脱氧核糖系统中胺催化的β-消除产生的糖残留物进行化学表征。结果预测在生理条件下在AP位点处胺催化的链切割具有可逆地产生非典型切割产物的潜力，所述非典型切割产物包括顺式-烯醛、3-硫代-2，3-二脱氧核糖和2-脱氧核糖基团以及链断裂的3 '-末端上的典型反式-烯醛残基。因此，模型反应提供的证据表明，在细胞DNA中的脱碱基位点处由胺催化的链切割产生的产物可能比通常认为的更复杂，其中反式-α，β-不饱和亚胺鎓离子中间体位于相互转化产物混合物的中心。这些结果扩展了可能的3 '-糖残留物的列表，这些残留物是由DNA中脱碱基位点的胺催化裂解产生的，必须通过化学或酶促方法去除这些残留物，以完成细胞中的碱基切除修复和单链断裂修复。
Abasic sites are common in cellular and synthetic DNA. As a result, it is important to characterize the chemical fate of these lesions. Amine-catalyzed strand cleavage at abasic sites in DNA is an important process in which conversion of small amounts of the ring-opened abasic aldehyde residue to an iminium ion facilitates β-elimination of the 3’-phosphoryl group. This reaction generates a trans-α,β-unsaturated iminium ion on the 3’-terminus of the strand break as an obligate intermediate. The canonical product expected from amine-catalyzed cleavage at an AP site is the corresponding trans-α,β-unsaturated aldehyde sugar remnant resulting from hydrolysis of this iminium ion. Interestingly, a handful of studies have reported noncanonical 3’-sugar remnants generated by amine-catalyzed strand cleavage, but the formation and properties of these products are not well understood. To address this knowledge gap, a nucleoside system was developed that enabled chemical characterization of the sugar remnants generated by amine-catalyzed β-elimination in the 2-deoxyribose system. The results predict that amine-catalyzed strand cleavage at an AP site under physiological conditions, has the potential to reversibly generate noncanonical cleavage products including cis-alkenal, 3-thio-2,3-dideoxyribose, and 2-deoxyribose groups alongside the canonical trans-alkenal residue on the 3’-terminus of the strand break. Thus, the model reactions provide evidence that the products generated by amine-catalyzed strand cleavage at abasic sites in cellular DNA may be more complex that commonly thought, with trans-α,β-unsaturated iminium ion intermediates residing at the hub of interconverting product mixtures. The results expand the list of possible 3’-sugar remnants arising from amine-catalyzed cleavage of abasic sites in DNA that must be chemically or enzymatically removed for completion of base excision repair and single-strand break repair in cells.
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影响因子：
4.1
作者：
Cai, Jian;Bhatnagar, Aruni;Pierce, William M., Jr.
通讯作者：
Pierce, William M., Jr.
影响因子：
7.4
作者：
Abbotts R;Wilson DM 3rd
通讯作者：
Wilson DM 3rd
DOI：
10.1016/0005-2787(76)90174-x
发表时间：
1976-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CRINE, P;VERLY, WG
通讯作者：
VERLY, WG
影响因子：
64.8
作者：
CRICK, F
通讯作者：
CRICK, F
影响因子：
56.9
作者：
Church, George M.;Gao, Yuan;Kosuri, Sriram
通讯作者：
Kosuri, Sriram