Insights into the Direct Oxidative Repair of Etheno Lesions: MD and QM/MM Study on the Substrate Scope of ALKBH2 and AlkB.
Insights into the Direct Oxidative Repair of Etheno Lesions: MD and QM/MM Study on the Substrate Scope of ALKBH2 and AlkB.
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DOI：
10.1016/j.dnarep.2020.102944
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发表时间：
2020-12
期刊：
影响因子：
3.8
通讯作者：
Wetmore SD
中科院分区：
文献类型：
--
作者：
Lenz SAP;Li D;Wetmore SD
大肠杆菌ALKB和人类ALKBH2属于ALKB家族，其中包含几种α-酮戊二酸酯（α-KG）/Fe（II）依赖性的二氧酶，可修复烷基化的DNA，以促进Alkb酶的替代型α-碱基化的含量。 s。在1，N2-乙烯氨酸（1，n2-hime）上的偏好（1，N6-him-hisenoadeeniine（1，N6-εa）和3，N4-乙烯基细胞菌（3，N4-am））（1，n2-n2-hime），但是，n2-3-乙甲诺（N2-3-埃塞诺伊（n2-ethenogimg））的偏好缺乏对大肠杆菌ALKB和人类ALKBH2的差异活动的结构理解，这是由于挑战的原子体细节所涉及的一系列挑战使用实验的底物使用分子动力学（MD）模拟和ONIOM（QM：MM）计算，以确定活跃位点在结合每个乙烯加合物时如何变化，并表征了相应的催化影响。物种并允许有效相比之下，氧化是通过增加的损坏相对于Fe（IV） - 氧气部分的修复，而N2-εG的修复是通过增加的溶液来减轻活性位点的溶液，而Fe（IV） - 氧气（IV）-Oxo之间的距离更大。 Fe（IV） - 氧化物，导致禁止氧化物催化的高障碍。我们的计算提供了第一个结构性洞察力，以使ALKB和ALKBH2的实验报告的底物规范合理化，从而突出了几个活跃位点在埃塞内诺加成的维修中保留的角色，这些效果可能与这些养育策略直接相关。类似的关键生物学作用，包括表观遗传和翻译后调节。
E. coli AlkB and human ALKBH2 belong to the AlkB family enzymes, which contain several α-ketoglutarate (α-KG)/Fe(II)-dependent dioxygenases that repair alkylated DNA. Specifically, the AlkB enzymes catalyze decarboxylation of α-KG to generate a high-valent Fe(IV)-oxo species that oxidizes alkyl groups on DNA adducts. AlkB and ALKBH2 have been reported to differentially repair select etheno adducts, with preferences for 1,N6-ethenoadenine (1,N6-εA) and 3,N4-ethenocytosine (3,N4-εC) over 1,N2-ethenoguanine (1,N2-εG). However, N2,3-ethenoguanine (N2,3-εG), the most common etheno adduct, is not repaired by the AlkB enzymes. Unfortunately, a structural understanding of the differential activity of E. coli AlkB and human ALKBH2 is lacking due to challenges acquiring atomistic details for a range of substrates using experiments. This study uses both molecular dynamics (MD) simulations and ONIOM(QM:MM) calculations to determine how the active site changes upon binding each etheno adduct and characterizes the corresponding catalytic impacts. Our data reveal that the preferred etheno substrates (1,N6-εA and 3,N4-εC) form favorable interactions with catalytic residues that situate the lesion near the Fe(IV)-oxo species and permit efficient oxidation. In contrast, although the damage remains correctly aligned with respect to the Fe(IV)-oxo moiety, repair of 1,N2-εG is mitigated by increased solvation of the active site and a larger distance between Fe(IV)-oxo and the aberrant carbons. Binding of non-substrate N2,3-εG in the active site disrupts key DNA–enzyme interactions, and positions the aberrant carbon atoms even further from the Fe(IV)-oxo species, leading to prohibitively high barriers for oxidative catalysis. Overall, our calculations provide the first structural insight required to rationalize the experimentally-reported substrate specificities of AlkB and ALKBH2 and thereby highlight the roles of several active site residues in the repair of etheno adducts that directly correlates with available experimental data. These proposed catalytic strategies can likely be generalized to other α-KG/Fe(II)-dependent dioxygenases that play similar critical biological roles, including epigenetic and post-translational regulation.
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影响因子：
5.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1007/s12539-010-0092-z
发表时间：
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影响因子：
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作者：
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通讯作者：
Cisneros, G. Andres
DOI：
10.1073/pnas.0403489101
发表时间：
2004-09-28
影响因子：
11.1
作者：
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影响因子：
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