Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.
Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.
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DOI：
10.1093/nar/gkv1469
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发表时间：
2016-01-29
影响因子：
14.9
通讯作者：
David SS
中科院分区：
文献类型：
--
作者：
Woods RD;O'Shea VL;Chu A;Cao S;Richards JL;Horvath MP;David SS
MutY腺嘌呤糖基化酶通过将腺嘌呤从促突变的8-氧代-7，8-二氢鸟嘌呤（OG）：A错配中切除来防止DNA突变。在这里，我们描述的MutY活性位点绑定到azaribose过渡态类似物的结构特征，这表明了催化作用的Tyr 126和方法的水亲核试剂在同一侧的离开腺嘌呤基地。Tyr 126参与催化的想法，最近通过建模计算预测，强烈支持诱变和看到这个残基的羟基和过渡态类似物的azaribose部分之间的密切接触。MutY甲醇分解产物的NMR分析证实了腺嘌呤去除与保留立体化学的机制。基于这些结果，我们提出了一个修订的机制MutY，涉及两个亲核置换步骤类似的机制接受的“保留”O-糖苷酶。这种新的MutY但熟悉的机制也可能在相关的碱基切除修复糖基化酶中起作用，并为分析与遗传性结直肠癌相关的人类MutY（MUTYH）变体提供了一个关键框架。
MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for ‘retaining’ O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer.
影响因子：
2.9
作者：
Admiraal SJ;O'Brien PJ
通讯作者：
O'Brien PJ