New Family of Deamination Repair Enzymes in Uracil-DNA Glycosylase Superfamily
New Family of Deamination Repair Enzymes in Uracil-DNA Glycosylase Superfamily
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DOI：
10.1074/jbc.m111.249524
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Cao, Weiguo
中科院分区：
文献类型：
--
作者：
Lee, Hyun-Wook;Dominy, Brian N.;Cao, Weiguo
DNA 糖基化酶在修复脱氨基 DNA 损伤中发挥着重要作用。先前的研究确定了尿嘧啶-DNA 糖基化酶 (UDG) 超家族中的五个家族。迄今为止研究的超家族内的所有酶均表现出尿嘧啶-DNA 糖基化酶活性。在这里，我们在 UDG 超家族中鉴定出一类缺乏 UDG 活性的新 DNA 糖基化酶。相反，这些酶在体外和体内充当次黄嘌呤-DNA 糖基化酶。分子建模和结构引导突变分析使我们能够确定此类 DNA 糖基化酶中独特的催化中心。基于前所未有的生化特性和系统发育分析，我们提出了存在于细菌、古细菌和真核生物中的这一类新的DNA修复糖基化酶家族6，并将其命名为次黄嘌呤-DNA糖基化酶家族。这项研究证明了酶功能进化中底物特异性和催化灵活性基础的结构进化性。
DNA glycosylases play a major role in the repair of deaminated DNA damage. Previous investigations identified five families within the uracil-DNA glycosylase (UDG) superfamily. All enzymes within the superfamily studied thus far exhibit uracil-DNA glycosylase activity. Here we identify a new class of DNA glycosylases in the UDG superfamily that lacks UDG activity. Instead, these enzymes act as hypoxanthine-DNA glycosylases in vitro and in vivo. Molecular modeling and structure-guided mutational analysis allowed us to identify a unique catalytic center in this class of DNA glycosylases. Based on unprecedented biochemical properties and phylogenetic analysis, we propose this new class of DNA repair glycosylases that exists in bacteria, archaea, and eukaryotes as family 6 and designate it as the hypoxanthine-DNA glycosylase family. This study demonstrates the structural evolvability that underlies substrate specificity and catalytic flexibility in the evolution of enzymatic function.