Structural and biochemical studies of a plant formamidopyrimidine-DNA glycosylase reveal why eukaryotic Fpg glycosylases do not excise 8-oxoguanine.
Structural and biochemical studies of a plant formamidopyrimidine-DNA glycosylase reveal why eukaryotic Fpg glycosylases do not excise 8-oxoguanine.
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DOI：
10.1016/j.dnarep.2012.06.004
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发表时间：
2012-09-01
期刊：
影响因子：
3.8
通讯作者：
Doublie, Sylvie
中科院分区：
文献类型：
--
作者：
Duclos, Stephanie;Aller, Pierre;Jaruga, Pawel;Dizdaroglu, Miral;Wallace, Susan S.;Doublie, Sylvie
甲脒嘧啶-DNA糖基化酶（formamidopy嘧啶-DNA glycosylase， Fpg; MutM）是一种广泛存在于细菌体内的DNA修复酶。Fpg识别和切除氧化修饰的嘌呤，4,6-二氨基-5-甲脒嘧啶，2,6-二氨基-4-羟基-5-甲脒嘧啶和8-氧鸟嘌呤（8-oxoG），具有相似的切除动力学。它对8-氧腺苷表现出较小的活性。Fpg酶也存在于一些植物和真菌物种中。真核Fpg同源物对含有8-oxoG的DNA表现出很少或没有活性，但它们能识别和处理其氧化产物，鸟嘌呤酰脲（Gh）和螺酰亚胺酰脲（Sp）。迄今为止，已经发表了几种细菌Fpg酶的非配体结构或与含有受损碱基的DNA复合物的结构，但没有真核Fpg的结构。在这里，我们描述了植物Fpg的第一个晶体结构，拟南芥（AthFpg），非配体并结合到含有基本位点类似物四氢呋喃（THF）的DNA上。尽管AthFpg与其他Fpg糖基酶具有共同的结构，但它含有一个无锌指，这是先前在Nei酶的一个子集中描述的，如人类NEIL1和Mimivirus Nei1。重要的是，在细菌Fpg活性位点覆盖8-oxoG的“αF-β10环”在AthFpg中非常短。除了8-oxoG外，大肠杆菌Fpg （EcoFpg）中含有213 - 229残基的片段和对应的“αF-β10环”的缺失不影响对氧化损伤DNA碱基损伤的识别和去除。虽然这个环的确切作用还有待进一步探索，但现在已经很清楚，这个蛋白质片段对8-oxoG的加工是特异性的。
Formamidopyrimidine-DNA glycosylase (Fpg; MutM) is a DNA repair enzyme widely distributed in bacteria. Fpg recognizes and excises oxidatively modified purines, 4,6-diamino-5-formamidopyrimidine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine and 8-oxoguanine (8-oxoG), with similar excision kinetics. It exhibits some lesser activity toward 8-oxoadenine. Fpg enzymes are also present in some plant and fungal species. The eukaryotic Fpg homologs exhibit little or no activity on DNA containing 8-oxoG, but they recognize and process its oxidation products, guanidinohydantoin (Gh) and spiroiminohydantoin (Sp). To date, several structures of bacterial Fpg enzymes unliganded or in complex with DNA containing a damaged base have been published but there is no structure of a eukaryotic Fpg. Here we describe the first crystal structure of a plant Fpg, Arabidopsis thaliana (AthFpg), unliganded and bound to DNA containing an abasic site analog, tetrahydrofuran (THF). Although AthFpg shares a common architecture with other Fpg glycosylases, it harbors a zincless finger, previously described in a subset of Nei enzymes, such as human NEIL1 and Mimivirus Nei1. Importantly the “αF-β10 loop” capping 8-oxoG in the active site of bacterial Fpg is very short in AthFpg. Deletion of a segment encompassing residues 213 to 229 in Escherichia coli Fpg (EcoFpg) and corresponding to the “αF-β10 loop” does not affect the recognition and removal of oxidatively damaged DNA base lesions, with the exception of 8-oxoG. Although the exact role of the loop remains to be further explored, it is now clear that this protein segment is specific to the processing of 8-oxoG.
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影响因子：
14.9
作者：
Dunn AR;Kad NM;Nelson SR;Warshaw DM;Wallace SS
通讯作者：
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影响因子：
4.8
作者：
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DOI：
10.1107/s0907444904019158
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：
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DOI：
10.1107/s0907444904007929
发表时间：
2004-06-01
影响因子：
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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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