Moroz Olga V, Murzin Alexey G, Makarova Kira S, Koonin Eugene V, Wilson Keith S, Galperin Michael Y
York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK.
J Mol Biol. 2005 Mar 25;347(2):243-55. doi: 10.1016/j.jmb.2005.01.030. Epub 2005 Jan 27.
Structure-guided analysis of the new dimeric dUTPase family revealed its sequence relationship to the phage T4 dCTPase, phosphoribosyl-ATP pyrophosphatase HisE, NTP pyrophosphatase MazG, and several uncharacterized protein families, including the human protein XTP3TPA (RS21-C6), which is overexpressed in embryonic and cancer cells. Comparison with the recently determined structure of a MazG-like protein from Sulfolobus solfataricus supported the unification of these enzymes in one superfamily of all-alpha NTP pyrophosphatases, suggesting that dimeric dUTPases evolved from a tetrameric MazG-like ancestor by gene duplication. Analysis of the structure of the Sulfolobus MazG points to 2-hydroxyadenosine (isoguanosine) triphosphate, a product of oxidative damage of ATP, as the most likely substrate. We predict that uncharacterized members of this superfamily perform "house-cleaning" functions by hydrolyzing abnormal NTPs and are functionally analogous to the structurally unrelated hydrolases of the Nudix superfamily. We outline probable tertiary and quaternary structures of the all-alpha NTP pyrophosphatase superfamily members.
对新的二聚体dUTPase家族进行的结构导向分析揭示了其与噬菌体T4 dCTPase、磷酸核糖基-ATP焦磷酸酶HisE、NTP焦磷酸酶MazG以及几个未表征的蛋白质家族的序列关系，其中包括在胚胎细胞和癌细胞中过表达的人类蛋白质XTP3TPA（RS21-C6）。与最近确定的来自嗜热栖热菌的类MazG蛋白结构进行比较，支持了这些酶在所有α-NTP焦磷酸酶的一个超家族中的统一，这表明二聚体dUTPases通过基因复制从四聚体类MazG祖先进化而来。对嗜热栖热菌MazG结构的分析表明，2-羟基腺苷（异鸟苷）三磷酸（一种ATP氧化损伤的产物）是最可能的底物。我们预测，这个超家族中未表征的成员通过水解异常NTPs发挥“清理”功能，并且在功能上类似于Nudix超家族中结构不相关的水解酶。我们概述了所有α-NTP焦磷酸酶超家族成员可能的三级和四级结构。
