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首页> 外文期刊>Biochemistry >Human DNA Polymerase delta Diverged in Evolution from DNA Polymerase beta toward Specific Mn~++ Depence: a Kinetic and Thermodynamic Study
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Human DNA Polymerase delta Diverged in Evolution from DNA Polymerase beta toward Specific Mn~++ Depence: a Kinetic and Thermodynamic Study

机译：人类DNA聚合酶δ从DNA聚合酶β演变为特定的Mn〜++依赖性：动力学和热力学研究

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摘要

The recently discovered human DNA polymerase lambda (DNA pol lambda) has been implicated in translesion DNA synthesis across abasic sites. One remarkable feature of this enzyme is its preference for Mn~(2+) over Mg~(2+) as the activating metal ion, but the molecular basis for this preference is not known. Here, we present a kinetic and thermodvamic analysis of the DNA polymerase reaction catalyzed by full length human DNA pol lambda, showing that Mn~(2+) favors specifically the catalytic step of nucleotide incorporation. Besides acting as a poor coactivator for catalysis, Mg~(2+) appeared to bind also to an allosteric site, resulting in the inhibition of the synthetic activity of DNA pol lambda and in an increased sensitivity to end product (pyrophosphate) inhibition. Comparison with the closely related enzyme human DNA pol beta, as well as well as with othe rDNA synthesising enzymes (mammalian DNA pol alpha and DNA pol delta, Escherichia coli DNA pol I, and HIV-1 reverse transcriptase) indicated that these features are unique to DNA pol lambda. A deletion mutant of DNA pol lambda, which contained the highly conserved catalystic core only representing the C-terminal half of the protein, showed biochemical properties comparable to the full length enzyme but clearly different from the close homologue DNA pol beta, highlighting the existence of important differences between DNA pol lambda and DNA pol beta, despite a high degree of sequence similarity.
机译：最近发现的人类DNA聚合酶lambda（DNA pol lambda）与跨脱碱基位点的跨病变DNA合成有关。该酶的一个显着特征是它相对于Mg〜（2+）更倾向于使用Mn〜（2+）作为活化金属离子，但是这种偏好的分子基础尚不清楚。在这里，我们提出了由全长人DNA pol lambda催化的DNA聚合酶反应的动力学和热动力学分析，表明Mn〜（2+）特别有利于核苷酸掺入的催化步骤。 Mg〜（2+）除了充当催化的弱共活化剂外，似乎还与变构位点结合，导致DNA pol lambda合成活性的抑制作用以及对终产物（焦磷酸盐）抑制作用的敏感性增加。与密切相关的人类DNA polβ酶以及其他rDNA合成酶（哺乳动物DNA pol alpha和DNA pol delta，大肠杆菌DNA pol I和HIV-1逆转录酶）的比较表明，这些特征是独特的DNA pol lambda。 DNA pol lambda的缺失突变体包含高度保守的催化核心，仅代表蛋白质的C端一半，显示出与全长酶相当的生化特性，但与紧密同源的DNA pol beta明显不同，突显了尽管序列高度相似，但DNA pol lambda和DNA pol beta之间仍存在重要差异。

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