Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism.
Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism.
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DOI：
10.1016/j.dnarep.2014.07.005
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发表时间：
2014-11
期刊：
影响因子：
3.8
通讯作者：
Ziegler M
中科院分区：
文献类型：
--
作者：
Gossmann TI;Ziegler M
这项研究显示了自然选择在真核生物NAD代谢中的作用。在进化速度上存在着很大的异质性。NAD生物合成酶表现出较强的进化约束。NAD降解/信号传导酶进化得更快，并经历正向选择。PARP家族成员显示出持续的功能多样化的特征。NAD不仅是氧化还原反应中的重要辅因子，而且由于其在代谢调节、DNA修复和信号传导中的生理重要性，近年来也受到关注。与氧化还原反应相反，这些调节过程涉及NAD的降解，因此需要不断补充其细胞库。NAD生物合成酶是所有进化枝中几乎所有物种所共有的，但NAD降解酶的数量在不同分类群中有很大差异。特别地，脊椎动物，包括人类，具有多种NAD降解酶，其需要高的NAD转换。由于目前缺乏系统的研究，自然选择如何塑造参与NAD代谢的酶，我们进行了全面的进化分析的基础上种内变异和种间分歧。我们比较了四种真核生物模式物种中的NAD生物合成和降解酶，并随后关注人类NAD代谢酶及其在其他脊椎动物中的直系同源物。我们发现，大多数参与NAD代谢的酶受到不同程度的纯化选择。虽然NAD生物合成酶似乎经历了相当高水平的进化限制，但有证据表明介导NAD依赖性信号传导的酶之间存在正选择。这对于PARP家族的成员尤其明显，PARP家族是参与DNA损伤修复和程序性细胞死亡的不同蛋白质家族。基于单倍型信息和置换率分析，我们确定了正选择的潜在目标。我们还将我们的发现与三维结构联系起来，这表明正选择发生在负责DNA结合和聚合的结构域，而不是NAD催化结构域。总之，我们的研究结果表明，脊椎动物NAD代谢仍在进行功能多样化。
This study shows the role of natural selection in eukaryotic NAD metabolism. There is substantial heterogeneity in the evolutionary rates. NAD biosynthetic enzymes show stronger evolutionary constraint. NAD degrading/signaling enzymes evolve more rapidly and undergo positive selection. PARP family members show signatures of an ongoing functional diversification. NAD is not only an important cofactor in redox reactions but has also received attention in recent years because of its physiological importance in metabolic regulation, DNA repair and signaling. In contrast to the redox reactions, these regulatory processes involve degradation of NAD and therefore necessitate a constant replenishment of its cellular pool. NAD biosynthetic enzymes are common to almost all species in all clades, but the number of NAD degrading enzymes varies substantially across taxa. In particular, vertebrates, including humans, have a manifold of NAD degrading enzymes which require a high turnover of NAD. As there is currently a lack of a systematic study of how natural selection has shaped enzymes involved in NAD metabolism we conducted a comprehensive evolutionary analysis based on intraspecific variation and interspecific divergence. We compare NAD biosynthetic and degrading enzymes in four eukaryotic model species and subsequently focus on human NAD metabolic enzymes and their orthologs in other vertebrates. We find that the majority of enzymes involved in NAD metabolism are subject to varying levels of purifying selection. While NAD biosynthetic enzymes appear to experience a rather high level of evolutionary constraint, there is evidence for positive selection among enzymes mediating NAD-dependent signaling. This is particularly evident for members of the PARP family, a diverse protein family involved in DNA damage repair and programmed cell death. Based on haplotype information and substitution rate analysis we pinpoint sites that are potential targets of positive selection. We also link our findings to a three dimensional structure, which suggests that positive selection occurs in domains responsible for DNA binding and polymerization rather than the NAD catalytic domain. Taken together, our results indicate that vertebrate NAD metabolism is still undergoing functional diversification.
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通讯作者：
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