How well is enzyme function conserved as a function of pairwise sequence identity?
How well is enzyme function conserved as a function of pairwise sequence identity?
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DOI：
10.1016/j.jmb.2003.08.057
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发表时间：
2003-10-31
影响因子：
5.6
通讯作者：
Skolnick, J
中科院分区：
文献类型：
--
作者：
Tian, WD;Skolnick, J
酶功能保守性已被用来推导将功能从已知功能的蛋白质转移到未知蛋白质所需的序列同一性阈值。通过成对序列比较，多项研究表明，当序列同一性高于 40% 时，酶功能得到很好的保守。相反，罗斯特认为，由于数据库偏差，这种简单的成对比较的结果可能会产生误导。因此，通过根据序列相似性将酶序列分为家族并选择代表性序列进行比较，他发现当序列同一性低于70%时，酶功能开始迅速分化。在这里，我们采用类似于 Rost 的策略来减少数据库偏差；然而，我们不仅根据序列相似性，而且根据功能相似性对酶家族进行分类，即每个家族中的序列必须具有相同的四位数字或相同的酶委员会（EC）编号的前三位数字。此外，我们不是选择代表性序列进行比较，而是计算每个酶家族的功能保守性，然后对所有酶家族的酶功能保守程度进行平均。我们的分析表明，对于功能可转移性，40% 序列同一性仍然可以用作转移 EC 编号前三位数字的置信阈值；然而，要转移 EC 编号的所有四位数字，需要 60% 以上的序列同一性才能获得至少 90% 的准确性。此外，当使用PSI-BLAST时，发现E值的大小与PSI-BLAST第三次迭代中酶功能保守的程度弱相关。因此，应谨慎使用基于 PSI-BLAST E 值的功能注释。我们还表明，通过采用酶家族特异性序列同一性阈值（高于该阈值需要 100% 功能保守性），可以准确地完成未知序列的功能推断。然而，这是有代价的：低于此阈值的那些真阳性序列无法被唯一识别。 (C) 2003 年，爱思唯尔有限公司出版。
Enzyme function conservation has been used to derive the threshold of sequence identity necessary to transfer function from a protein of known function to an unknown protein. Using pairwise sequence comparison, several studies suggested that when the sequence identity is above 40%, enzyme function is well conserved. In contrast, Rost argued that because of database bias, the results from such simple pairwise comparisons might be misleading. Thus, by grouping enzyme sequences into families based on sequence similarity and selecting representative sequences for comparison, he showed that enzyme function starts to diverge quickly when the sequence identity is below 70%. Here, we employ a strategy similar to Rost's to reduce the database bias; however, we classify enzyme families based not only on sequence similarity, but also on functional similarity, i.e. sequences in each family must have the same four digits or the same first three digits of the enzyme commission (EC) number. Furthermore, instead of selecting representative sequences for comparison, we calculate the function conservation of each enzyme family and then average the degree of enzyme function conservation across all enzyme families. Our analysis suggests that for functional transferability, 40% sequence identity can still be used as a confident threshold to transfer the first three digits of an EC number; however, to transfer all four digits of an EC number, above 60% sequence identity is needed to have at least 90% accuracy. Moreover, when PSI-BLAST is used, the magnitude of the E-value is found to be weakly correlated with the extent of enzyme function conservation in the third iteration of PSI-BLAST. As a result, functional annotation based on the E-values from PSI-BLAST should be used with caution. We also show that by employing an enzyme family-specific sequence identity threshold above which 100% functional conservation is required, functional inference of unknown sequences can be accurately accomplished. However, this comes at a cost: those true positive sequences below this threshold cannot be uniquely identified. (C) 2003 Published by Elsevier Ltd.