哺乳动物细胞色素P450酶中底物识别位点与功能的进化关系

Evolutionary Relationship of Substrate Recognition Sites with Protein Functions of Mammalian Cytochrome P450 Enzymes

细胞色素P450（cytochromeP450，CYP）酶存在于所有哺乳动物中，它们从共同的祖先通过基因倍增进化而来，以一种“爆炸性”的趋势形成了庞大的超家族。除代谢脂质等内源性物质外，部分CYP酶还在药物等外源性物质的代谢方面起到重要作用。通过收集和注释哺乳动物CYP酶的序列发现，家族规模发生显著变化的七个活跃亚家族均属于CYPl～4家族．相比之下，非CYPl～4家族的家族规模则基本保持稳定。基于二级结构的预测结果，六段底物识别位点（substrerecognitionsites，SRSs）的进化速率在CYPl～4家族中，特别是活跃的亚家族中，也显著快于非CYPl～4家族。同时，SRSl～3的进化速率显著快于SRS4~6，说明SRSl．3在更大程度上决定了CYP酶在进化过程中所获得的新功能。

Cytochrome P450 （CYPs） enzymes exist in all kinds of mammals, which are descended from a single common ancestor via gene duplication and constitute a large superfamily through the expansion. Besides the lipid metabolism, CYPs are also engaged in the xenobiotics biodegradation and metabolism, especially the members of human CYP1~4 families which play important roles in drug metabolism. Seven active subfamilies （CYP2A, CYP2C, CYP2D, CYP2E, CYP2J, CYP3A and CYP4F） were found by sequence alignment and annotation, which have a strong trend to expand or shrink on the scale of family size during the evolution. In contrast, the family size of non-CYP1-4 families remains nearly the same among mammals. Evolutionary rates of six substrate recognition sites （SRSs） in CYP1-4 families, especially in the active subfamilies, are significantly higher than those in other families. In addition, SRS1-3 have faster evolutionary rates than SRS4~6, which indicates that SRS1-3 are more likely to determine the new functions of CYP enzymes during the evolution.