Pan Shu-Ting, Xue Danfeng, Li Zhi-Ling, Zhou Zhi-Wei, He Zhi-Xu, Yang Yinxue, Yang Tianxin, Qiu Jia-Xuan, Zhou Shu-Feng
Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Nanchang University, Nanchang 330003, China.
Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
Int J Mol Sci. 2016 Jun 28;17(7):1020. doi: 10.3390/ijms17071020.
The human cytochrome P450 (CYP) superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA ("Orthologous MAtrix") Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery.
由57个功能基因组成的人类细胞色素P450（CYP）超家族是最重要的I相药物代谢酶组，可氧化大量的外源性物质和内源性化合物，包括治疗药物和环境毒物。CYP超家族已被证明通过基因复制进行自身扩张，其中一些由于基因突变而成为假基因。直系同源基因和旁系同源基因分别是物种形成或复制产生的同源基因。为了探究人类CYP的进化和功能关系，我们开展了这项生物信息学研究，以鉴定它们相应的旁系同源基因、同源基因和直系同源基因。随后讨论了其在药物发现和进化生物学中的功能意义。利用GeneCards和Ensembl鉴定人类CYP的旁系同源基因。我们使用了一系列在线数据库来鉴定人类CYP基因的直系同源基因：NCBI、Ensembl Compara、GeneCards、OMA（“直系同源矩阵”）浏览器、PATHER、TreeFam、EggNOG和Roundup。结果表明，使用GeneCards和Ensembl时，每个人类CYP都有不同数量的旁系同源基因和直系同源基因。例如，CYP2A6的旁系同源基因包括CYP2A7、2A13、2B6、2C8、2C9、2C18、2C19、2D6、2E1、2F1、2J2、2R1、2S1、2U1和2W1；CYP11A1有6个旁系同源基因，包括CYP11B1、11B2、24A1、27A1、27B1和27C1；CYP51A1只有3个旁系同源基因：CYP26A1、26B1和26C1；而CYP20A1没有旁系同源基因。由于其在生理学和外源性物质处置中的重要功能，大多数人类CYP从植物、两栖动物、鱼类或哺乳动物到人类都得到了很好的保守。当有实验数据时，来自不同方法的数据也会进行交叉验证和验证。这些发现有助于我们理解人类CYP超家族在药物发现中的进化关系和功能意义。
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