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人类Ⅱ相药物毒物代谢酶非同义单核苷酸多态性的表型预测:分子进化观

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摘要 药物毒物代谢酶编码区的非同义单核苷酸多态性(nsSNPs)导致氨基酸改变,从而可能改变相应蛋白质的功能,使人体对有关药物毒物产生异常反应,亦与疾病易感性关联.在人类Ⅱ相代谢酶基因中已发现大量nsSNPs,但对这些酶nsSNPs基因型和表型间的关系了解甚少.本研究从Ensembl基因组数据库和NCBISNP数据库识别出104个人类Ⅱ相酶基因的923个经确认的nsSNPs.用PolyPhen,Panther和SNAP算法预测,发现44%~59%的nsSNPs影响到蛋白质功能.本研究的预测结果与已有实验研究证据基本吻合.68%的已知有害nsSNPs被正确预测为有害.本研究识别出多个尚未经实验研究的功能氨基酸.Panther和PolyPhen的预测结果吻合,SNAP非中性预测结果与PolyPhen预测分值亦吻合.进化上非中性的(去稳定化的)氨基酸替换可能是Ⅱ相酶活性改变,产生疾病易感性和药物/外源物毒性的致病基础.本研究还在有害nsSNPs预测的框架内阐明了Ⅱ相酶的分子进化模式.
出处 《中国科学:生命科学》 CSCD 北大核心 2011年第2期97-108,共12页 Scientia Sinica(Vitae)
基金 国家科技重大专项(批准号:2008ZX10005-004) 辽宁省教育厅计划(批准号:2009A120) 中国博士后科学基金(批准号:20080440019和200902069)资助项目
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