论文部分内容阅读
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.
Non-synonymous single-nucleotide polymorphisms (nsSNPs) in the coding region of drug toxin-metabolizing enzymes lead to amino acid changes that may alter the function of the corresponding proteins, causing the human body to react abnormally to drug-related toxicants and to disease susceptibility. A large number of nsSNPs have been found in human phase II metabolic enzymes, but little is known about the relationship between the genotypes and phenotypes of these nsnsPs.In this study, 923 human phase Ⅱ enzyme genes were identified from Ensembl genome database and NCBISNP database Confirmed nsSNPs. Predicted by PolyPhen, Panther and SNAP algorithms, it was found that 44% -59% of nsSNPs affected protein function.The prediction results of this study are in good agreement with the experimental evidence that 68% of known harmful nsSNPs are correctly Which is predicted to be harmful.This study identified a number of functional amino acids that have not been experimentally studied.The predictions of Panther and PolyPhen are in good agreement with the results of SNAP non-neutrality prediction and PolyPhen predictive score.The evolutionarily non-neutral (destabilization ) Amino acid substitutions may be responsible for the altered phase II enzyme activity leading to disease susceptibility and drug / foreign toxicity.This study is also in the box of harmful nsSNPs prediction The framework elucidates the molecular evolution pattern of phase II enzymes.