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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetics of P450 oxidoreductase: Sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations
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Genetics of P450 oxidoreductase: Sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations

机译：P450氧化还原酶的遗传学：四个种族的842个人的序列变异和15个错义突变的活动

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摘要

P450 oxidoreductase (POR) is an electron-donating flavoprotein required for the activity of all microsomal cytochrome P450 enzymes. We sequenced 5,655 bp of the POR gene in a representative population of 842 healthy unrelated individuals in four ethnic groups: 218 African Americans, 260 Caucasian Americans, 179 Chinese Americans, and 185 Mexican Americans. One hundred forty SNPs were detected, of which 43 were found in ≥ 1% of alleles. Twelve SNPs were in the POR promoter region. Fifteen of 32 exonic variations altered the POR amino acid sequence; 13 of these 15 are previously undescribed missense variations. We found eight indels, only one of which was in the coding region. A previously described variant, A503V, was found on 27.9% of all alleles with some ethnic predilection (19.1% in African Americans, 26.4% in Caucasian Americans, 36.7% Chinese Americans, and 31.0% in Mexican Americans). We built cDNA expression vectors for the 13 previously undescribed missense variants, expressed each protein lacking 27 N-terminal residues in Escherichia coli, and assayed the apparent K_m and V_(max) of each in four assays: reduction of cytochrome c, oxidation of NADPH, 17α-hydroxylase activity of P450c17, and 17,20 lyase activity of P450c17. The catalytic activities of several missense mutants differed substantially in these assays, indicating that each POR mutant must be assayed separately with each potential target P450 enzyme. The activity of A503V was reduced to a modest but statistically significant degree in all four assays, suggesting that it may play an important role in interindi-vidual variation in drug response.
机译：P450氧化还原酶（POR）是所有微粒体细胞色素P450酶的活性所必需的供电子黄素蛋白。我们在四个种族的842名健康无关个体的代表性人群中测序了5655 bp的POR基因：218个非洲裔美国人，260个白人美国人，179个华裔美国人和185个墨西哥裔美国人。检测到一百四十个SNP，其中在≥1％的等位基因中发现了43个。在POR启动子区域中有十二个SNP。 32个外显子变异中有15个改变了POR氨基酸序列；这15个中的13个是先前未描述的错义变体。我们发现了八个插入缺失，其中只有一个位于编码区。在所有等位基因的27.9％中发现了先前描述的变体A503V，其中有一些种族偏爱（非裔美国人中为19.1％，高加索裔美国人中为26.4％，华裔美国人中为36.7％，墨西哥裔美国人中为31.0％）。我们构建了13个先前未描述的错义变体的cDNA表达载体，表达了每种蛋白在大肠杆菌中缺少27个N端残基，并通过四种测定法分别测定了它们的表观K_m和V_（max）：细胞色素c的还原，NADPH的氧化，P450c17的17α-羟化酶活性和P450c17的17,20裂合酶活性。在这些测定中，几种错义突变体的催化活性存在显着差异，表明每种POR突变体必须与每种潜在的靶P450酶分开进行测定。在所有四种测定中，A503V的活性均降低到中等水平，但在统计学上具有显着意义，表明A503V可能在药物反应的个体差异中发挥重要作用。

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