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首页> 外文期刊>Pharmacogenetics >Human nicotinamide N-methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization.
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Human nicotinamide N-methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization.

机译：人烟酰胺N-甲基转移酶的药理学：基因序列分析和启动子表征。

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Nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and structurally related pyridines. NNMT enzymatic activity in human liver varies over a five-fold range with a bimodal frequency distribution - raising the possibility of regulation by a genetic polymorphism. We set out to characterize molecular genetic mechanisms that might be involved in the regulation of individual variation in human liver NNMT activity. After Northern blot analysis confirmed that NNMT is highly expressed in the liver, eight human hepatic biopsy samples, four each with 'low' or 'high' levels of activity, were used to perform quantitative Western blot analysis. There was a highly significant correlation (r(s) = 0.96, P < 0.0001) between NNMT activity and immunoreactive protein in these samples. We next determined that a potent promoter was located within the initial 700 bp of the 5'-flanking region of the human NNMT gene. That gene consists of 3 exons, with an initial 1240 bp intron and a second intron that is approximately 14 kb in length. We subsequently isolated DNA from 27 human liver biopsy samples with low, intermediate or high levels of NNMT activity. The three exons, all 1240 bp of intron 1 and approximately 700 bp of the 5'-flanking region of the NNMT gene were amplified from each of these samples with the polymerase chain reaction, followed by DNA sequencing to identify genetic polymorphisms that might correlate with 'NNMT phenotype'. No single nucleotide polymorphisms (SNPs) or insertion/deletion events were detected within either the exons or 5'-flanking regions of NNMT for these 27 samples. Although there were eight SNPs within intron 1, none were systematically related to level of NNMT activity. These results indicate that the exons and 5'-flanking region of the NNMT gene display little or no sequence variation. Therefore, polymorphisms within these areas of the gene are unlikely to be related to wide individual variations in the level of this enzyme activity in the human liver.
机译：烟酰胺N-甲基转移酶（NNMT）催化烟酰胺和与结构相关的吡啶的N-甲基化。人肝中NNMT的酶活性在五倍范围内变化，具有双峰频率分布-增加了通过遗传多态性进行调节的可能性。我们着手表征可能参与人类肝脏NNMT活性个体变异调控的分子遗传机制。在Northern blot分析证实NNMT在肝脏中高表达后，使用了8个人类肝活检样品，其中4个具有“低”或“高”活性水平，进行了定量Western blot分析。在这些样品中，NNMT活性与免疫反应蛋白之间存在高度显着的相关性（r（s）= 0.96，P <0.0001）。接下来，我们确定了有效的启动子位于人NNMT基因5'侧翼区域的最初700 bp之内。该基因由3个外显子组成，具有一个初始1240 bp内含子和一个长度约14 kb的第二个内含子。随后，我们从27种具有低，中或高水平NNMT活性的人肝活检样品中分离了DNA。通过聚合酶链反应从每个样本中扩增出三个外显子，即内含子1的全部1240 bp和NNMT基因的5'侧翼区域的约700 bp，然后进行DNA测序以鉴定可能与之相关的遗传多态性。 “ NNMT表型”。对于这27个样品，在NNMT的外显子或5'侧翼区域内均未检测到单核苷酸多态性（SNP）或插入/缺失事件。尽管内含子1中有8个SNP，但它们均与NNMT活性水平系统相关。这些结果表明NNMT基因的外显子和5'侧翼区域显示很少或没有序列变异。因此，基因在这些区域内的多态性不太可能与人类肝脏中这种酶活性水平的广泛个体差异有关。

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