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首页> 外文期刊>Pharmacogenetics >The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation.
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The T341C (Ile114Thr) polymorphism of N-acetyltransferase 2 yields slow acetylator phenotype by enhanced protein degradation.

机译：N-乙酰基转移酶2的T341C（Ile114Thr）多态性通过增强的蛋白质降解产生缓慢的乙酰化剂表型。

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OBJECTIVES: Human N-acetyltransferase 2 (NAT2) plays a significant role in the clearance and biotransformation of many drugs and carcinogens. A TC (Ile114Thr) single nucleotide polymorphism (SNP) of NAT2 is commonly found in slow acetylators, leading to altered drug response and toxicity and possibly cancer susceptibility from carcinogens. The objective of this study was to investigate the mechanism by which this SNP causes slow acetylator phenotype. METHODS: A cDNA expression system was used to compare the NAT2*4 reference allele with an identical one possessing the TC SNP in COS-1 cells. The recombinant human NAT2 enzymes were compared in regard to catalytic activity, kinetic parameters, thermostability, immunoreactive protein level, mRNA level and in-vivo protein degradation. RESULTS: The TC (Ile114Thr) SNP significantly reduced enzyme activity without changing the apparent kinetic parameters Km and Vmax (normalized for NAT2 protein), indicating that Ile114Thr did not change substrate or cofactor binding affinities or catalytic efficiency. Furthermore, no significant difference in NAT2 mRNA level was observed, indicating no impairment of transcription. The TC (Ile114Thr) SNP did not alter thermostability of NAT2 at either 37 or 50 degrees C. However, this SNP significantly reduced cytosolic NAT2 immunoreactive protein through enhanced protein degradation. CONCLUSION: This is the first report indicating that protein degradation is an important mechanism of human NAT2 slow acetylator phenotype.
机译：目的：人类N-乙酰基转移酶2（NAT2）在许多药物和致癌物的清除和生物转化中起重要作用。 NAT2的TC（Ile114Thr）单核苷酸多态性（SNP）通常在慢速乙酰化剂中发现，从而导致药物反应和毒性改变，并可能由致癌物引起癌症。这项研究的目的是调查这种SNP导致慢速乙酰化剂表型的机制。方法：使用cDNA表达系统比较NAT2 * 4参考等位基因与COS-1细胞中具有TC SNP的相同等位基因。比较了重组人NAT2酶的催化活性，动力学参数，热稳定性，免疫反应蛋白水平，mRNA水平和体内蛋白降解。结果：TC（Ile114Thr）SNP显着降低了酶的活性，而没有改变表观动力学参数Km和Vmax（针对NAT2蛋白标准化），表明Ile114Thr不会改变底物或辅因子的结合亲和力或催化效率。此外，没有观察到NAT2 mRNA水平的显着差异，表明没有转录损伤。 TC（Ile114Thr）SNP不会在37或50摄氏度下改变NAT2的热稳定性。但是，此SNP通过增强蛋白质降解而显着降低了胞浆NAT2免疫反应蛋白。结论：这是第一个报告，表明蛋白质降解是人类NAT2慢乙酰化酶表型的重要机制。

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