Aggresome formation and pharmacogenetics: sulfotransferase 1A3 as a model system
Aggresome formation and pharmacogenetics: sulfotransferase 1A3 as a model system
复制标题
DOI：
10.1016/j.bbrc.2004.10.040
复制
发表时间：
2004-12-10
影响因子：
3.1
通讯作者：
Weinshilboum, RM
中科院分区：
文献类型：
--
作者：
Wang, LW;Yee, VC;Weinshilboum, RM
药物反应中药物遗传学改变的常见原因是编码氨基酸序列的遗传变异。我们已经使用了儿茶酚胺和药物代谢酶磺基转移酶（SULT）1A 3创建一个人工模型系统来研究机制，特别是可能的侵略形成的遗传改变的氨基酸序列可能会影响功能。具体来说，我们创建了一个双变体SULTIA 3等位酶，包括天然存在的Asn 234多态性加上额外的Trp 172 Arg突变。对SULTIA 3 X射线晶体结构的分析表明，Trp 172 Arg突变可能会破坏蛋白质结构的稳定性。在COS-1细胞中表达SULTIA 3 Arg 172，Asn 234导致检测不到酶活性和实际上缺乏酶蛋白。兔网织红细胞裂解物降解研究表明，双变体等位酶降解更迅速地比野生型SULTIA 3的泛素-蛋白酶体依赖性过程。此外，在COS-1细胞中表达后，双变体等位酶定位于侵袭体，这是先前在药物遗传学中未描述或研究的过程。因此，仅一个或两个氨基酸的改变可导致蛋白质水平的降低，这是攻击组形成和加速降解的结果。在药物遗传学中攻击基因组形成的可能作用应该在编码氨基酸序列具有遗传改变的自然发生系统中进行评估。(C)2004爱思唯尔公司All rights reserved.
A common cause for pharmacogenetic alteration in drug response is genetic variation in encoded amino acid sequence. We have used the catecholamine and drug-metabolizing enzyme sulfotransferase (SULT)1A3 to create an artificial model system to study mechanisms-especially possible aggresome formation-by which genetic alteration in amino acid sequence might influence function. Specifically, we created a double variant SULTIA3 allozyme that included the naturally occurring Asn234 polymorphism plus an additional Trp172Arg mutation. Analysis of the SULTIA3 X-ray crystal structure had indicated that the Trp172Arg mutation might destabilize the protein's structure. Expression of SULTIA3 Arg172,Asn234 in COS-1 cells resulted in undetectable enzyme activity and a virtual lack of enzyme protein. Rabbit reticulocyte lysate degradation studies showed that the double variant allozyme was degraded much more rapidly than was wild type SULTIA3 by a ubiquitin-proteasome-dependent process. In addition, after expression in COS-1 cells, the double variant allozyme localized to aggresomes, a process not previously described or studied in pharmacogenetics. Therefore, the alteration of only one or two amino acids can lead to decreased levels of protein as a result of both aggresome formation and accelerated degradation. The possible role of aggresome formation in pharmacogenetics should be evaluated in naturally occurring systems with inherited alteration in encoded amino acid sequence. (C) 2004 Elsevier Inc. All rights reserved.