Elucidating the pathway for arsenic methylation
Elucidating the pathway for arsenic methylation
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DOI：
10.1016/j.taap.2003.10.020
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发表时间：
2004-08-01
影响因子：
3.8
通讯作者：
Styblo, M
中科院分区：
文献类型：
--
作者：
Thomas, DJ;Waters, SB;Styblo, M
虽然砷的生物甲基化研究已经进行了世纪，但人类对无机砷的甲基化的明确证明仅发生在大约30年前。由于无机砷的甲基化使其活化为更具反应性和毒性的形式，因此阐明这种类金属甲基化的途径是一个相当重要的主题。了解砷代谢是公共卫生问题，因为数百万人长期饮用含有高浓度无机砷的饮用水。因此，我们的研究重点是阐明从无机砷到甲基化和二甲基化砷的途径中各个步骤的分子基础。在这里，我们描述了一个新的S-腺苷甲硫氨酸（蛋氨酸）依赖的甲基转移酶从大鼠肝细胞质，催化亚砷酸盐转化为甲基化和二甲基化的物种。这种42 kDa的蛋白质具有许多非核酸甲基转移酶所共有的序列基序，并且与先前未知功能的甲基转移酶密切相关，这些甲基转移酶已通过小鼠和人类基因组的cyt 19基因的概念翻译鉴定。因此，我们指定大鼠肝砷甲基转移酶cyt 19，并建议orthopathic cyt 19基因编码的砷甲基转移酶在小鼠和人类基因组。我们的研究与重组大鼠cyt 19发现，在外源性或生理还原剂的存在下，这种蛋白质可以催化整个序列的反应，将亚砷酸盐转化为甲基化代谢产物。提出了cyt 19和硫氧还蛋白-硫氧还蛋白还原酶在砷的甲基化和还原反应中的联系方案。(C)2004年爱思唯尔公司All rights reserved.
Although biomethylation of arsenic has been studied for more than a century, unequivocal demonstration of the methylation of inorganic arsenic by humans occurred only about 30 years ago. Because methylation of inorganic arsenic activates it to more reactive and toxic forms, elucidating the pathway for the methylation of this metalloid is a topic of considerable importance. Understanding arsenic metabolism is of public health concern as millions of people chronically consume drinking water that contains high concentrations of inorganic arsenic. Hence, the focus of our research has been to elucidate the molecular basis of the steps in the pathway that leads from inorganic arsenic to methylated and dimethylated arsenicals. Here we describe a new S-adenosylmethionine (AdoMet)-dependent methyltransferase from rat liver cytosol that catalyzes the conversion of arsenite to methylated and dimethylated species. This 42-kDa protein has sequence motifs common to many nonnucleic acid methyltransferases and is closely related to methyltransferases of previously unknown function that have been identified by conceptual translations of cyt19 genes of mouse and human genomes. Hence, we designate rat liver arsenic methyltransferase as cyt19 and suggest that orthologous cyt19 genes encode an arsenic methyltransferase in the mouse and human genomes. Our studies with recombinant rat cyt19 find that, in the presence of an exogenous or a physiological reductant, this protein can catalyze the entire sequence of reactions that convert arsenite to methylated metabolites. A scheme linking cyt19 and thioredoxin-thioredoxin reductase in the methylation and reduction of arsenicals is proposed. (C) 2004 Elsevier Inc. All rights reserved.