The human arsenic methylation pathway

描述(申请人提供)：环境保护局称砷是美国最普遍的环境毒素和致癌物(网址：www.atsdr.cdc.gov/cercla/07list.html)。砷会导致心血管和外周血管疾病、神经疾病、糖尿病和各种形式的癌症，如皮肤癌和膀胱癌。砷被肝酶生物甲基化为(III)S-腺苷甲硫氨酸甲基转移酶(AS3MT)，形成单甲基化和二甲基化物种。由于三价产物甲基亚砷酸盐(Mas(III))和二甲基亚砷酸盐(DMAS(III))比无机亚砷酸盐具有更强的毒性，它们被认为与人体砷的致癌和其他疾病有关。具有AS3MT多态的个体产生更多的甲基化物种。甲基化如何导致疾病取决于人类AS3MT的机制以及野生型和多态酶之间的差异。甲基化结果的不确定性使得了解这种酶是如何工作的势在必行。本研究的总体目标是阐明hAS3MT的结构和功能及其多态形式。

DESCRIPTION (provided by applicant): The Environmental Protection Agency calls arsenic the most prevalent environmental toxin and carcinogen in the United States (://www.atsdr.cdc.gov/cercla/07list.html). Arsenic causes cardiovascular and peripheral vascular diseases, neurological disorders, diabetes mellitus and various forms of cancer such as skin and bladder cancer. Arsenic is biomethylated by the liver enzyme As (III) S-adenosylmethionine (SAM) methyltransferase (AS3MT) to mono- and dimethylated species. Because the trivalent products methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)) are more toxic than inorganic arsenite, they have been proposed to be associated with arsenic carcinogenesis and other diseases in humans. Individuals with AS3MT polymorphisms produce increased amounts of methylated species. How methylation contributes to disease depends on the mechanism of human AS3MT and differences between wild type and polymorphic enzymes. The uncertainty over the consequences of methylation makes it imperative to understand how this enzyme works. The overall goal of this study is elucidation of the structure and function of hAS3MT and its polymorphic forms.