The human arsenic methylation pathway

描述（由申请人提供）：环境保护署称砷是美国最普遍的环境毒素和致癌物（://www.atsdr.cdc.gov/cercla/07list.html）。砷会导致心血管和周围血管疾病、神经系统疾病、糖尿病和各种癌症，如皮肤癌和膀胱癌。砷被肝脏酶As (III) s -腺苷蛋氨酸（SAM）甲基转移酶（AS3MT）生物甲基化为单甲基化和二甲基化。由于三价产物甲基亚砷酸盐（MAs(III)）和二甲基亚砷酸盐（DMAs(III)）比无机亚砷酸盐毒性更大，因此有人提出它们与砷致癌和人类其他疾病有关。具有AS3MT多态性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性酶之间的差异。甲基化后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及其多态形式的结构和功能。

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.