The human arsenic methylation pathway

人类砷甲基化途径

基本信息

批准号：
9187032
负责人：
BARRY P. ROSEN
金额：
$ 32.21万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-11 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187032
关键词：
Affect African American American Arsenic Arsenites Binding Binding Sites Biological Models Cardiovascular system Catalysis Cells Code Crystallization Cysteine Data Diabetes Mellitus Disease Environmental Carcinogens Enzymes European Genetic Polymorphism Genome Glutathione S-Transferase Goals Human Human Genome In Vitro Individual Italy Kinetics Lead Liver Malignant Neoplasms Malignant neoplasm of urinary bladder Metabolic Clearance Rate Methylation Methyltransferase Methyltransferase Gene Missense Mutation Modeling Mono-S Mutation National Heart, Lung, and Blood Institute Nature Pathway interactions Peripheral Vascular Diseases Physiological Production Property Reaction Reduced Glutathione Reducing Agents Risk Role S-Adenosylmethionine Scheme Skin Cancer Structure Sum TXN gene Toxic Environmental Substances Uncertainty United States United States Environmental Protection Agency Variant Work carcinogenesis disulfide bond exome sequencing glutathione S-transferase pi in vivo nervous system disorder oxidation public health relevance repository screening thioredoxin reductase

项目摘要

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.

描述（由申请人提供）：美国环境保护局称砷为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、糖尿病和各种形式的癌症，例如皮肤癌和膀胱癌。砷被肝酶 As (III) S-腺苷甲硫氨酸 (SAM) 甲基转移酶 (AS3MT) 生物甲基化为单甲基化和二甲基化物质。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，因此它们被认为与砷致癌和人类其他疾病有关。具有 AS3MT 多态性的个体会产生更多的甲基化物质。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的工作原理势在必行。本研究的总体目标是阐明 hAS3MT 及其多态性的结构和功能。