The human arsenic methylation pathway

人类砷甲基化途径

基本信息

批准号：
8812743
负责人：
BARRY P. ROSEN
金额：
$ 32.25万
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/8812743
关键词：
Affect African American American Arsenic Arsenites Binding Binding Sites Biological Models Cardiovascular system Catalysis Cells Code Cysteine Data Diabetes Mellitus Disease Environmental Carcinogens Enzymes European Genes Genetic Polymorphism Genome Glutathione S-Transferase Goals Human Human Genome In Vitro Individual Kinetics Lead Life Liver Malignant Neoplasms Malignant neoplasm of urinary bladder Metabolic Clearance Rate Methylation Methyltransferase 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 Solutions Structure Subarachnoid Hemorrhage Sum Thioredoxin 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）：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）。砷引起心血管和周围血管疾病，神经系统疾病，糖尿病以及各种形式的癌症，例如皮肤和膀胱癌。通过肝酶为（III）s-腺苷甲硫代氨酸（SAM）甲基转移酶（AS3MT）将砷化为（III）s-腺苷甲基硫氨酸（SAM）和二甲基化物质。由于三价产物甲基磷酸盐（MAS（III））和二甲基霉菌（DMAS（III））比无机砷矿更具毒性，因此已建议它们与砷癌和人类的其他疾病有关。患有AS3MT多态性的个体会产生增加甲基化的物种。甲基化如何促进疾病取决于人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必须了解该酶的工作原理。这项研究的总体目标是阐明HAS3MT及其多态性形式的结构和功能。