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.
Arsenic is the most pervasive environmental toxin and carcinogen in the United States, causing cardiovascular and peripheral vascular diseases, neurological disorders, diabetes mellitus and various forms of cancer such as skin and bladder cancer. We have characterized the enzyme As(III) S-adenosylmethionine methyltransferase (AS3MT) from a model system. In this application we propose to elucidate the mechanism of the human AS3MT to understand its role in arsenic-related diseases.
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|Packianathan, Charles; Kandavelu, Palani; Rosen, Barry P (2018) The Structure of an As(III) S-Adenosylmethionine Methyltransferase with 3-Coordinately Bound As(III) Depicts the First Step in Catalysis. Biochemistry 57:4083-4092|
|Chen, Jian; Yoshinaga, Masafumi; Rosen, Barry P (2018) The antibiotic action of methylarsenite is an emergent property of microbial communities. Mol Microbiol :|
|Li, Jiaojiao; Packianathan, Charles; Rossman, Toby G et al. (2017) Nonsynonymous Polymorphisms in the Human AS3MT Arsenic Methylation Gene: Implications for Arsenic Toxicity. Chem Res Toxicol 30:1481-1491|
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