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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES023779-05
Application #
9606072
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Tyson, Frederick L
Project Start
2014-12-11
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Florida International University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Packianathan, Charles; Li, Jiaojiao; Kandavelu, Palani et al. (2018) Reorientation of the Methyl Group in MAs(III) is the Rate-Limiting Step in the ArsM As(III) S-Adenosylmethionine Methyltransferase Reaction. ACS Omega 3:3104-3112
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 :
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