Date of this Version
11-17-2015
Document Type
Article
Abstract
Arsenic is the most ubiquitous environmental toxin and carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease, and diabetes. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent mono- and dimethyl species that are more toxic and potentially more carcinogenic than inorganic arsenic. Modulators of hAS3MT activity may be useful for the prevention or treatment of arsenic-related diseases. Using a newly developed high-throughput assay for hAS3MT activity, we identified 10 novel noncompetitive small molecule inhibitors. In silico docking analysis with the crystal structure of an AS3MT orthologue suggests that the inhibitors bind in a cleft between domains that is distant from either the As(III) or SAM binding sites. This suggests the presence of a possible allosteric and regulatory site in the enzyme. These inhibitors may be useful tools for future research in arsenic metabolism and are the starting-point for the development of drugs against hAS3MT.
Originally Published In
Chemical Research in Toxicology
PMID
26577531
DOI
10.1021/acs.chemrestox.5b00432
Recommended Citation
Dong, Hui; Madegowda, Mahendra; Nefzi, Adel; Houghten, Richard A.; Giulianotti, Marc A.; and Rosen, Barry P., "Identificationof Small Molecule Inhibitors of HumanAs(III) S-Adenosylmethionine Methyltransferase(AS3MT)" (2015). All Faculty. 102.
https://digitalcommons.fiu.edu/all_faculty/102
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Comments
This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.