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ELUCIDATING THE PATHWAY FOR ARSENIC METHYLATION
Citation:
Thomas, D J., S. B. Waters, AND M Styblo. ELUCIDATING THE PATHWAY FOR ARSENIC METHYLATION. TOXICOLOGICAL AND APPLIED PHARMICOLOGY. Elsevier Science BV, Amsterdam, Netherlands, 198:319-326, (2004).
Impact/Purpose:
To help explain the methylation of arsenic
Description:
Enzymatically-catalyzed methylation of arsenic is part of a metabolic pathway that converts inorganic arsenic into methylated products. Hence, in humans chronically exposed to inorganic arsenic, methyl and dimethyl arsenic account for most of the arsenic that is excreted in the urine. Although methylation was originally thought to detoxify inorganic arsenic, methylated arsenicals containing trivalent arsenic that are formed as intermediates in the course of arsenic metabolism are more reactive than inorganic arsenic and may play important roles in toxicity and carcinogenicity associated with chronic arsenic exposure. In the work reported here, we isolated, purified, and characterized from rat liver cytosol a novel S-adenosylmethionine-dependent methyltransferase that converts arsenite to methyl and dimethyl arsenic. This 369-residue protein (molecular mass = 41056) has features common to many non-nucleic acid methyltransferases. It is closely related to methyltransferases of unknown function that were identified by conceptual translations of cyt19 gene in mouse and humans. Therefore, we designate rat liver arsenic methyltransferase as cyt19 and suggest that cyt19 is also an arsenic methyltransferase in mice and humans. Studies with either purified or recombinant rat cyt19 show that this protein efficiently catalyzes the conversion of arsenite to methyl and dimethyl arsenic. The activity of the protein is dependent on the availability of reducing equivalents. These may be supplied by dithiothreitol or tris-(2-carboxyethyl)phosphine. An enzymatic system consisting of thioredoxin, thioredoxin reductase, and NADPH can also provide reducing equivalents to support the catalytic function of cyt19.
Manuscript submitted to Fifth International Conference on Arsenic Exposure and Health Effects - San Diego, july 14-18, 2002