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CLONING, EXPRESSION, AND CHARACTERIZATION OF RAT S-ADENOSYL-L-METHIONINE: ARSENIC (III) METHYLTRANSFERASE (CYT19)
Styblo, M, Z. Drobna, Walton, Felecia S, S. B. Waters, K. M. HerbinDavis, AND D J. Thomas. CLONING, EXPRESSION, AND CHARACTERIZATION OF RAT S-ADENOSYL-L-METHIONINE: ARSENIC (III) METHYLTRANSFERASE (CYT19). Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
CLONING, EXPRESSION, AND CHARACTERIZATION OF RAT S-ADENOSYL-L-METHIONINE: ARSENIC(III) METHYLTRANSFERASE (cyt19)
Stephen B. Waters1 , Felicia Walton1 , Miroslav Styblo1 , Karen Herbin-Davis2, and David J. Thomas2 1 School of Medicine, University of North Carolina at Chapel Hill, and 2 PKB, NHEERL, ORD, US EPA, Research Triangle Park, North Carolina
S-adenosyl-L-methionine: arsenic(III) methyltransferase, an enzyme purified from rat liver, catalyzes the formation of methyl and dimethyl arsenic from trivalent inorganic arsenic. Because the predicted amino acid sequence of this enzyme resembles those of the predicted products of cyt19 genes in the human and mouse genomes, the rat protein is designated cyt19. Rat, mouse, and human cyt19 contain amino acid motifs commonly found in non-nucleic acid methyltransferases. Rat cyt19 contains 13 cysteine residues; three of the final eight C-terminal residues are cysteines. Expression of the cloned rat cyt19 yields a protein that methylates trivalent inorganic arsenic, producing methyl and dimethyl arsenic as minor and major metabolites, respectively. Omission of S-adenosyl-L-methionine or a reductant abolishes the its catalytic activity. Dithiothreitol and tris-(2-carboxyethyl)phosphine are approximately equipotent as reductants. A thioredoxin-thioredoxin reductase generation system can also function as a reductant. The capacity of rat cyt19 to catalyze both the oxidative methylation of arsenicals and the putative reduction of arsenicals to the trivalent oxidation state suggests that this protein has both methyltransferase and reductive functions. Selenite and methylselenol are potent inhibitors of cyt19-catalyzed formation of methylated arsenicals from inorganic arsenic. Selenite (Ki = 1.4 M) is a more potent inhibitor than is methylselenol (Ki = 19 M) and neither dimethylated or trimethylated selenium compounds inhibit cyt19. Alteration of cyt19-catalyzed production of methylated arsenicals by selenium-containing compounds could be a locus of interaction between these metalloids. (This abstract does not necessarily reflect EPA policy.)