You are here:
ENZYMOLOGY OF ARSENIC METHYLATION
Citation:
Thomas, D J. ENZYMOLOGY OF ARSENIC METHYLATION. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Enzymology of Arsenic Methylation
David J. Thomas, Pharmacokinetics Branch, Experimental Toxicology Division, National
Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
A remarkable aspect of arsenic metabolism in many species is its conversion from inorganic species into methylated species. Thus, individuals ingesting inorganic arsenic excrete in urine inorganic and methylated arsenicals containing trivalent or pentavalent arsenic. Cyt19, an S-adenosyl-L-methionine-dependent-arsenic(III) methyltransferase purified from rat liver converts inorganic arsenic into methylated arsenicals. The protein is encoded by a cyt19 gene orthologous to mouse and human genes. Although exogenous reductants (dithiothreitol or tris (2-carboxylethyl) phosphine) support catalysis by recombinant rat cyt19 (rrcyt19), endogenous reductants that support its activity are unknown. Glutathione (GSH), the most abundant endogenous reductant, does not support catalysis by rrcyt19. However, the endogenous reductants, thioredoxin, glutaredoxin, and dihydrolipoic acid, coupled with thioredoxin reductase or glutathione reductase and NADPH, support its activity. Glutaredoxin and dihydrolipoic acid support its function in the presence of GSH. Aurothioglucose, an inhibitor of thioredoxin reductase, decreases arsenic methylation by rrcyt19 in thioredoxin-supported reactions. Endogenous reductants in guinea pig liver cytosol, a poor source of arsenic methyltransferase activity, support its catalytic activity. Dependence of enzyme activity on reductants is consistent with its function as an arsenate reductase. A CX7R motif in rrcyt19 resembles a CX5R motif of the P-loop structure in known arsenate reductases; like these proteins, cyt19 activity is stimulated by the presence of an oxyanion, phosphate. Endogenous reductants may be required by rrcyt19 to catalyze the reduction of a methylarsonic (MAs(V)) intermediate to trivalency as a prerequisite for its conversion to a dimethylated product. Thus, cyt19 encodes a protein possessing both As(III) methyltransferase and arsenate reductase activities. Variation in cyt19 genotype may underlie phenotypic variation in the capacity to metabolize arsenic and interindividual differences in susceptibility to arsenic-induced diseases. (This abstract does not represent policies of the U.S. Environmental Protection Agency.)
sot04sympabst.wpd