Elucidating the pathway for arsenic methylation

Although biomethylation of arsenic has been studied for more than a century, unequivocal demonstration of the methylation of inorganic arsenic by humans occurred only about 30 years ago. Because methylation of inorganic arsenic activates it to more reactive and toxic forms, elucidating the pathway for the methylation of this metalloid is a topic of considerable importance. Understanding arsenic metabolism is of public health concern as millions of people chronically consume drinking water that contains high concentrations of inorganic arsenic. Hence, the focus of our research has been to elucidate the molecular basis of the steps in the pathway that leads from inorganic arsenic to methylated and dimethylated arsenicals. Here we describe a new S-adenosylmethionine (AdoMet)-dependent methyltransferase from rat liver cytosol that catalyzes the conversion of arsenite to methylated and dimethylated species. This 42-kDa protein has sequence motifs common to many nonnucleic acid methyltransferases and is closely related to methyltransferases of previously unknown function that have been identified by conceptual translations of cyt19 genes of mouse and human genomes. Hence, we designate rat liver arsenic methyltransferase as cyt19 and suggest that orthologous cyt19 genes encode an arsenic methyltransferase in the mouse and human genomes. Our studies with recombinant rat cyt19 find that, in the presence of an exogenous or a physiological reductant, this protein can catalyze the entire sequence of reactions that convert arsenite to methylated metabolites. A scheme linking cyt19 and thioredoxin-thioredoxin reductase in the methylation and reduction of arsenicals is proposed. (C) 2004 Elsevier Inc. All rights reserved.