Elucidating the pathway for arsenic methylation

Here we describe a new -adenosylmethionine (Ado Met)-dependent methyltransferase from rat liver cytosol that catalyzes the conversion of arsenite to methylated and dimethylated species.

This 42-k Da protein has sequence motifs common to many non-nucleic acid methyltransferases and is closely related to methyltransferases of previously unknown function that have been identified by conceptual translations of genes encode an arsenic methyltransferase in the mouse and human genomes.

Significance: This work clearly elucidates the completely ordered mechanism of arsenite methylation by a rapid equilibrium kinetic model.

In the human body, arsenic is metabolized by methylation.

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.

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We used the rapid equilibrium kinetic model to study the reaction sequence of arsenite methylation.Inorganic arsenic exposure via drinking water has been associated with cancer and serious injury in various internal organs, as well as with peripheral neuropathy and diverse effects in the circulatory and nervous system.Acute intoxication that produces initial gastrointestinal or cardiovascular symptoms can be followed by the delayed onset of central or peripheral nervous system involvement.Conclusion: The methyl transfer step occurs on h AS3MT.Reductant reduces a disulfide bond and exposes the active site cysteine residues.The results suggest that the mechanism for arsenite methylation is a completely ordered mechanism that is also of general interest in reaction systems with different reductants, such as tris(2-carboxyethyl)phosphine, cysteine, and glutathione.

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