Structure of an As(III) S-adenosylmethionine methyltransferase: insights into the mechanism of arsenic biotransformation

Biochemistry. 2012 Jul 10;51(27):5476-85. doi: 10.1021/bi3004632. Epub 2012 Jun 29.


Enzymatic methylation of arsenic is a detoxification process in microorganisms but in humans may activate the metalloid to more carcinogenic species. We describe the first structure of an As(III) S-adenosylmethionine methyltransferase by X-ray crystallography that reveals a novel As(III) binding domain. The structure of the methyltransferase from the thermophilic eukaryotic alga Cyanidioschyzon merolae reveals the relationship between the arsenic and S-adenosylmethionine binding sites to a final resolution of ∼1.6 Å. As(III) binding causes little change in conformation, but binding of SAM reorients helix α4 and a loop (residues 49-80) toward the As(III) binding domain, positioning the methyl group for transfer to the metalloid. There is no evidence of a reductase domain. These results are consistent with previous suggestions that arsenic remains trivalent during the catalytic cycle. A homology model of human As(III) S-adenosylmethionine methyltransferase with the location of known polymorphisms was constructed. The structure provides insights into the mechanism of substrate binding and catalysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Arsenic / metabolism*
  • Biotransformation
  • Environmental Pollutants / metabolism*
  • Humans
  • Methyltransferases / chemistry*
  • Methyltransferases / metabolism*
  • Models, Molecular
  • Protein Structure, Tertiary
  • Rhodophyta / enzymology
  • S-Adenosylmethionine / metabolism
  • Sequence Homology, Amino Acid


  • Environmental Pollutants
  • S-Adenosylmethionine
  • Methyltransferases
  • AS3MT protein, human
  • Arsenic