Structure of an As(III) S-adenosylmethionine methyltransferase: insights into the mechanism of arsenic biotransformation.
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.
Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, 33199, United States.
A Abdul
AA
Ajees
Kavitha
K
Marapakala
Charles
C
Packianathan
Banumathi
B
Sankaran
Barry P
BP
Rosen
D001151:Arsenic / Q000378:metabolism*; D001711:Biotransformation; D004785:Environmental Pollutants / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D000461:Rhodophyta / Q000201:enzymology; D012436:S-Adenosylmethionine / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D004785:Environmental Pollutants; D012436:S-Adenosylmethionine; D008780:Methyltransferases; C505756:AS3MT protein, human; D001151:Arsenic