Reorientation of the Methyl Group in MAs(III) is the Rate-Limiting Step in the ArsM As(III) S -Adenosylmethionine Methyltransferase Reaction
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida 33134, United States
- SER-CAT and the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, United States
- Molecular Biophysics and Integrated Biology, Lawrence Berkeley Laboratory, Berkeley, California 94720, United States
The most common biotransformation of trivalent inorganic arsenic (As(III)) is methylation to mono-, di-, and trimethylated species. Methylation is catalyzed by As(III) S-adenosylmethionine (SAM) methyltransferase (termed ArsM in microbes and AS3MT in animals). Methylarsenite (MAs(III)) is both the product of the first methylation step and the substrate of the second methylation step. When the rate of the overall methylation reaction was determined with As(III) as the substrate, the first methylation step was rapid, whereas the second methylation step was slow. In contrast, when MAs(III) was used as the substrate, the rate of methylation was as fast as the first methylation step when As(III) was used as the substrate. These results indicate that there is a slow conformational change between the first and second methylation steps. The structure of CmArsM from the thermophilic alga Cyanidioschyzon merolae sp. 5508 was determined with bound MAs(III) at 2.27 Å resolution. The methyl group is facing the solvent, as would be expected when MAs(III) is bound as the substrate rather than facing the SAM-binding site, as would be expected for MAs(III) as a product. We propose that the rate-limiting step in arsenic methylation is slow reorientation of the methyl group from the SAM-binding site to the solvent, which is linked to the conformation of the side chain of a conserved residue Tyr70.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- DOE Contract Number:
- AC02-05CH11231
- OSTI ID:
- 1427851
- Journal Information:
- ACS Omega, Vol. 3, Issue 3; ISSN 2470-1343
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
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