Arsenic (+3 oxidation state) methyltransferase and the inorganic arsenic methylation phenotype.
Inorganic arsenic is enzymatically methylated; hence, its ingestion results in exposure to the parent compound and various methylated arsenicals. Both experimental and epidemiological evidences suggest that some of the adverse health effects associated with chronic exposure to inorganic arsenic may be mediated by these methylated metabolites. If iAs methylation is an activation process, then the phenotype for inorganic arsenic methylation may determine risk associated with exposure to this metalloid. We examined inorganic arsenic methylation phenotypes and arsenic (+3 oxidation state) methyltransferase genotypes in four species: three that methylate inorganic arsenic (human (Homo sapiens), rat (Rattus norwegicus), and mouse (Mus musculus)) and one that does not methylate inorganic arsenic (chimpanzee, Pan troglodytes). The predicted protein products from arsenic (+3 oxidation state) methyltransferase are similar in size for rat (369 amino acid residues), mouse (376 residues), and human (375 residues). By comparison, a 275-nucleotide deletion beginning at nucleotide 612 in the chimpanzee gene sequence causes a frameshift that leads to a nonsense mutation for a premature stop codon after amino acid 205. The null phenotype for inorganic arsenic methylation in the chimpanzee is likely due to the deletion in the gene for arsenic (+3 oxidation state) methyltransferase that yields an inactive truncated protein. This lineage-specific loss of function caused by the deletion event must have occurred in the Pan lineage after Homo-Pan divergence about 5 million years ago.
Li
Jiaxin
J
Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Waters
Stephen B
SB
Drobna
Zuzana
Z
Devesa
Vicenta
V
Styblo
Miroslav
M
Thomas
David J
DJ
D000818:Animals; D001151:Arsenic / Q000378:metabolism*; D001483:Base Sequence / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D019143:Evolution, Molecular; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D005838:Genotype; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D002679:Pan troglodytes / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D013045:Species Specificity; D013997:Time Factors
D008780:Methyltransferases; D003545:Cysteine; D001151:Arsenic