Arsenic (+3 oxidation state) methyltransferase and the inorganic arsenic methylation phenotype

Abstract

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. D

Human Arsenic Methyltransferase (AS3MT) Pharmacogenetics

“…Specifically, ORF nucleotide 1057 in our sequence is missing from the NCBI cDNA annotation, resulting in a frameshift and truncation of the protein within exon 10, with exon 11 converted entirely to 3Ј-UTR. Furthermore, there are 4 variant nucleotides in exon 5 of the present NCBI cDNA annotation, one synonymous and three resulting in the following alterations in encoded amino acids: I132F, Y135N, and G140A (33). Those nucleotides were not polymorphic in any of our resequencing studies of 240 alleles, and the deletion at nucleotide 1057 was also not present in any of our 120 DNA samples.…”

Attenuation and protective efficacy of an O-antigen-deficient mutant of Francisella tularensis LVS

“…The tertiary structures of the wild-type protein WbtI, and mutant proteins WbtI S187Y and WbtI G191V were modelled as previously described (Li et al, 2005) to predict the conformational changes caused by residue substitution. Helicobacter pylori aminotransferase Psec (PDB_ID52FNU, Chain_ID52FNU_B) with 375 amino acids from the Protein Data Bank (PDB) was used as template for WbtI on the 3D-JIGSAW version 2.0 comparative modelling server (Bates & Sternberg, 1999) (http://www.bmm.icnet.uk/ 3djigsaw/).…”

Phase II Drug Metabolism

“…Liver is considered to be the primary site for the methylation of inorganic arsenic (iAs) and arsenic (+3 oxidation state) methyltransferase (AS3MT) is shown to be critical specifically for the arsenic metabolism, and thus may be pharmacologically important as well. Methylated and dimethylated arsenic are the major urinary metabolites in human and many other species (Li et al, 2005). Two reaction schemes (Fig.…”