Elucidating pathway arsenic methylation

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Furthermore, widespread recognition that humans who ingested i As often exhibited a strong garlic-like odor on expired breath led to a common understanding that humans must also form methylated arsenicals.Following Braman and Foreback (2) who reported the presence of i As, methyl arsenic (MA), and dimethyl arsenic (DMA) in human urine, Crecelius (3) provided the first definitive report of the presence of these arsenicals in the urine of a volunteer who ingested wine or water containing inorganic arsenite (i As).Motif I, with a consensus sequence of (V/I/L)(L/V)(D/I)LG(G/C)G(T/P)G with an invariant G in position 5 occurred as the sequence (I/V/ L)LDLGSGSG in AS3MT.This sequence in AS3MT conformed to the rule of hh (D/E)h GXGXG, where h was a hydrophobic amino acid, and X was any amino acid.Multiple-Sequence Alignments of Human AS3MT and Eight Animal Homologues Illustrate Conserved Motifs I, II, and III, Conserved Asp at I′, and Five Conserved Cys Residues.Underlined sequence is Ubi E methyltransferase domain.

The Motif II consensus sequence ((P/G)(Q/T)(F/Y/A)DA(I/V/Y)(F/I)(C/ V/L) with an invariant aspartate at position 4 occurred as the sequence (E/N/T)(S/A)(Y/H/M/F)DI(V/I)(I/V)S in AS3MT.In particular, these studies show that many animal species convert i As into MAs and DMAs, which are excreted in urine.Determining the basis for this conversion of i As into methylated species depended on development of strategies to isolate, purify, and characterize the molecules that are involved in each step of the pathway that leads from i As to its methylated metabolites and development of sufficiently sensitive and specific analytical methods to identify intermediates and products formed in the methylation pathway.The AS3MT protein was the first As methyltransferase to be sufficiently purified to permit cloning of the corresponding gene (7, 8).Sequence information on rat AS3MT has provided a starting point to seek a broader perspective on its structure and function as an As methyltransferase, using genomic data to investigate the occurrence of homologous genes across a wide range of species.

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