EPA Science Inventory

Monomethylioarsenicals are substratres for human arsenic (+3 oxidation state) methyltransferase

Citation:

Thomas, D., M. Kohan, J. Naratilova, Z. Drobna, M. Styblo, K. Bradham, P. Alava, AND J. Creed. Monomethylioarsenicals are substratres for human arsenic (+3 oxidation state) methyltransferase. Presented at Society of Toxicology, Phoenix, AZ, March 23 - 27, 2014.

Description:

Monomethylthioarsenicals are substrates for human arsenic (+3 oxida1tion state) methyltransferase Methylated thioarsenicals are structural analogs of methylated oxyarsenic in which one or more oxygen atom bound to arsenic is replaced by a sulfur atom. In sulfide-rich environments, methylated thioarsenicals form from corresponding methylated oxyarsenicals. Thus monomethylarsonic acid (MMA) is readily converted to monomethylmonothioarsenate (MMMTA), monomethyldithioarsenate (MMDTA), and monomethyltrithioarsenate. The metabolic fate of these m thylated thioarsenicals is unknown. Human arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes transfer of a methyl group from S-adenosylmethionine (AdoMet) to an arsenical substrate. To date, all identified substrates for AS3MT-catalyzed methylation are oxyarsenicals that contain arsenic in the trivalent oxidation state; oxyarsenicals with arsenic in the pentavalent oxidation state (e.g., MMA) are not substrates for AS3MT catalyzed methylation. Thus, MMMTA and MMDTA which contain arsenic in the pentavalent oxidation state are unlikely candidates for AS3MT-catalyzed methylation. Using anaerobic conditions to prevent oxidation of thioarsenicals, MMMTA or MMDTA were added to reaction mixtures containing AS3MT, AdoMet, and the non-thiol reductant TCEP. Reaction products were separated by ion-exchange chromatography and detected by ICP-MS. Incubation of MMMTA with AS3MT yields dimethylmonothioarsenate (DMMTA) as the primary metabolite and of MMDTA with AS3MT yields dimethyldithioarsenate (DMDTA) as the primary metabolite. The absence of other metabolites in reaction mixtures suggests that MMMTA and MMDTA are substrates for AS3MT-catalyzed reactions then interconversion which add a methyl group to substrates to produce DMMTA and DMDTA. If MMMTA and MMDTA are substrates for AS3MT-catalyzed reactions, then interconversion of oxy- and thio-arsenicals occurs not only by exchange of oxygen and sulfur moieties but also by direct competition for enzymatically catalyzed methylation. (This abstract does not reflect the policy of the U.S. Environmental Protection Agency.)

Purpose/Objective:

This abstract examines the use of monomethylated thioarsenicals as substrates of methylation of human arsenic (+3 oxidation state) methyltransferase. Under anaerobic conditions, these thioarsenicals are substrates for methylation. These findings suggest a novel pathway for the conversion of arsenicals which complements previously described pathways for activation of inorganic arsenic.

URLs/Downloads:

DTHOMASABSTRACT.PDF   (PDF,NA pp, 449.953 KB,  about PDF)

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Completion Date: 05/22/2014
Record Last Revised: 05/22/2014
Record Created: 05/22/2014
Record Released: 05/22/2014
OMB Category: Other
Record ID: 276527

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

PHARMACOKINETICS BRANCH