Nonsynonymous Polymorphisms in the Human AS3MT Arsenic Methylation Gene: Implications for Arsenic Toxicity.

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Arsenic methylation pathways deciphered with a biochemical approach

Expert opinion

Arsenic is a natural metalloid substance that has been well known to both “healers” and the “poisoner” throughout history. Through its several metabolites, Arsenic toxicity is a global health problem affecting many millions of people worldwide. Contamination is caused by arsenic from natural geological sources leaching into aquifers and contaminating drinking water and may also result from mining and other industrial processes. Arsenic is ubiquitous in our environment and is both a potent neurological and liver toxin as well as a lung, bladder, and skin carcinogen.
Nonetheless, not every individual responds to Arsenic exposure in the same manner, indicating that individuals may metabolize arsenic differently. What is the underlying biological rational?
In the liver, Arsenic methylated metabolites are produced by an enzyme called AS3MT, which demonstrates S-adenosylmethionine methyltransferase (SAM) activity. By using several variants of AS3MT, reflecting Single-Nucleotide Polymorphisms (SNPs) naturally found in several populations in different countries, Jiaojiao Li studied their potency with respect to Arsenic methylation and the types of metabolites produced. Full kinetic parameter characterization was conducted using a straightforward in-vitro assay using recombinant AS3MT variants.
The polymorphism of individual responses towards arsenic toxicity has now been assessed clearly at the molecular level and is controlled by a key enzyme, AS3MT.
Nero knew that Arsenic was a powerful poison and used it to murder his stepbrother Britannicus, thus becoming Emperor of Rome. Unfortunately for him, Britannicus did not have the protective AS3MT variant to protect him from this tragic outcome. When science explains history…

Abstract

Arsenic methylation, the primary biotransformation in the human body, is catalyzed by the enzyme As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT). This process is thought to be protective from acute high-level arsenic exposure. However, with long-term low-level exposure, hAS3MT produces intracellular methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)), which are considerably more toxic than inorganic As(III) and may contribute to arsenic-related diseases. Several single nucleotide polymorphisms (SNPs) in putative regulatory elements of the hAS3MT gene have been shown to be protective. In contrast, three previously identified exonic SNPs (R173W, M287T, and T306I) may be deleterious. The goal of this study was to examine the effect of single amino acid substitutions in hAS3MT on the activity of the enzyme that might explain their contributions to adverse health effects of environmental arsenic. We identified five additional intragenic variants in hAS3MT (H51R, C61W, I136T, W203C, and R251H). We purified the eight polymorphic hAS3MT proteins and characterized their enzymatic properties. Each enzyme had low methylation activity through decreased affinity for substrate, lower overall rates of catalysis, or lower stability. We propose that amino acid substitutions in hAS3MT with decreased catalytic activity lead to detrimental responses to environmental arsenic and may increase the risk of arsenic-related diseases.

Details

Chemical Research in Toxicology. 2017 Jul 17;30(7):1481-1491.

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