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

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.

Natural variation in C. elegans arsenic toxicity is explained by differences in branched chain amino acid metabolism

“…In this study, we characterized the effects of C. elegans natural genetic variation on physiological responses to the pervasive environmental toxin arsenic trioxide. Though the effects of this toxin have been extensively studied in a variety of systems (Ratnaike, 2003; Mandal and Suzuki, 2002; Bergquist et al, 2009; Paul et al, 2014; Shen et al, 2013), recent evidence from human population studies have revealed local adaptations within region-specific subpopulations (Schlebusch et al, 2015; Fujihara et al, 2009; Gomez-Rubio et al, 2010; Li et al, 2017). Our investigation into the natural variation in C. elegans responses to arsenic trioxide led to the discovery of a novel mechanism by which this compound could elicit toxicity.…”

Synonymous single nucleotide polymorphism in arsenic (+3) methyltransferase of the Western mosquitofish (Gambusia affinis) and its gene expression among field populations

“…In human MDR1 (multidrug resistance 1), silent SNPs post-transcriptionally affected timing of cotranslational folding, resulted in altered structure of substrate and inhibitor interaction sites (Kimchi-Sarfaty et al 2007). In humans, nonsynonymous as3mt SNPs also changed arsenic-affinity and stability of as3mt through conformational structure changes of proteins, but not by changing gene expression (Li et al 2017).…”

Arsenic Methyltransferase and Methylation of Inorganic Arsenic

“…Mutants with residue at 32 and 61 can still methylate MMA to DMA, but, mutants at 174 and 224 cannot take part in any of the two methylation steps [ 48 ]. With the discovery of new polymorphic sites in human AS3MTs [ 51 ], all eight mutant proteins showed decreased methylation activity in vitro due to among other factors, their low substrate affinity, and stability [ 52 ].…”