AS3MT (arsenite methyltransferase) is a cytosolic enzyme that catalyzes the sequential methylation of trivalent arsenicals using S-adenosylmethionine as a methyl donor 1. The enzyme converts arsenite to methylarsonate, which is then reduced to methylarsonite and subsequently methylated to form the less toxic dimethylarsinate (cacodylate) 1. AS3MT exhibits tissue-specific expression patterns, being present in liver, brain, and adrenal gland but absent in keratinocytes and certain endothelial cells, indicating transcriptional regulation involving the Sp1 transcription factor binding to a GC box in the promoter region 2. Genetic polymorphisms in AS3MT significantly impact arsenic metabolism, with variants like rs3740390, rs11191439, and rs11191453 altering urinary arsenic metabolite concentrations and potentially affecting disease susceptibility 3. A human-specific AS3MT isoform (AS3MTd2d3) lacks methyltransferase activity but is associated with schizophrenia risk through the 10q24.32 locus 4. This isoform disrupts mitotic spindle orientation and neural differentiation during brain development, leading to altered cell fate decisions and behavioral deficits in transgenic mouse models 5. AS3MT polymorphisms are also linked to type 2 diabetes risk in arsenic-exposed populations, highlighting its broader role in arsenic-related health outcomes 6.