Arsenite methyltransferase (AS3MT) (AS3MT)

Arsenite methyltransferase (AS3MT) is the primary enzyme responsible for the biotransformation of inorganic arsenic in humans, a process often referred to as arsenic transformation (9, 11). This enzyme catalyzes the sequential methylation of trivalent inorganic arsenic (arsenite) using S-adenosylmethionine as the methyl donor and glutathione as a reducing agent, producing monomethylated and dimethylated species (3, 12). While historically viewed as a detoxification pathway that facilitates excretion, this process is now understood to be an activation mechanism that generates highly reactive trivalent intermediates, such as monomethylarsonous acid (MMAIII), which are significantly more toxic and carcinogenic than the parent inorganic compounds (3, 10). Chronic exposure to arsenic and its metabolic products is linked to various diseases, including skin, bladder, and lung cancers, as well as cardiovascular disorders and diabetes (9, 16). AS3MT is considered a relevant therapeutic target because its modulation could potentially reduce the production of these toxic trivalent intermediates and alleviate the long-term health risks of arsenic exposure (3, 6). Small molecule inhibitors of hAS3MT have been identified in experimental high-throughput screens as potential tools for preventing arsenic-related diseases (3). Furthermore, AS3MT plays a critical role in the metabolism of arsenic trioxide, a clinical drug used for treating acute promyelocytic leukemia, making the enzyme's activity and genetic variability important determinants of drug efficacy and safety (9, 15). Individual susceptibility to arsenic toxicity is significantly influenced by polymorphisms in the AS3MT gene, which affect the efficiency of arsenic transformation (10, 11).

Other names

Arsenic biotransformationArsenic metabolismAs(III) methyltransferaseS-adenosyl-L-methionine:arsenic(III) methyltransferaseCYT19Methyltransferase AS3MT

Experimental drugs target AS3MT via noncompetitive inhibition of methyltransferase activity to block the formation of toxic trivalent methylated arsenic species (3). Arsenic trioxide acts as a substrate for AS3MT-mediated metabolic conversion, affecting its clearance and therapeutic activity (9, 14).