Mechanistic Insights into As^III S-Adenosylmethionine Methyltransferase with Selenoimidazolium-Based Methylating...

Arsenite S-adenosylmethionine methyltransferase (ArsM), together with S-adenosylmethionine (SAM) cofactor, catalyzes the stepwise methylation of arsenite (iAs^III) to carcinogenic monomethylated (MMAs) and less toxic di- or trimethylated arsenicals (DMAs or TMAs). The molecular origins of the widely varying methylation efficiencies of ArsMs across organisms remain unclear. Here, we report a series of selenoimidazolium-based methylating agents that display distinct reactivity profiles and varying efficiencies in converting iAs^III to DMAs^V. The selenium analogues significantly outperform both their sulfur counterparts and SAM, the universal biological methyl donor. Methylation efficiency-governed by Se-CH₃ bond activation, transition-state stabilization, and reduction of pentavalent MMAs^V intermediate-increases in the order 2 < 5 < 6 ≪ 7 ≪ 9. Notably, the macrocyclic agent 9 displays exceptional reactivity, achieving 98% conversion and rate enhancements of up to ∼90-fold relative to SAM, driven by a network of cooperative noncovalent interactions that facilitate an S_N2 pathway. Consistent with this mechanism, steric enlargement of the alkyl group suppresses reactivity. Furthermore, in situ generated selone byproducts facilitate reduction of pentavalent MMAs^V intermediate, thereby accelerating DMAs formation in the arsenic methylation cycle. Collectively, these findings establish selenoimidazolium methyl donors as highly effective biomimetic methylating agents and provide design principles for advanced arsenic detoxification strategies.