The Structure of an As(III) S‑Adenosylmethionine Methyltransferase with 3‑Coordinately Bound As(III) Depicts the First Step in Catalysis

Arsenic is a ubiquitous environmental toxic substance and a Class 1 human carcinogen. Arsenic methylation by the enzyme As­(III) S-adenosylmethionine (SAM) methyltransferase (ArsM in microbes or AS3MT in animals) detoxifies As­(III) in microbes but transforms it into more toxic and potentially more carcinogenic methylated species in humans. We previously proposed a reaction pathway for ArsM/AS3MT that involves initial 3-coordinate binding of As­(III). To date, reported structures have had only 2-coordinately bound trivalent arsenicals. Here we report a crystal structure of CmArsM from Cyanidioschyzon sp.5508 in which As­(III) is 3-coordinately bound to three conserved cysteine residues with a molecule of the product S-adenosyl-l-homocysteine bound in the SAM binding site. We propose that this structure represents the first step in the catalytic cycle. In a previously reported SAM-bound structure, a disulfide bond is formed between two conserved cysteine residues. Comparison of these two structures indicates that there is a conformational change in the N-terminal domain of CmArsM that moves a loop to allow formation of the 3-coordinate As­(III) binding site. We propose that this conformational change is an initial step in the As­(III) SAM methyltransferase catalytic cycle.