Sulfonium‐Based Homolytic Substitution Observed for the Radical SAM Enzyme HemN

Abstract Sulfur‐based homolytic substitution (S H reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S‐adenosyl‐ l ‐methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di‐(5′‐deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical‐mediated S H reaction on the sulfonium center of SAM. The sulfonium‐based S H reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium‐based S H reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.