Iron-sulfur clusters are ubiquitous and extensively studied cofactors in biology, but are still providing surprising functions and novel chemistry. Biochemical studies in the 1990s pointed to a role for iron-sulfur clusters in radical initiation, and led to identification of the radical SAM enzyme superfamily, an evolutionarily related group of enzymes that utilize a [4Fe-4S] cluster and S-adenosyl-L-methionine (SAM) to initiate diverse radical-based reactions throughout all kingdoms of life. Despite the limited sequence similarity and vastly divergent reactions catalyzed, the radical SAM enzymes appear to employ a common mechanism for initiation of radical chemistry, a mechanism we have helped to clarify over the last 25 years. A reduced [4Fe-4S]+cluster provides the electron needed for the reductive cleavage of SAM. The resulting [4Fe-4S]2+cluster can be re-reduced either by an external reductant with SAM acting as a cosubstrate, or by an electron provided during the re-formation of SAM in cases where SAM is used as a cofactor. The amino and carboxylate groups of SAM bind to the unique iron of the catalytic [4Fe-4S] cluster, placing the sulfonium of SAM in close proximity to the cluster. Surprising recent results have shown that the initial enzymatic cleavage of SAM generates an organometallic intermediate prior to liberation of the 5’-deoxyadenosyl radical, which initiates radical chemistry on substrate. This organometallic intermediate, denoted Ω, has a 5’-deoxyadenosyl moiety directly bound to the unique iron of the [4Fe-4S] cluster via the 5’-C, giving a structure that is directly analogous to Co-(5’-C) bond of the organometallic cofactor adenosylcobalamin. Our observation that this intermediate Ω is formed throughout the superfamily suggests that this is a key intermediate in initiating radical SAM reactions, and indicating that organometallic chemistry is much more broadly relevant in biology than previously thought.

Award Address (Alfred Bader Award in Bioinorganic or Bioorganic Chemistry sponsored by the Alfred R. Bader Fund). Novel chemistry for biological iron-sulfur clusters: Radical initiation via organometallic chemistry

2019 Spring National Meeting

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