Thematic minireview series
on radical SAM enzymes

S-adenosyl-L-methionine, or SAM, is one of the most common enzyme cofactors and serves as a ubiquitous methyl and sulfur donor for a variety of biological and chemical processes including macromolecule methylation and biosynthesis of organic molecules. One enzyme group that uses SAM is the radical SAM enzyme family, which is only partially understood and characterized. While the radical SAM enzyme family originally was thought to be relatively small, this family is now known to be quite large and highly prevalent. The Journal of Biological Chemistry recently published a thematic minireview series coordinated by associate editor Ruma Banerjee, at the University of Michigan, Ann Arbor, featuring six short review articles that describe the diversity of chemical reactions catalyzed by these enzymes and demonstrate their shared structural and mechanistic themes.

Members of the radical SAM enzyme family use SAM and an iron-sulfur (4Fe-4S) cluster to catalyze a wide array of chemical reactions. These enzymes share structural and mechanistic motifs despite their functional diversity.

In the first minireview, Catherine L. Drenann and coworkers at the Massachusetts Institute of Technology describe the SPASM and Twitch domains in radical SAM enzymes. In addition to a core CX3CX2C motif required for interaction with a (4Fe-4S) cluster, the SPASM and Twitch domains in several radical SAM enzymes form extensions that can interact with an additional (4Fe-4S) cluster. These extensions provide a platform to facilitate functional and substrate diversification.

While the structures of the SPASM and Twitch domains potentially can provide mechanistic insight into other radical SAM enzymes, several complex chemical mechanisms need to be elucidated. In the second minireview, Joseph Jarret of the University of Hawaii at Manoa discusses sulfur insertion chemistry required for a variety of biological cofactors and macromolecules. Mechanistically, radical SAM enzymes generate a highly reactive radical to introduce functional groups into normally unreactive positions containing carbon or phosphorus.

Continuing with elucidating the diverse and complex chemical reactions of radical SAM enzymes, Tadhg P. Begley of Texas A&M University and collaborators describe SAM enzymes’ roles in the synthesis of several biologically active cofactors, including the iron cofactor heme involved in oxygen transport in red blood cells. The authors describe the active site of radical SAM enzymes as a unique, protected environment that allows the generated radical to undergo complex and unprecedented organic chemical reactions.

Not surprisingly, the generation of unique metal-bearing cofactors requires a unique enzyme family. In the fourth minireview, Joan B. Broderick and colleagues at Montana State University describe the role of SAM enzymes involved in the generation of three unique metal cofactors. These metallocofactors are unusual in that they coordinate with unusual nonprotein ligands.

In the fifth minireview, Squire Booker and coworkers at the Pennsylvania State University cover methylation reactions mediated by radical SAM enzymes. While methylation of relatively unreactive carbon or phosphorus atoms in a variety of biomolecules is a common function of SAM enzymes, the mechanisms of methyl transfer for these reactions are diverse. The authors discuss the classification of radical SAM methyltransferase into four groups based on the components involved in the transfer reaction.

In the final minireview, Linlin Yang and Lei Li at Indiana University-Purdue University Indianapolis discuss the role of bacterial spore photoproduct lyase, a radical SAM enzyme, in ultraviolet-induced DNA damage repair. While the first several steps in DNA damage repair mediated by SPL have been elucidated, several questions remain as to the mechanism of the remainder of the catalytic cycle.

While the thematic minireviews provide multiple perspectives on our current knowledge of the enzyme superfamily, it is clear that we have only scratched the surface of these complex enzymes.

David Iaea David B. Iaea is a graduate student in the Tri-Institutional Program in Chemical Biology at Weill Cornell Medical College.