TY - JOUR
T1 - The new epoch of structural insights into radical SAM enzymology
AU - Lachowicz, Jake
AU - Lee, James
AU - Sagatova, Alia
AU - Jew, Kristen
AU - Grove, Tyler L.
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/12
Y1 - 2023/12
N2 - The Radical SAM (RS) superfamily of enzymes catalyzes a wide array of enzymatic reactions. The majority of these enzymes employ an electron from a reduced [4Fe–4S]+1 cluster to facilitate the reductive cleavage of S-adenosyl-L-methionine, thereby producing a highly reactive 5′-deoxyadenosyl radical (5′-dA⋅) and L-methionine. Typically, RS enzymes use this 5′-dA⋅ to extract a hydrogen atom from the target substrate, starting the cascade of an expansive and impressive variety of chemical transformations. While a great deal of understanding has been gleaned for 5′-dA⋅ formation, because of the chemical diversity within this superfamily, the subsequent chemical transformations have only been fully elucidated in a few examples. In addition, with the advent of new sequencing technology, the size of this family now surpasses 700,000 members, with the number of uncharacterized enzymes and domains also rapidly expanding. In this review, we outline the history of RS enzyme characterization in what we term “epochs” based on advances in technology designed for stably producing these enzymes in an active state. We propose that the state of the field has entered the fourth epoch, which we argue should commence with a protein structure initiative focused solely on RS enzymes to properly tackle this unique superfamily and uncover more novel chemical transformations that likely exist.
AB - The Radical SAM (RS) superfamily of enzymes catalyzes a wide array of enzymatic reactions. The majority of these enzymes employ an electron from a reduced [4Fe–4S]+1 cluster to facilitate the reductive cleavage of S-adenosyl-L-methionine, thereby producing a highly reactive 5′-deoxyadenosyl radical (5′-dA⋅) and L-methionine. Typically, RS enzymes use this 5′-dA⋅ to extract a hydrogen atom from the target substrate, starting the cascade of an expansive and impressive variety of chemical transformations. While a great deal of understanding has been gleaned for 5′-dA⋅ formation, because of the chemical diversity within this superfamily, the subsequent chemical transformations have only been fully elucidated in a few examples. In addition, with the advent of new sequencing technology, the size of this family now surpasses 700,000 members, with the number of uncharacterized enzymes and domains also rapidly expanding. In this review, we outline the history of RS enzyme characterization in what we term “epochs” based on advances in technology designed for stably producing these enzymes in an active state. We propose that the state of the field has entered the fourth epoch, which we argue should commence with a protein structure initiative focused solely on RS enzymes to properly tackle this unique superfamily and uncover more novel chemical transformations that likely exist.
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U2 - 10.1016/j.sbi.2023.102720
DO - 10.1016/j.sbi.2023.102720
M3 - Review article
C2 - 37862762
AN - SCOPUS:85174174537
SN - 0959-440X
VL - 83
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
M1 - 102720
ER -