Beyond native reactivity: radical SAM enzymes as platforms for new-to-nature chemistry
- 1aNational Engineering Research Center for Carbohydrate Synthesis, College of Chemistry and Materials, Jiangxi Normal University, Nanchang 330022, China.
- 2bSchool of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
Abstract
Radical S-adenosylmethionine (rSAM) enzymes constitute one of the largest and most versatile enzyme superfamilies in biology, catalyzing diverse radical-mediated reactions essential for metabolism, cofactor biosynthesis, nucleic acid modification, and natural product formation. Central to their chemistry is the reductive cleavage of S-adenosylmethionine (SAM) by an iron–sulfur cluster, generating the highly reactive 5′-deoxyadenosyl radical (5′-dAdo˙), which initiates a broad range of challenging transformations. Recent advances have expanded the reactivity of rSAM enzymes beyond their natural roles, revealing unprecedented mechanistic flexibility and synthetic potential. Photochemical activation strategies now enable light-driven reduction of [4Fe–4S] clusters in the presence of biological or chemical photosensitizers, thereby initiating radical formation. In parallel, cobalamin-dependent radical SAM methyltransferases have opened new avenues for ethyl and fluoromethyl transfer chemistry using corresponding SAM analogues. Notably, the use of a strategically engineered, stable analogue, such as 7-deazaadenine-tetrazole-substituted F-SAM (F-7dz-tSAM), has successfully overcome inherent cofactor degradation. Noncanonical radical reactivity, exemplified by ArsL-catalyzed C–As bond formation and NosL-mediated photoinduced trifluoromethylation, demonstrates the capacity of rSAM enzymes to perform new-to-nature transformations. Lastly, the repurposing of rSAM enzymes for formylglycine generation has enabled orthogonal aldehyde-tag formation for bioorthogonal protein labeling, further expanding their utility in chemical biology. Collectively, these advances establish rSAM enzymes as versatile platforms for radical biocatalysis, chemical biology, and new-to-nature chemistry.
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BibTeX
@article{liu2026beyond,
title = {{Beyond native reactivity: radical SAM enzymes as platforms for new-to-nature chemistry}},
author = {Xuxue Liu and Xiangyang Gao and Sasipa Booranamonthol and Peng Wu and Rung-Yi Lai and Qi Zhang},
journal = {RSC Chemical Biology},
year = {2026},
month = sep,
doi = {10.1039/d6cb00249h},
url = {https://doi.org/10.1039/d6cb00249h},
note = {CC BY 3.0},
}
RIS
TY - JOUR
TI - Beyond native reactivity: radical SAM enzymes as platforms for new-to-nature chemistry
AU - Xuxue Liu
AU - Xiangyang Gao
AU - Sasipa Booranamonthol
AU - Peng Wu
AU - Rung-Yi Lai
AU - Qi Zhang
PY - 2026
DA - 2026/09/01
JO - RSC Chemical Biology
DO - 10.1039/d6cb00249h
UR - https://doi.org/10.1039/d6cb00249h
AB - Radical S-adenosylmethionine (rSAM) enzymes constitute one of the largest and most versatile enzyme superfamilies in biology, catalyzing diverse radical-mediated reactions essential for metabolism, cofactor biosynthesis, nucleic acid modification, and natural product formation. Central to their chemistry is the reductive cleavage of S-adenosylmethionine (SAM) by an iron–sulfur cluster, generating the highly reactive 5′-deoxyadenosyl radical (5′-dAdo˙), which initiates a broad range of challenging transformations. Recent advances have expanded the reactivity of rSAM enzymes beyond their natural roles, revealing unprecedented mechanistic flexibility and synthetic potential. Photochemical activation strategies now enable light-driven reduction of [4Fe–4S] clusters in the presence of biological or chemical photosensitizers, thereby initiating radical formation. In parallel, cobalamin-dependent radical SAM methyltransferases have opened new avenues for ethyl and fluoromethyl transfer chemistry using corresponding SAM analogues. Notably, the use of a strategically engineered, stable analogue, such as 7-deazaadenine-tetrazole-substituted F-SAM (F-7dz-tSAM), has successfully overcome inherent cofactor degradation. Noncanonical radical reactivity, exemplified by ArsL-catalyzed C–As bond formation and NosL-mediated photoinduced trifluoromethylation, demonstrates the capacity of rSAM enzymes to perform new-to-nature transformations. Lastly, the repurposing of rSAM enzymes for formylglycine generation has enabled orthogonal aldehyde-tag formation for bioorthogonal protein labeling, further expanding their utility in chemical biology. Collectively, these advances establish rSAM enzymes as versatile platforms for radical biocatalysis, chemical biology, and new-to-nature chemistry.
SN - 2633-0679
ER -