Beyond native reactivity: radical SAM enzymes as platforms for new-to-nature chemistry
Year: 2026
Type: review
Abstract: -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.
Source: RSC Chemical Biology
DOI: 10.1039/d6cb00249h
Institutions: Jiangxi Normal University, Suranaree University of Technology
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,962
OpenAlex ID: W7212220392