biostudies-literatureFu BHoward Hughes Medical InstituteNational Institutes of HealthNIGMS NIH HHSNational Science Foundation29645-29655https://www.ebi.ac.uk/biostudies/studies/S-EPMC11528403biostudies-literatureUnknown146(43)Radical enzymes, including the evolutionarily ancient glycyl radical enzyme (GRE) family, catalyze chemically challenging reactions that are involved in a myriad of important biological processes. All GREs possess an essential, conserved backbone glycine that forms a stable, catalytically essential α-carbon radical. Through close examination of the GRE family, we unexpectedly identified hundreds of noncanonical GRE homologs that encode either an alanine, serine, or threonine in place of the catalytic glycine residue. Contrary to a long-standing belief, we experimentally demonstrate that these aminoacyl radical enzymes (AAREs) form stable α-carbon radicals on the three cognate residues when activated by partner activating enzymes. The previously unrecognized AAREs are widespread in microbiaJournal of the American Chemical SocietyDiscovery of a New Class of Aminoacyl Radical Enzymes Expands Nature's Known Radical Chemistry.PMC11528403F32 GM140713T32 GM095450MCB-1908587R35 GM131889GM131889GM111097F32GM140713DGE11441525T32GM095450R01 GM111097CHE-2038052Fu BYang HBeller HRHoffman BHKountz DJBroderick WEBroderick JBBalskus EPLundahl MNfalseDiscovery of a New Class of Aminoacyl Radical Enzymes Expands Nature's Known Radical Chemistry.Radical enzymes, including the evolutionarily ancient glycyl radical enzyme (GRE) family, catalyze chemically challenging reactions that are involved in a myriad of important biological processes. All GREs possess an essential, conserved backbone glycine that forms a stable, catalytically essential α-carbon radical. Through close examination of the GRE family, we unexpectedly identified hundreds of noncanonical GRE homologs that encode either an alanine, serine, or threonine in place of the catalytic glycine residue. Contrary to a long-standing belief, we experimentally demonstrate that these aminoacyl radical enzymes (AAREs) form stable α-carbon radicals on the three cognate residues when activated by partner activating enzymes. The previously unrecognized AAREs are widespread in microbia2024-01-01T00:00:00Z2024 Oct2026-06-02T04:01:33.088Z2025-04-06T23:17:31.824ZS-EPMC115284033939272010.1021/jacs.4c10348