Discovery of a New\nClass of Aminoacyl Radical Enzymes\nExpands Nature’s Known Radical Chemistry

Radical enzymes, including the evolutionarily ancient\nglycyl radical\nenzyme (GRE) family, catalyze chemically challenging reactions that\nare involved in a myriad of important biological processes. All GREs\npossess an essential, conserved backbone glycine that forms a stable,\ncatalytically essential α-carbon radical. Through close examination\nof the GRE family, we unexpectedly identified hundreds of noncanonical\nGRE homologs that encode either an alanine, serine, or threonine in\nplace of the catalytic glycine residue. Contrary to a long-standing\nbelief, we experimentally demonstrate that these aminoacyl radical\nenzymes (AAREs) form stable α-carbon radicals on the three cognate\nresidues when activated by partner activating enzymes. The previously\nunrecognized AAREs are widespread in microbial genomes, highlighting\ntheir biological importance and potential for exhibiting new reactivity.\nCollectively, these studies expand the known radical chemistry of\nliving systems while raising questions about the evolutionary emergence\nof the AAREs.