Discovery of a New Class of Aminoacyl Radical Enzymes Expands Nature’s Known Radical Chemistry

• Published in: Journal of the American Chemical Society Vol. 146; no. 43; pp. 29645 - 29655
• Main Authors: Fu, Beverly, Yang, Hao, Kountz, Duncan J., Lundahl, Maike N., Beller, Harry R., Broderick, William E., Broderick, Joan B., Hoffman, Brian H., Balskus, Emily P.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30.10.2024
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.4c10348

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 microbial genomes, highlighting their biological importance and potential for exhibiting new reactivity. Collectively, these studies expand the known radical chemistry of living systems while raising questions about the evolutionary emergence of the AAREs.