Radical chemistry uses high-energy intermediates to carry out difficult reactions or even ones impossible to perform by the so-called polar chemistry. In nature, these reactions are fine-tuned by the structural environment within dedicated enzymes. Radical SAM proteins use an iron-sulfur cluster and S-adenosyl-L-methionine to initiate several radical reactions. These metalloproteins are notably involved in the biosynthesis of numerous cofactors and in the modification of peptides with antibiotic properties. The crystal structure of ThiH, involved in the anaerobic synthesis of vitamin B1, allowed us, by combining structural analysis and theoretical calculations, to understand how the substrate is recognized by the protein and how it is activated. In particular, hydrogen atom transfer is facilitated by a tunnel effect which allows the lowering of the activation barrier.
In conclusion, this work showed how a sum of small changes allowed to modify both the substrate selectivity and the specificity of a chemical reaction within this important family of proteins, thus paving the way to future molecular engineering approaches for more extensive use of these proteins as a biotechnological tool.
L-tyrosine-bound ThiH structure reveals C-C bond break differences within radical SAM aromatic amino acid lyases. Amara P, Saragaglia C, Mouesca JM, Martin L, Nicolet Y. Nature Communications; 13(1):2284
Contact : Yvain Nicolet( IBS/Metalloproteins group)