Stereoretentive Post-Translational Protein Editing
Xia‐Ping Fu, Yizhi Yuan, Ajay Jha, Nikita Levin, Andrew M. Giltrap, Jack Ren, Dimitrios Mamalis, Shabaz Mohammed, Benjamin G. Davis
Abstract
High Resolution Image Download MS PowerPoint Slide Chemical post-translational methods allow convergent side-chain editing of proteins without needing to resort to genetic intervention. Current approaches that allow the creation of constitutionally native side chains via C–C bond formation, using off-protein carbon-centered C· radicals added to unnatural amino acid radical acceptor (SOMOphile, singly occupied molecular orbital (SOMO)) “tags” such as dehydroalanine, are benign and wide-ranging. However, they also typically create epimeric mixtures of d /l -residues. Here, we describe a light-mediated desulfurative method that, through the creation and reaction of stereoretained on-protein l -alanyl C β · radicals, allows C β –H γ, C β –O γ, C β –Se γ, C β –B γ, and C β –C γ bond formation to flexibly generate site-selectively edited proteins with full retention of native stereochemistry under mild conditions from a natural amino acid precursor. This methodology shows great potential to explore protein side-chain diversity and function and in the construction of useful bioconjugates.