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J Am Chem Soc. 2018 Apr 18;140(15):4995-4999. doi: 10.1021/jacs.8b01087. Epub 2018 Apr 5.

Genetically Encoding Fluorosulfate-l-tyrosine To React with Lysine, Histidine, and Tyrosine via SuFEx in Proteins in Vivo.

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Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute , University of California San Francisco , 555 Mission Bay Boulevard South , San Francisco , California 94158 , United States.
College of Life Sciences , Zhejiang Sci-Tech University , Hangzhou 310018 , China.
Department of Chemistry and Center for Therapeutics and Diagnostics , Georgia State University , Atlanta , Georgia 30302 , United States.
Hangzhou Research Institute of Technical Institute of Physics and Chemistry , Chinese Academy of Sciences , Hangzhou 310018 , China.


Introducing new chemical reactivity into proteins in living cells would endow innovative covalent bonding ability to proteins for research and engineering in vivo. Latent bioreactive unnatural amino acids (Uaas) can be incorporated into proteins to react with target natural amino acid residues via proximity-enabled reactivity. To expand the diversity of proteins amenable to such reactivity in vivo, a chemical functionality that is biocompatible and able to react with multiple natural residues under physiological conditions is highly desirable. Here we report the genetic encoding of fluorosulfate-l-tyrosine (FSY), the first latent bioreactive Uaa that undergoes sulfur-fluoride exchange (SuFEx) on proteins in vivo. FSY was found nontoxic to Escherichia coli and mammalian cells; after being incorporated into proteins, it selectively reacted with proximal lysine, histidine, and tyrosine via SuFEx, generating covalent intraprotein bridge and interprotein cross-link of interacting proteins directly in living cells. The proximity-activatable reactivity, multitargeting ability, and excellent biocompatibility of FSY will be invaluable for covalent manipulation of proteins in vivo. Moreover, genetically encoded FSY hereby empowers general proteins with the next generation of click chemistry, SuFEx, which will afford broad utilities in chemical biology, drug discovery, and biotherapeutics.

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