Tunable Amine-Reactive Electrophiles for Selective Profiling of Lysine
Kuei-Chien Tang
Present address: Department of Chemistry, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorDr. Jian Cao
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorLisa M. Boatner
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Present address: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorLinwei Li
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorJonathan Farhi
Department of Radiation Oncology, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorProf. Dr. Kendall N. Houk
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorProf. Dr. Jennifer Spangle
Department of Radiation Oncology, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorProf. Dr. Keriann M. Backus
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Present address: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorCorresponding Author
Prof. Dr. Monika Raj
Present address: Department of Chemistry, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorKuei-Chien Tang
Present address: Department of Chemistry, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorDr. Jian Cao
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorLisa M. Boatner
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Present address: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorLinwei Li
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorJonathan Farhi
Department of Radiation Oncology, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorProf. Dr. Kendall N. Houk
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorProf. Dr. Jennifer Spangle
Department of Radiation Oncology, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorProf. Dr. Keriann M. Backus
Department of Chemistry and Biochemistry, College of Arts and Sciences, UCLA, Los Angeles, CA, 90095 USA
Present address: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095 USA
Search for more papers by this authorCorresponding Author
Prof. Dr. Monika Raj
Present address: Department of Chemistry, Emory University, Atlanta, GA, 30322 USA
Search for more papers by this authorAbstract
Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of tunable amine-reactive electrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective probes for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins in different cell lines, and for the selective identification of lysines in the human proteome on a global scale.
Conflict of interest
The authors declare no conflict of interest.
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