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Nat Chem. 2017 Mar;9(3):234-243. doi: 10.1038/nchem.2645. Epub 2016 Oct 31.

Chemoproteomic profiling and discovery of protein electrophiles in human cells.

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Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
Bioinformatics Solutions Inc., Waterloo, Ontario N2L 6J2, Canada.
Chemistry and Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
École polytechnique fédérale de Lausanne, CH-1015 Lausanne, Switzerland.


Activity-based protein profiling (ABPP) serves as a chemical proteomic platform to discover and characterize functional amino acids in proteins on the basis of their enhanced reactivity towards small-molecule probes. This approach, to date, has mainly targeted nucleophilic functional groups, such as the side chains of serine and cysteine, using electrophilic probes. Here we show that 'reverse-polarity' (RP)-ABPP using clickable, nucleophilic hydrazine probes can capture and identify protein-bound electrophiles in cells. Using this approach, we demonstrate that the pyruvoyl cofactor of S-adenosyl-L-methionine decarboxylase (AMD1) is dynamically controlled by intracellular methionine concentrations. We also identify a heretofore unknown modification-an N-terminally bound glyoxylyl group-in the poorly characterized protein secernin-3. RP-ABPP thus provides a versatile method to monitor the metabolic regulation of electrophilic cofactors and discover novel types of electrophilic modifications on proteins in human cells.

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