Matthews, M.L. et al. Nat. Chem. http://dx.doi.org/10.1038/nchem.2645 (2016).

Activity-based protein profiling (ABPP) is a technique used to profile the binding of small-molecule probes to proteins on a proteomic scale. The approach has been applied to assign functions to understudied enzymes. Typically, ABPP has been used to target reactive, nucleophilic amino acids such as serine and cysteine using electrophilic small-molecule probes. Matthews et al. turned this concept around to develop 'reverse-polarity' ABPP. By utilizing nucleophilic probes, they show it is now possible to capture electrophilic protein cofactors and post-translational modifications. Hydrazine-based ABPP probes covalently attach to electrophilic protein cofactors or modifications via click chemistry, enabling their purification and identification by mass-spectrometry-based proteomics. Using this approach, the authors discovered that the enzyme S-adenosyl-L-methionine decarboxylase contains a pyruvoyl cofactor that is controlled by intracellular methionine levels.