Culturing a discerning palette for spatiofunctional profiling

Recent innovations in proteomics have opened a window into how proteins distribute within cells. However, spatial reconnaissance is often not sufficient to inform on mechanism. Such information also does not inherently suggest how to functionally perturb proteins in specific regions, which is ultimately required for biological studies. We propose a new concept, spatiofunctional profiling that uses (preter)natural metabolites to census proteins that have the proclivity to engage with specific small-molecule ligands in a specific locale. Based on our studies on signaling by reactive (preter)natural metabolites, this strategy will index proteins within a specific locale that are susceptible to chemical manipulation. • Quantitative mapping of chemical actionability of local proteomes. • Challenges and limitations. • Translational applications and future prospects.