Experimental methods for dissecting the terraincognita of protein-metabolite interactomes

A single metabolite can have diverse biological functions, from biosynthetic intermediates to signaling molecules that binds to one or more proteins. Similarly, a single protein can interact with one or many different metabolites. The extensive and highly dynamic protein-metabolite interaction network affects and shapes all cellular processes. Recent progress in omics technologies has made global profiling of protein-metabolite interaction feasible. Herein, we aim to highlight experimental approaches developed to characterize protein-metabolite interactomes, with particular emphasis on co-fractionation mass spectrometry. We will also discuss remaining grand challenges, including the largely incomplete chemical characterization of metabolomes.