Emerging trends in chemoproteomics: Mapping the landscape of protein–metabolite interactions

Protein-metabolite interactions (PMIs) are fundamental regulators of cellular metabolism, influencing essential processes such as energy homeostasis, signal transduction, and gene expression. However, their transient and dynamic nature presents significant challenges for detection. Chemoproteomics has emerged as a powerful and versatile strategy for capturing and characterizing PMIs with proteome-wide resolution. These approaches can be broadly categorized into derivatization-based methods, which utilize chemically modified probes to enrich protein targets, and derivatization-free methods, which detect changes in protein physicochemical properties upon metabolite binding, aided by highly sensitive proteomic analysis. In this review, we discuss recent advancements in both strategies, highlighting their applications in mapping PMIs and their potential to deepen our understanding of cellular metabolism and disease mechanisms.