Recent Advancements in Phospholipid Metabolic Labeling Using Clickable Probes

Herein, we present a perspective on recent advancements in the field of metabolic labeling as a method for interrogating phospholipids in terms of their biosynthesis, trafficking, and localization. Phospholipids are crucial for establishing cell morphology and signaling processes mediated by interactions between nearly all relevant cellular substrates. Bioorthogonal chemistry has provided a convenient platform in which clickable probes that mimic biologically active precursors are deployed to generate labeled versions of phospholipids in cells, enabling the study of downstream lipid activities without affecting cell viability. The introduction of a clickable handle onto precursor analogs enables varied postderivatization techniques such as visualization with fluorescence microscopy, enhancement of mass spectrometric detection, as well as enrichment and identification following biotinylation, just to name a few. In this perspective, we outline how the sum of these studies has provided a strong chemical toolbox for investigating lipid interactions and functions within a cellular environment, enabling a deeper understanding of these indispensable biomolecules.