A chemistry that ‘clicks” with lipids

Phosphatidic acid species are essential for biosynthesis of cellular glycerophospholipids and functions as a modulator of various cell signaling enzymes. Tracking the plethora of sources of phosphatidic acid has long been a goal, but even with advances in mass spectrometry the identification of substrate‐product relations for such a complex and rapidly metabolized intermediate has been elusive. Alkyne‐modified phospholipids can be unambiguously identified and differentiated from native species in complex mixtures by formation of dicobalthexacarbonyl complexes. This reaction is specific for alkynes and is unaffected by other glycerophospholipid‐related moieties. Enrichment of cells with alkyne‐derivatized fatty acids or glycerophospholipids followed by solid‐phase sequestration and release is a promising new method for unequivocally monitoring individual glycerophospholipids following incorporation into cells. This robust method for tracking modified lipids, is similar in application to ‘click’ chemistry, in that it provides a platform for metabolomic and molecular tracking of pathways. This technology is being used to interrogate substrate‐product relationships in lipid signaling networks, particularly to define the differential origins of phosphatidic acid. The chemistry can be applied to a broad spectrum of biological molecules beyond lipids as well.