Chemical and Genetically Encoded Strategies for Spatiotemporal Control of Lipid Generation in Living Cells.

Mammalian cells synthesize thousands of distinct lipids, and lipid metabolism fundamentally influences signaling in both homeostatic and disease states. Despite considerable interest in the biological functions of diverse lipid species, direct study of their effects in biological systems has historically been limited by a lack of methods to modulate discrete lipid species with precise spatiotemporal control. Several efforts in lipid chemical biology focus on the development of technologies to generate individual lipid species with spatial and temporal control in living cells. Emerging strategies are enabling the on-demand generation of lipids in response to various stimuli. In this Perspective, we discuss three mechanistic approaches for controlled lipid generation: light-triggered production of lipids from modified precursors, orthogonal chemical release, and triggerable chemoenzymatic or genetically encoded enzymatic generation of lipids. We highlight the strengths and weaknesses of each platform, and we outline the design strategies that will shape the next generation of tools.