Diacylglycerol kinases: Molecular mechanism of cellular and physiological functions

Diacylglycerol (DAG) and phosphatidic acid (PA), being positioned in the central hub of glycerophospholipid biosynthesis pathways, are lipids vital for the structural and functional integrity of the cell. DAG kinases (DGKs) are the enzymes responsible for the conversion of DAG to PA to regulate the dynamically changing spatiotemporal levels of these lipids in various organelles and cellular structures. DAG and PA thereby function intricately in mechanistic events like cell signaling in association with the intracellular lipid profiles controlling membrane physiology. In mammalian cells, there are ten DGK isoforms, i.e., α, β, γ, δ, η, κ, ε, ζ, ι, θ, and their splice variants. Recent advancement of structural prediction algorism enables us to gain unparalleled insights into their molecular architectures, despite limited experimental data available to date. The structural information gives fundamental clues to understand pertinent cellular events that are reviewed in this work on a broad range of topics in health and disease. Upon cell stimuli, DAG is formed by hydrolysis of a phospholipid such as phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P₂) via a phospholipase C (PLC). While relationship of the DGK activity with specific lipid acyl-chain species is being recognized, that with the sn-1 ether linkage like the vinyl ether has not yet been revealed. Importance of these relationships may be evident, considering the known regulation of the PLC activity by lipid rafts. Elucidation of molecular details of DGK functions in the context of membrane biophysics is thus essential for our understanding of cellular events in the individual tissues and organs.