Diacylglycerol kinase (DGK or DAGK) is a family of enzymes that catalyzes the conversion ofdiacylglycerol (DAG) tophosphatidic acid (PA), utilizingATP as a source of the phosphate.[1] In non-stimulated cells, DGK activity is low, allowing DAG to be used forglycerophospholipid biosynthesis, but on receptor activation of thephosphoinositide pathway, DGK activity increases, driving the conversion of DAG to PA. As both lipids are thought to function as bioactivelipid signaling molecules with distinct cellular targets, DGK therefore occupies an important position, effectively serving as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another.[2]
Currently, nine members of the DGK family have been cloned and identified. Although all family members have conserved catalytic domains and twocysteine rich domains, they are further classified into five groups according to the presence of additional functional domains and substrate specificity.[5] These are as follows:
Type 1 - DGK-α, DGK-β, DGK-γ - containEF-hand motifs and arecoverin homology domain
In a phenotypic screen for small molecules that could stimulateinterleukin-2 (IL2) secretion from primary T cells in the presence or absence ofPD-1 suppression, BMS-684 was found to be able to act as a T cell checkpoint inhibitor. Further optimization led to the compound BMS-496. Using lipid-based photoaffinity probes, DGKα was identified as the primary target of BMS-496. BMS-496 induces translocation of DGKα to the plasma membrane. Further study found that these compounds also inhibit DGKζ and similarly induce translocation of DGKζ to the plasma membrane. Preclinical studies found that this strategy of dual DGKα/ζ inhibition can potentiate the anticancer effects ofPD-1 blockade.[6][7]
^Shulga, Yulia V.; Topham, Matthew K.; Epand, Richard M. (2011). "Regulation and Functions of Diacylglycerol Kinases".Chemical Reviews.111 (10):6186–6208.doi:10.1021/cr1004106.PMID21800853.
^Mérida I, Avila-Flores A, Merino E (January 2008). "Diacylglycerol kinases: at the hub of cell signalling".The Biochemical Journal.409 (1):1–18.doi:10.1042/BJ20071040.PMID18062770.
^van Blitterswijk WJ, Houssa B (October 2000). "Properties and functions of diacylglycerol kinases".Cellular Signalling.12 (9–10):595–605.doi:10.1016/s0898-6568(00)00113-3.PMID11080611.
