Diacylglycerol Kinase-epsilon: Properties and Biological Roles

In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGK epsilon has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGK epsilon, is also the only DGK devoid of a regulatory domain. DGK epsilon is the only DGK isoform that has a hydrophobic segment that is predicted to form a transmembrane helix. As the only membrane-bound, constitutively active DGK isoform with exquisite specificity for particular molecular species of DAG, the functional overlap between DGK epsilon and other DGKs is predicted to be minimal. DGK epsilon exhibits specificity for DAG containing the same acyl chains as those found in the lipid intermediates of the phosphatidylinositol-cycle. It has also been shown that DGK epsilon affects the acyl chain composition of phosphatidylinositol in whole cells. It is thus likely that DGK epsilon is responsible for catalyzing one step in the phosphatidylinositol-cycle. Steps of this cycle take place in both the plasma membrane and the endoplasmic reticulum membrane. DGK epsilon is likely present in both of these membranes. DGK epsilon is the only DGK isoform that is associated with a human disease. Indeed, recessive loss-of-function mutations in DGK epsilon cause atypical hemolytic-uremic syndrome (aHUS). This condition is characterized by thrombosis in the small vessels of the kidney. It causes acute renal insufficiency in infancy and most patients develop end-stage renal failure before adulthood. Disease pathophysiology is poorly understood and there is no therapy. There are also data suggesting that DGK epsilon may play a role in epilepsy and Huntington disease. Thus, DGK epsilon has many unique molecular and biochemical properties when compared to all other DGK isoforms. DGK epsilon homologs also contain a number of conserved sequence features that are distinctive characteristics of either the rodents or specific groups of primate homologs. How cells, tissues and organisms harness DGK epsilon's catalytic prowess remains unclear. The discovery of DGK epsilon's role in causing aHUS will hopefully boost efforts to unravel the mechanisms by which DGK epsilon dysfunction causes disease.