Diacylglycerol kinases: Relationship to other lipid kinases

Abstract

Lipid kinases regulate a wide variety of cellular functions and have emerged as one the most promising targets for drug design. Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the ATP-dependent phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PtdOH). Despite the critical role in lipid biosynthesis, both DAG and PtdOH have been shown as bioactive lipids mediating a number of signaling pathways. Although there is increasing recognition of their role in signaling systems, our understanding of the key enzyme which regulate the balance of these two lipid messages remain limited. Solved structures provide a wealth of information for understanding the function and regulation of these enzymes. Solving the structures of mammalian DGKs by traditional NMR and X-ray crystallography approaches have been challenging and so far, there are still no three-dimensional structures of these DGKs. Despite this, some insights may be gained by examining the similarities and differences between prokaryotic DGKs and other mammalian lipid kinases. This review focuses on summarizing and comparing the structure of prokaryotic and mammalian DGKs as well as two other lipid kinases: sphingosine kinase and phosphatidylinositol-3-kinase. How these known lipid kinases structures relate to mammalian DGKs will also be discussed.

Figure 1.

DgkB and SK1 overlap structurally. A. DgkB in yellow with the ATP binding site (PDB ID 2QV7). B. SK1 in Marine Blue with the ATP binding site shown with a black box. C. DgkB as an electrostatic surface shown the positive patch close to the ATP binding site (View from the top). D. SK1 as an electrostatic surface shown the positive patch close to the ATP binding site (View from the top).

Figure 2.

Structural model of p110α/iSH2 homodimer. A. Scheme of the p110α/p85α domain organization. B. p110α/iSH2 homodimer with labeled ATP-binding site and ribbon diagram of the kinase domain.