Membrane Interactions and Diacylglycerol Kinases

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Most lipids of biological membranes have a polar portion (headgroup) and a non-polar portion (acyl chains). There has been relatively little work done to understand the role of the acyl chains, yet certain acyl chains are heavily enriched in specific lipid classes. Prime examples of this sorting are the acyl chains of the lipid intermediates of the phosphatidylinositol cycle (PI-cycle) that are highly enriched in the 1-stearoyl-2-arachidonoyl species. The selective distribution of acyl chains has important consequences for the formation of specific molecular species of lipids that can act as signals, as well as to determine the physical properties of membrane domains. One enzyme contributing to the enrichment of specific acyl chains in the PI-cycle is the epsilon isoform of diacylglycerol kinase (DGKe). Among the ten isoforms of DGK found in mammals, DGKe is unique in having specificity for substrates with the particular acyl chains. We have also identified the segment of DGKe that is responsible for this recognition. This is leading to a fundamental understanding of how acyl chains are sorted to different lipids in the cell. One of the acyl chains that is recognized is the arachidonoyl group. This moiety is found in several different lipid signalling systems. We have evidence that there is a common recognition mechanism among all of these systems. Another DGK, DGKd, greatly increases its expression level after differentiation of 3T3-L1 cells to adipocytes. DGKd has a potent regulatory role in lipid metabolism. There is currently a poor understanding of the mechanism by which this occurs. We will determine the signal transduction pathway used by DGKd to regulate lipid synthesis. Our studies on the mechanism of metabolic regulation by DGKd will allow a development of an understanding of the pathways affected by this enzyme and the mechanism of this regulation. DGKd appears to have particular importance to biology, since it is the only isoform that results in non-viable offspring when knocked out.