title: Biosynthesis of alkyl lysophosphatidic acid by diacylglycerol kinases.
abstract: Lysophosphatidic acid (LPA) designates a family of bioactive phosphoglycerides that differ in the length and degree of saturation of their radyl chain. Additional diversity is provided by the linkage of the radyl chain to glycerol: acyl, alkyl, or alk-1-enyl. Acyl-LPAs are the predominate species in tissues and biological fluids. Alkyl-LPAs exhibit distinct pharmacodynamics at LPA receptors, potently drive platelet aggregation, and contribute to ovarian cancer aggressiveness. Multiple biosynthetic pathways exist for alkyl-LPA production. Herein we report that diacylglycerol kinases (DGKs) contribute to cell-associated alkyl-LPA production involving phosphorylation of 1-alkyl-2-acetyl glycerol and document the biosynthesis of alkyl-LPA by DGKs in SKOV-3 ovarian cancer cells, specifically identifying the contribution of DGKα. Concurrently, we discovered that treating SKOV-3 ovarian cancer cell with a sphingosine analog stimulates conversion of exogenous 1-alkyl-2-acetyl glycerol to alkyl-LPA, indicating that DGKα contributes significantly to the production of alkyl-LPA in SKOV-3 cells and identifying cross-talk between the sphingolipid and glycerol lipid pathways.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gellett
authors.forename: Yugesh
authors.initials: Y
authors.lastname: Kharel
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
mesh_terms: D045744:Cell Line, Tumor; D019852:Diacylglycerol Kinase / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis*; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D008246:Lysophospholipids; D019852:Diacylglycerol Kinase; D013110:Sphingosine; C032881:lysophosphatidic acid