Lysophospholipid interactions with protein targets

Abstract

SummaryBioactive lysophospholipids include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), cyclic-phosphatidic acid (CPA) and alkyl glycerolphosphate (AGP). These lipid mediators stimulate a variety of responses that include cell survival, proliferation, migration, invasion, wound healing, and angiogenesis. Responses to lysophospholipids depend upon interactions with biomolecular targets in the G protein-coupled receptor (GPCR) and nuclear receptor families, as well as enzymes. Our current understanding of lysophospholipid interactions with these targets is based on a combination of lysophospholipid analog structure activity relationship studies as well as more direct structural characterization techniques such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and experimentally-validated molecular modeling. The direct structural characterization studies are the focus of this review, and provide the insight necessary to stimulate structure-based therapeutic lead discovery efforts in the future.

Lysophosphatidic Acid 2 Receptor-mediated Supramolecular Complex Formation Regulates Its Antiapoptotic Effect

“…It mediates diverse cellular responses important for cell survival, growth, differentiation, migration, inflammation, angiogenesis, and platelet aggregation (1,2). At least eight G protein-coupled LPA receptors have been identified: LPA 1 , LPA 2 , and LPA 3 of the endothelial differentiation gene family and the structurally distinct LPA 4 /P2Y9, LPA 5 /GPR92, LPA 6 /GPR87, LPA 7 /P2Y5, and LPA 8 /P2Y10 of the purinergic receptor cluster (3)(4)(5). These receptors couple to G i/o , G q/11 , G s , and/or G 12/13 proteins to activate various signaling pathways.…”

The Design and Synthesis of Autotaxin Inhibitors and Analogs of Lysophosphatidic Acid

“…Extracelular LPA is also generated via secreted PLA enzymes, phosphatidyl serine specific PLA 1 and secretory PLA 2 . Secretory type-II PLA 2 and phosphatidic acid selective PLA 1 , cleave surface exposed phosphatidic acid. LPA is also generated extracellularly by mild oxidation of low density lipoproteins.…”

“…It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. 1 Lysphosphatidic acid (LPA, Figure 1.1) is a simple phospholipid and consists of a glycerol backbone with a hydroxyl group at the sn-2 (or sn-1) position, a phosphate group at the sn-3 position, and a fatty acid chain at the sn-1 (or sn-2) position. Most of the LPA fatty acids are long chain saturated (16:0, 18:0) or unsaturated (18:1, 18:2, 20:4) fatty acids linked to the glycerol backbone by acyl or alkyl linkage.…”

“…LPA is generated from the hydrolysis of phosphatidic acid (PA) at sn-1 or sn-2 position by PLA 1 or PLA 2 , respectively. Activation of platelets results in LPA production by different mechanisms.…”

“…18 ATX is under feedback inhibition by its hydrolysis products LPA, CPA, and sphingosine-1-phosphate (S1P). 19 Lyso-PLD generates LPA by hydrolyzing the phosphodiester bond of lysphospholipids, which are formed by the action of PLA 1 and PLA 2 on phospholipids.…”