Structure/Activity Relationships in Lysophosphatidic Acid: The 2-Hydroxyl Moiety

Lynch, Kevin R.; Hopper, Darrin W.; Carlisle, Steven J.; Catalano, John G.; Zhang, Ming; Macdonald, Timothy L.

doi:10.1124/mol.52.1.75

Cited by 33 publications

(39 citation statements)

References 34 publications

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“…Furthermore, FAPs lack the glycerol backbone; thus, the present findings provide compelling evidence that it is not required for ligand activity. These observations are in complete agreement with earlier structure-activity studies in which LPA receptors showed a high degree of tolerance to analogs with serine, tyrosine, or ethanolamine in place of the glycerol backbone (Sugiura et al, 1994;Jalink et al, 1995;Lynch et al, 1997;Hooks et al, 1998).…”

Section: Discussionsupporting

confidence: 82%

Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of Lysophosphatidic Acid Receptors

et al. 2003

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A more complete understanding of the physiological and pathological role of lysophosphatidic acid (LPA) requires receptor subtype-specific agonists and antagonists. Here, we report the synthesis and pharmacological characterization of fatty alcohol phosphates (FAP) containing saturated hydrocarbon chains from 4 to 22 carbons in length. Selection of FAP as the lead structure was based on computational modeling as a minimal structure that satisfies the two-point pharmacophore developed earlier for the interaction of LPA with its receptors. Decyl and dodecyl FAPs (FAP-10 and FAP-12) were specific agonists of LPA 2 (EC 50 ϭ 3.7 Ϯ 0.2 M and 700 Ϯ 22 nM, respectively), yet selective antagonists of LPA 3 (K i ϭ 90 nM for FAP-12) and FAP-12 was a weak antagonist of LPA 1 . Neither LPA 1 nor LPA 3 receptors were activated by FAPs; in contrast, LPA 2 was activated by FAPs with carbon chains between 10 and 14. Computational modeling was used to evaluate the interaction between individual FAPs (8 to 18) with LPA 2 by docking each compound in the LPA binding site. FAP-12 displayed the lowest docked energy, consistent with its lower observed EC 50 . The inhibitory effect of FAP showed a strong hydrocarbon chain length dependence with C12 being optimum in the Xenopus laevis oocytes and in LPA 3 -expressing RH7777 cells. FAP-12 did not activate or interfere with several other G-protein-coupled receptors, including S1P-induced responses through S1P 1,2,3,5 receptors. These data suggest that FAPs are ligands of LPA receptors and that FAP-10 and FAP-12 are the first receptor subtype-specific agonists for LPA 2 .

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Section: Discussionsupporting

confidence: 82%

Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of Lysophosphatidic Acid Receptors

et al. 2003

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“…1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn-glycero-3-phosphate (monosodium salt; DOPA), 1,2-dioleoyl-sn-glycero-3-phosphoserine (sodium salt; DOPS), 1-oleoyl-sn-glycero-3-phosphate (sodium salt; LPA), and 1-oleoyl-sn-glycero-3-phosphocholine (LPC) were purchased from Avanti Polar Lipids (Birmingham, AL). 1-Oleoyl-3-(phosphoryl)propanediol (dehydroxy-LPA) was synthesized as reported previously (22). Lipid purity was checked by thin-layer chromatography and judged to be >99%.…”

Section: Methodsmentioning

confidence: 99%

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special?

et al. 2005

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Phosphatidic acid and lysophosphatidic acid are minor but important anionic bioactive lipids involved in a number of key cellular processes, yet these molecules have a simple phosphate headgroup.To find out what is so special about these lipids, we determined the ionization behavior of phosphatidic acid (PA) and lysophosphatidic acid (LPA) in extended (flat) mixed lipid bilayers using magic angle spinning 31 P NMR. Our data show two surprising results. First, despite identical phosphomonoester headgroups, LPA carries more negative charge than PA when present in a phosphatidylcholine bilayer. Dehydroxy-LPA [1-oleoyl-3-(phosphoryl)propanediol] behaves in a manner identical to that of PA, indicating that the difference in negative charge between LPA and PA is caused by the hydroxyl on the glycerol backbone of LPA and its interaction with the phosphomonoester headgroup. Second, deprotonation of phosphatidic acid and lysophosphatidic acid was found to be strongly stimulated by the inclusion of phosphatidylethanolamine in the bilayer, indicating that lipid headgroup charge depends on local lipid composition and will vary between the different subcellular locations of (L)PA. Our findings can be understood in terms of a hydrogen bond formed within the phosphomonoester headgroup of (L)PA and its destabilization by competing intra-or intermolecular hydrogen bonds. We propose that this hydrogen bonding property of (L)PA is involved in the various cellular functions of these lipids.Phosphatidic acid (PA) 1 and the related lipid lysophosphatidic acid (LPA) are important minor lipid species in the cell. They are involved in many intracellular processes, and are important intermediates in lipid biosynthesis (1). For example, binding of LPA to its receptors evokes various cellular responses, and the local formation of (L)PA is part of signaling cascades, in particular in the regulation of membrane dynamics such as fusion and fission events, either indirectly through the recruitment of downstream effectors or directly by mediating (local) changes in the biophysical properties of the membrane (2-12).PA and LPA have a relatively simple chemical structure consisting of only a glycerol, one (LPA) or two (PA) acyl chains, and a phosphate, and it is interesting to note that these simple phospholipids are involved in such diverse processes, and are able to bind specifically to so many different types of proteins (3, 13). The question then is what is so special about these lipids. An obvious suggestion relates to the phosphate headgroup, which is attached to the glycerol backbone as a phosphomonoester, a unique feature of these lipids. Phosphomonoesters have two pK a 's, one of which is expected to be in the physiological pH range. As a consequence, small changes in (physiological) pH will affect the charge and influence the molecular shape and lipid phase behavior of these lipids (14,15). Under physiological conditions at neutral pH, phosphatidic acid is a cone (type II)-shaped lipid with a negative spontaneous curvature clos...

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“…Calcium and cAMP Assays-Calcium mobilization assays were performed as described previously by us (13). Briefly, intercellular calcium fluxes were measured on cell populations (2-4 ϫ 10 6 cells) that had been loaded with the calcium-sensitive fluorophore, INDO-1.…”

Section: Methodsmentioning

confidence: 99%

“…In a wide variety of tissue culture cells, LPA elicits Ca 2ϩ mobilization with an EC 50 of 0.2-10 nM (11,12), inhibition of cAMP accumulation with an EC 50 of 50 -100 nM (1,13,14), cell rounding (15), and other cytoskeletal rearrangements such as formation of stress fibers and focal adhesions (16), fibrinogen binding (17), and neurite retraction (18) also with nanomolar potency.…”

mentioning

confidence: 99%

Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

Hooks¹,

Santos²,

Im³

et al. 2001

Journal of Biological Chemistry

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126

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Lysophosphatidic acid (LPA) is an extracellular signaling mediator with a broad range of cellular responses. Three G-protein-coupled receptors (Edg-2, -4, and -7) have been identified as receptors for LPA. In this study, the ectophosphatase lipid phosphate phosphatase 1 (LPP1) has been shown to down-regulate LPAmediated mitogenesis. Furthermore, using degradationresistant phosphonate analogs of LPA and stereoselective agonists of the Edg receptors we have demonstrated that the mitogenic and platelet aggregation responses to LPA are independent of Edg-2, -4, and -7. Specifically, we found that LPA degradation is insufficient to account for the decrease in LPA potency in mitogenic assays, and the stereoselectivity observed at the Edg receptors is not reflected in mitogenesis. Additionally, RH7777 cells, which are devoid of Edg-2, -4, and -7 receptor mRNA, have a mitogenic response to LPA and LPA analogs. Finally, we have determined that the ligand selectivity of the platelet aggregation response is consistent with that of mitogenesis, but not with Edg-2, -4, and -7.The structurally simple phospholipid lysophosphatidic acid (LPA, 1 1-acyl, 2-hydroxy-sn-glycerol-3-phosphate) has been shown in the past decades to mediate an array of biological responses that is anything but simple. LPA has been shown to signal such vital cellular events as mitogenesis (1), platelet aggregation (2), tumor cell invasion (3), and escape from apoptosis (4). LPA is present in serum at low (1-20 M) micromolar concentrations (5) and is produced and released by stimulated platelets (6). The autocrine activation of platelet aggregation, coupled with LPA's mitogenic effects on smooth muscle cells (7) and fibroblasts (8), suggests a functional role for LPA as a wound-healing hormone (see review (9)). Furthermore, LPA accumulates to high concentrations in ovarian cancer ascitic fluid and is mitogenic to ovarian cancer cells, implicating LPA as a marker and mediator of ovarian cancer progression (10).In Recently, specific G-protein-coupled receptors for LPA have been identified within a cluster of eight related receptors termed the Edg (Endothelial differentiation gene) cluster. To date, eight members of the Edg cluster have been described. Edg-2 (15, 19), -4 (20), and -7 (21, 22) have been shown to be LPA receptors and Edg-1 (23, 24), -3, -5 (25), -6 (26, 27), and -8 (28) are receptors for the structurally related phospholipid sphingosine 1-phosphate. The LPA receptors differ with respect to distribution and G-protein coupling. Edg-2 is widely expressed, with highest mRNA levels appearing in brain (20), reflecting expression in Schwann cells and oligodendrocytes (29,30). Edg-4 is most highly expressed in testis and leukocytes (20), whereas Edg-7 is very highly expressed in kidney and prostate (21,22). When stably transfected into the LPA-unresponsive cell line RH7777 (Rat Hepatoma), Edg-2 mediates inhibition of cAMP accumulation, whereas Edg-4 and Edg-7 mediate calcium mobilization (22). Because only the inhibition of cAMP accumulation is pertus...

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Structure/Activity Relationships in Lysophosphatidic Acid: The 2-Hydroxyl Moiety

Cited by 33 publications

References 34 publications

Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of Lysophosphatidic Acid Receptors

Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of Lysophosphatidic Acid Receptors

What Makes the Bioactive Lipids Phosphatidic Acid and Lysophosphatidic Acid So Special?

Lysophosphatidic Acid-induced Mitogenesis Is Regulated by Lipid Phosphate Phosphatases and Is Edg-receptor Independent

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