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Lysophosphatidic acid

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https://www.readbyqxmd.com/read/28731719/discovery-structure-activity-relationship-and-binding-mode-of-imidazo-1-2-a-pyridine-series-of-autotaxin-inhibitors
#1
Agnès Joncour, Nicolas Desroy, Christopher Housseman, Xavier Bock, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Christophe Peixoto, Denis Annoot, Luce Lepissier, Jörg Heiermann, Willem Jan Hengeveld, Gregor Pilzak, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, René Galien, Christelle David, Nele Vandervoort, Thierry Christophe, Katja Conrath, Mia Jans, Alexandre Wohlkonig, Robert Touitou, Damien Fleury, Lionel Vercheval, Patrick Mollat, Nicolas Triballeau, Ellen Van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases and inflammation among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high throughput screening (HTS). A co-crystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site...
July 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28716732/lysophosphatidic-acid-signaling-regulates-the-klf9-ppar%C3%AE-axis-in-human-induced-pluripotent-stem-cell-derived-neurons
#2
Tamotsu Tsukahara, Shuhei Yamagishi, Yoshikazu Matsuda, Hisao Haniu
Lysophosphatidic acid (LPA) is a lipid signaling molecule that plays several significant roles in the nervous system during development and injury. In this study, we differentiated human induced pluripotent stem cells (iPSCs) into neurons as an in vitro model to examine the specific effects of LPA. We demonstrated that LPA activates peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated nuclear receptor, as well as its cognate receptor LPA1 on human iPSC-derived neurons to enhance proliferation and neurite outgrowth...
July 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28714993/a-two-helix-motif-positions-the-lysophosphatidic-acid-acyltransferase-active-site-for-catalysis-within-the-membrane-bilayer
#3
Rosanna M Robertson, Jiangwei Yao, Stefan Gajewski, Gyanendra Kumar, Erik W Martin, Charles O Rock, Stephen W White
Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3-phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase αβ-domain that contains the catalytic HX4D motif. PlsC dictates the acyl chain composition of the 2-position of phospholipids, and the acyl chain selectivity 'ruler' is an appropriately placed and closed hydrophobic tunnel...
July 17, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28712726/sengers-syndrome-associated-mitochondrial-acylglycerol-kinase-is-a-subunit-of-the-human-tim22-protein-import-complex
#4
Yilin Kang, David A Stroud, Michael J Baker, David P De Souza, Ann E Frazier, Michael Liem, Dedreia Tull, Suresh Mathivanan, Malcolm J McConville, David R Thorburn, Michael T Ryan, Diana Stojanovski
Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins...
July 11, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28712724/acylglycerol-kinase-mutated-in-sengers-syndrome-is-a-subunit-of-the-tim22-protein-translocase-in-mitochondria
#5
Milena Vukotic, Hendrik Nolte, Tim König, Shotaro Saita, Maria Ananjew, Marcus Krüger, Takashi Tatsuta, Thomas Langer
Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane...
July 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28708504/study-of-lysophosphatidic-acid-receptors-lpars-in-buffalo-uterus-demonstrated-upregulation-of-lpar1-and-lpar6-in-early-pregnancy
#6
Abdul Sadam, Subhashree Parida, Amol R Padol, Ankita D Verma, Naseer Ahmad Baba, Wanta M Khuman, Vivek Srivastava, Manjit Panigrahi, Thakur Uttam Singh, Souvendra Nath Sarkar
Lysophosphatidic acid (LPA) is an important factor involved in embryo implantation and pregnancy establishment in humans and domestic livestock. LPA exerts its action through six G-protein-coupled receptors (LPA1-LPA6). We investigated the types of LPA receptors expressed in buffalo uterus and also their differential expression in the nonpregnant, and early-pregnant endometrium. The nonpregnant, and early-pregnant (<42 days) uteri were collected from the local slaughterhouse. RT-PCR experiments detected mRNAs of all the six LPA receptors (LPAR1-LPAR6) in both nonpregnant, and early-pregnant endometrial tissues...
May 27, 2017: Theriogenology
https://www.readbyqxmd.com/read/28705936/cd14-is-a-key-mediator-of-both-lysophosphatidic-acid-and-lipopolysaccharide-induction-of-foam-cell-formation
#7
Dong An, Feng Hao, Fuqiang Zhang, Wei Kong, Jerold Chun, Xuemin Xu, Mei-Zhen Cui
Macrophage uptake of oxidized lowdensity lipoprotein (oxLDL) plays an important role in foam cell formation and the pathogenesis of atherosclerosis. We report here that lysophosphatidic acid (LPA) enhances lipopolysaccharide (LPS)-induced oxLDL uptake in macrophages. Our data revealed that both LPA and LPS highly induce the CD14 expression at messenger RNA and protein levels in macrophages. The role of CD14, one component of the LPS receptor cluster, in LPA-induced biological functions has been unknown. We took several steps to examine the role of CD14 in LPA signaling pathways...
July 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28687529/design-synthesis-and-biological-evaluation-of-2-4-dihydropyrano-2-3-c-pyrazole-derivatives-as-autotaxin-inhibitors
#8
Tatu Pantsar, Prosanta Singha, Tapio J Nevalainen, Igor Koshevoy, Jukka Leppänen, Antti Poso, Juha M A Niskanen, Sanna Pasonen-Seppänen, Juha R Savinainen, Tuomo Laitinen, Jarmo T Laitinen
Inhibition of Autotaxin (ATX) is a potential treatment strategy for several diseases, including tumors with elevated ATX-lysophosphatidic acid (LPA) signaling. Combining structure-based virtual screening together with hen egg-white Autotaxin (ewATX) activity assays enabled the discovery of novel small-molecule ATX inhibitors with a 2,4-dihydropyrano[2,3-c]pyrazole scaffold. These compounds are suggested to bind to the lipophilic pocket, leaving the active site unrestrained. Our most potent compound, (S)-6-amino-4-(3,4-dichlorophenyl)-3-(4-[(4-fluorobenzyl)oxy]phenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile [(S)-25], inhibited human ATX (hATX) with an IC50-value of 134nM...
July 5, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28684865/dynamic-relocalization-of-nherf1-mediates-chemotactic-migration-of-ovarian-cancer-cells-toward-lysophosphatidic-acid-stimulation
#9
Yong-Seok Oh, Kyun Heo, Eung-Kyun Kim, Jin-Hyeok Jang, Sun Sik Bae, Jong Bae Park, Yun Hee Kim, Minseok Song, Sang Ryong Kim, Sung Ho Ryu, In-Hoo Kim, Pann-Ghill Suh
NHERF1/EBP50 (Na(+)/H(+) exchanger regulating factor 1; Ezrin-binding phosphoprotein of 50 kDa) organizes stable protein complexes beneath the apical membrane of polar epithelial cells. By contrast, in cancer cells without any fixed polarity, NHERF1 often localizes in the cytoplasm. The regulation of cytoplasmic NHERF1 and its role in cancer progression remain unclear. In this study, we found that, upon lysophosphatidic acid (LPA) stimulation, cytoplasmic NHERF1 rapidly translocated to the plasma membrane, and subsequently to cortical protrusion structures, of ovarian cancer cells...
July 7, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28674249/effects-of-gintonin-enriched-fraction-in-an-atopic-dermatitis-animal-model-involvement-of-autotaxin-regulation
#10
Byung-Hwan Lee, Ho-Kyoung Kim, Minhee Jang, Hyeon-Joong Kim, Sun-Hye Choi, Sung-Hee Hwang, Hyoung-Chun Kim, Hyewhon Rhim, Ik-Hyun Cho, Seung-Yeol Nah
Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C18 : 2 with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28669075/origin-and-evolution-of-group-xi-secretory-phospholipase-a2-from-flax-linum-usitatissimum-based-on-phylogenetic-analysis-of-conserved-domains
#11
Payal Gupta, Raman Saini, Prasanta K Dash
Phospholipase A2 (PLA2) belongs to class of lipolytic enzymes (EC 3.1.1.4). Lysophosphatidic acid (LPA) and free fatty acids (FFAs) are the products of PLA2 catalyzed hydrolysis of phosphoglycerides at sn-2 position. LPA and FFA that act as second mediators involved in the development and maturation of plants and animals. Mining of flax genome identified two phospholipase A2 encoding genes, viz., LusPLA 2 I and LusPLA 2 II (Linum usitatissimum secretory phospholipase A2). Molecular simulation of LusPLA2s with already characterized plant sPLA2s revealed the presence of conserved motifs and signature domains necessary to classify them as secretory phospholipase A2...
July 2017: 3 Biotech
https://www.readbyqxmd.com/read/28667502/lysophosphatidic-acid-protects-against-endotoxin-induced-acute-kidney-injury
#12
Koryun Mirzoyan, Colette Denis, Audrey Casemayou, Marion Gilet, Dimitri Marsal, Dominique Goudounéche, Stanislas Faguer, Jean-Loup Bascands, Joost P Schanstra, Jean-Sébastien Saulnier-Blache
Septic shock is the most common cause of acute kidney injury (AKI), but the underlying mechanisms remain unclear and no targeted therapies exist. Lysophosphatidic acid (LPA) is a bioactive lipid which in vivo administration was reported to mitigate inflammation and injuries caused by bacterial endotoxemia in the liver and lung. The objective of the present study was to determine whether LPA can protect against sepsis-associated AKI. C57BL/6 mice were treated with LPA 18:1 (5 mg/kg, i.p.) 1 h before being injected with the endotoxin lipopolysaccharide (LPS), and AKI was evaluated after 24 h...
June 30, 2017: Inflammation
https://www.readbyqxmd.com/read/28657680/lysophosphatidic-acid-triggered-pathways-promote-the-acquisition-of-trophoblast-endovascular-phenotype-in-vitro
#13
Jimena S Beltrame, Micaela S Sordelli, Vanesa A Cañumil, Ana M Franchi, María L Ribeiro
Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Defects in this mechanism correlate with severe obstetric complications as implantation failure and preeclampsia. Lysophosphatidic acid (LPA) participates in embryo implantation and contributes to vascular physiology in different biological systems. However, the role of LPA on trophoblast endovascular transformation has not been studied. Due to difficulties in studying human pregnancy in vivo, we adopted a pharmacological approach in vitro to investigate LPA action in various aspects of trophoblast endovascular response, such as the formation of endothelial capillary-like structures, migration and proliferation...
June 28, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28655732/chemical-tools-for-studying-lipid-binding-class-a-g-protein-coupled-receptors
#14
REVIEW
Anna Cooper, Sameek Singh, Sarah Hook, Joel D A Tyndall, Andrea J Vernall
Cannabinoid, free fatty acid, lysophosphatidic acid, sphingosine 1-phosphate, prostanoid, leukotriene, bile acid, and platelet-activating factor receptor families are class A G protein-coupled receptors with endogenous lipid ligands. Pharmacological tools are crucial for studying these receptors and addressing the many unanswered questions surrounding expression of these receptors in normal and diseased tissues. An inherent challenge for developing tools for these lipid receptors is balancing the often lipophilic requirements of the receptor-binding pharmacophore with favorable physicochemical properties to optimize highly specific binding...
July 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28652252/glycerol-3-phosphate-acyltransferase-1-promotes-tumor-cell-migration-and-poor-survival-in-ovarian-carcinoma
#15
Rosemarie Marchan, Bettina Büttner, Jörg Lambert, Karolina Edlund, Iris Glaeser, Meinolf Blaszkewicz, Gregor Leonhardt, Lisa Marienhoff, Darius Kaszta, Moritz Anft, Carsten Watzl, Katrin Madjar, Marianna Grinberg, Eugen Rempel, Roland Hergenröder, Silvia Selinski, Jörg Rahnenführer, Michaela S Lesjak, Joanna D Stewart, Cristina Cadenas, Jan G Hengstler
Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration...
June 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28648739/g-protein-coupled-receptor-35-contributes-to-mucosal-repair-in-mice-via-migration-of-colonic-epithelial-cells
#16
Takuya Tsukahara, Nahla Hamouda, Daichi Utsumi, Kenjiro Matsumoto, Kikuko Amagase, Shinichi Kato
G protein-coupled receptor 35 (GPR35), a receptor for lysophosphatidic acid, is highly expressed in the gastrointestinal tract. Recently, GPR35 has been implicated in the onset of inflammatory bowel disease (IBD), but its role in physiological and pathological processes in the colon remains undefined. In this study, we investigated the contribution of GPR35-mediated signalling to mucosal repair of colonic epithelium in IBD. GPR35 function was examined in a wound healing model, using young adult mouse colon epithelium (YAMC) cells, and in a dextran sulphate sodium (DSS)-induced mouse model of colitis...
June 23, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28616586/the-autotaxin-lysophosphatidic-acid-pathway-emerges-as-a-therapeutic-target-to-prevent-liver-cancer
#17
Derek J Erstad, Andrew M Tager, Yujin Hoshida, Bryan C Fuchs
Using transcriptome meta-analysis, we recently identified the autotaxin (ATX)-lysophosphatidic acid (LPA) pathway as a regulator of hepatocellular carcinoma (HCC) risk in human cirrhosis patients. Pharmacological targeting of this pathway reduced fibrosis progression and HCC development in animals, identifying ATX-LPA signaling as a novel chemoprevention strategy for cirrhosis and HCC.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/28611684/protective-role-for-lpa3-in-cardiac-hypertrophy-induced-by-myocardial-infarction-but-not-by-isoproterenol
#18
Lin Cai, Guangpu Fan, Fang Wang, Si Liu, Tiewei Li, Xiangfeng Cong, Jerold Chun, Xi Chen
Background: We previously reported that lysophosphatidic acid (LPA) promoted cardiomyocyte hypertrophy in vitro via one of its G protein-coupled receptor subtypes, LPA3. In this study, we examined the role of LPA3 in cardiac hypertrophy induced by isoproterenol (ISO) and myocardial infarction. Methods:In vitro, neonatal rat cardiomyocytes (NRCMs) were subjected to LPA3 knocked-down, or pretreated with a β-adrenergic receptor (β-AR) antagonist (propranolol) before LPA/ISO treatment. Cardiomyocyte size and hypertrophic gene (ANP, BNP) mRNA levels were determined...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28591560/implications-of-the-lysophosphatidic-acid-signaling-axis-in-liver-cancer
#19
REVIEW
Chiara Lopane, Pasquale Agosti, Isabella Gigante, Carlo Sabbà, Antonio Mazzocca
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in western countries. The major risk factors for HCC are hepatitis C or B viruses, alcohol and metabolic disorders. The increasing risk of HCC in patients with metabolic disorders (i.e. obesity, diabetes and non-alcoholic steatohepatitis/NASH) regardless of the presence of liver cirrhosis is becoming relevant. Nevertheless, molecular mechanisms linking these risk factors to liver oncogenesis are unclear. This review focuses on the pathogenic role of the lysophosphatidic acid (LPA) pathway in HCC, highlighting the implications of this bioactive phospholipid in liver cancer biology and metabolism and as potential therapeutic target...
June 4, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28590455/machine-learned-data-structures-of-lipid-marker-serum-concentrations-in-multiple-sclerosis-patients-differ-from-those-in-healthy-subjects
#20
Jörn Lötsch, Michael Thrun, Florian Lerch, Robert Brunkhorst, Susanne Schiffmann, Dominique Thomas, Irmgard Tegder, Gerd Geisslinger, Alfred Ultsch
Lipid metabolism has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS). With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research. We used unsupervised machine-learning to analyze lipid marker serum concentrations, pursuing the hypothesis that for the most relevant markers the emerging data structures will coincide with the diagnosis of MS. Machine learning was implemented as emergent self-organizing feature maps (ESOM) combined with the U*-matrix visualization technique...
June 7, 2017: International Journal of Molecular Sciences
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