- Preference for Glucose over Inositol Headgroup during Lysolipid Activation of G Protein-Coupled Receptor 55
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G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-d-glucoside (LysoPtdGlc). To characterize lysolipid-GPR55 interaction, synthetic access to LysoPtdGlc and selected analogues was established utilizing a phosphorus(III)-based chemical approach. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropism assay in primary sensory neurons. Combined with molecular dynamics simulations the potential ligand entry port and binding pocket specifics are discussed. These results highlight the preference for gluco- over inositol- and galacto-configured headgroups.
- Guy, Adam T.,Kano, Koki,Ohyama, Jyunpei,Kamiguchi, Hiroyuki,Hirabayashi, Yoshio,Ito, Yukishige,Matsuo, Ichiro,Greimel, Peter
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- Continuous lipase-catalyzed production of pseudo-ceramides in a packed-bed bioreactor
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Ceramides are spingolipid compounds that are very attractive as active components in both the pharmaceutical and the cosmetic industries. In this study, the synthesis of ceramide analogs, the so-called pseudo-ceramides, was carried out using for the first time a two-step continuous enzymatic process with immobilized Candida antarctica lipase B (Novozym435) in a packed-bed bioreactor. The first step involved the selective N-acylation of 3-amino-1,2-propanediol using stearic acid as the first acyl donor (i). This was followed by the selective O-acylation of the N-stearyl 3-amino-1,2-propanediol synthesized in the first step, with myristic acid as the second acyl donor, to produce a N,O-diacyl 3-amino-1,2-propanediol-type pseudo-ceramide, namely 1-O-myristyl,3-N-stearyl 3-amino-1,2-propanediol (ii). The process was first optimized by evaluating the influences of three factors: feed flow rate, quantity of biocatalyst and substrate concentration. Under optimal conditions an amide synthesis yield of 92% and a satisfying production rate of almost 3.15 mmol h-1gbiocatalyst-1(1128 mg h-1gbiocatalyst-1) were obtained. The second step, N-acyl 3-amino-1,2-propanediol O-acylation, was similarly optimized and in addition the effect of the substrate molar ratio was studied. Thus, an optimal pseudo-ceramide synthesis yield of 54% and a production rate of 0.46 mmol h-1gbiocatalyst-1(261 mg h-1gbiocatalyst-1) were reached at a 1:3 ratio of amide to fatty acid. In addition, it was demonstrated that this two-step process has great potential for the production of N,O-diacyl 3-amino-1,2-propanediol-type pseudo-ceramides on an industrial scale. It was shown in particular that Novozym435 could be used for more than 3 weeks without a drop in the yield during the first step of 3-amino-1,2-propanediol N-acylation, proving that this biocatalyst is very stable under these operational conditions. This factor would greatly reduce the need for biocatalyst replacement and significantly lower the associated cost.
- Le Joubioux, Florian,Bridiau, Nicolas,Sanekli, Mehdi,Graber, Marianne,Maugard, Thierry
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p. 143 - 153
(2014/12/10)
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- Monoacylglycerols as transmembrane Cl- anion transporters
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We report that the amphiphilic natural product, monoacylglycerol 1, functions as a transmembrane Cl-/NO3- anion transporter. The 1,2-diol group is crucial for the transport function since diacylglycerol and triacylglycerol analogs are not anion transporters. Furthermore, adding another hydrogen bond donor to the glycerol head-group and perfluorination of the acyl tail gave synthetic analogs with improved Cl - membrane transport properties.
- Bahmanjah, Soheila,Zhang, Ning,Davis, Jeffery T.
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supporting information; experimental part
p. 4432 - 4434
(2012/06/18)
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- Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative
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In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs. 2009 American Chemical Society.
- Iwashita, Masazumi,Makide, Kumiko,Nonomura, Taro,Misumi, Yoshimasa,Otani, Yuko,Ishida, Mayuko,Taguchi, Ryo,Tsujimoto, Masafumi,Aoki, Junken,Arai, Hiroyuki,Ohwada, Tomohiko
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experimental part
p. 5837 - 5863
(2010/03/24)
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- Modified oligonucleotides for telomerase inhibition
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Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in
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Page/Page column 13
(2008/06/13)
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- Structure-activity relationship for enhancement of paracellular permeability across Caco-2 cell monolayers by 3-alkylamido-2-alkoxypropylphosphocholines
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Paracellular permeability enhancers have been used to improve the oral bioavailability of hydrophilic drugs; however, the mechanism of action of many enhancers is poorly understood. In this study, highly potent enhancers of paracellular permeability were
- Ouyang, Hui,Morris-Natschke, Susan L.,Ishaq, Khalid S.,Ward, Peter,Liu, Dongzhou,Leonard, Sarah,Thakker, Dhiren R.
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p. 2857 - 2866
(2007/10/03)
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- Structure-activity relationships for enhancement of paracellular permeability by 2-alkoxy-3-alkylamidopropylphosphocholines across Caco-2 cell monolayers
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The oral route is the preferred route of delivery for a large number of drug molecules. However, the intestinal epithelium presents a formidable barrier for delivery of drugs into systemic circulation. Phospholipids are among compounds that enhance the ab
- Liu, Dong-Zhou,Morris-Natschke, Susan L.,Kucera, Louis S.,Ishaq, Khalid S.,Thakker, Dhiren R.
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p. 1169 - 1174
(2007/10/03)
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- Method of treating hepatitis virus infections
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A method of treating hepatitis virus infection is disclosed. The method comprising administering to a human subject in need of such treatment an effective hepatitis virus-combatting amount of an alkyl lipid or alkyl lipid derivative.
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- Effects of Sulfur-Containing Analogues of Stearic Acid on Growth and Fatty Acid Biosynthesis in the Protozoan Crithidia fasciculata
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A variety of analogues of stearic acid in which one of the methylene groups was replaced by a sulfur atom were examined as inhibitors of growth and fatty acid biosynthesis in the trypanosomatid protozoan Crithidia fasciculata.The 8-, 9-, 10-, and 11-thiastearic acids were found to suppress the synthesis of the cyclopropane-containing fatty acid dihydrosterculic acid (9,10-methyleneoctadecanoic acid) at micromolar concentrations in the growth medium, and all but the 9-thiastearate were found to inhibit the growth of the protozoa at comparable concentrations.The most potent inhibitor, 8-thiastearic acid (I50 for growth = 0.8 μM; I50 dihydrosterculate synthesis = 0.4 μM), was also observed to inhibit the synthesis of γ-linolenic acid at a similar concentration.The sulfoxide derivatives of the 9- and 10-thiastearates were found to have little effect on growth or fatty acid synthesis, and several long-chain amides of 3-amino-1,2-propanediol were found to have effects similar to those of the fatty acids from which they were derived.
- Rahman, Mohammad D.,Ziering, David L.,Mannarelli, Sara J.,Swartz, Karen L.,Huang, Ded-Shih,Pascal, Robert A.
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p. 1656 - 1659
(2007/10/02)
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