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T1 - Synthesis of GM1 ganglioside derivatives

In generalized gangliosidosis, GM1 accumulates in the nervoussystem leading to mental retardation and liver enlargement.

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Synthesis of N-thioacetyl gangliosides GM1 and GM3

We report on the preparation of a set of new ganglioside internal standards for the major mammalian brain gangliosides and the tumor-associated gangliosides, GM2 and GD2. The title substances were prepared from a mixture of gangliosides from bovine brain, which was separated first into ganglioside classes and then into pure lipoforms. Nonnatural chain lengths in the fatty acid part were introduced by selective chemical and enzymatic deacylation and reacylation. Furthermore, we developed a new method for the modification of the sphingosine chain length by olefin cross metathesis (). The method was applied for the synthesis of a lyso-GM1 and a lyso-GM2 standard.

T1 - Isolation of variants of BALB/c 3T3 cells defective in complex ganglioside biosynthesis

AB - Ganglioside GM1 and its seven potential catabolic products: asialo-GM1, GM2, asialo-GM2, GM3, Lac-Cer, Glc-Cer and Cer, were labeled with tetramethylrhodamine (TMR) to permit ultra-sensitive analysis using laser-induced fluorescence (LIF) detection. The preparation involved acylation of the homogenous C18 lyso-forms of GM1, Lac-Cer, Glc-Cer and Cer with the N-hydroxysuccinimide ester of a β-alanine-tethered 6-TMR derivative, followed by conversion of these labeled products using galactosidase, sialidase, and sialyltransferase enzymes. The TMR-glycolipid analogs produced are detectable on TLC down to the 1 ng level by the naked eye. All eight compounds could be separated within 4 min in capillary electrophoresis where they could be detected at the zeptomole (ca. 1000 molecule) level using LIF.

synthesis of gangliosides GM1 ..

In addition, a method based on an olefin metathesis has been established that is suitable for the synthesis of modified lysogangliosides.

The specific receptors for the B subunit of toxins ontargetcells or tissues are usually sialogangliosides (glycoproteins) called G-proteinson the cell membrane. For example, the cholera toxin utilizes thegangliosideGM1, and tetanus toxin utilizes ganglioside GT1 and/or GD1b asreceptorson host cells.

This report thus extends our previous studies by demonstrating that tumor-derived TNFα enhances RCC apoptogenicity not only by inducing ganglioside synthesis but also by initiating receptor-dependent apoptosis in T cells in which the nuclear factor-Kκ activation pathway has been inhibited by GM1.",}

Regulation of ganglioside biosynthesis in the nervous …

Total synthesis of gangliosides GM1 and GM2.

We developed a synthetic method based on the olefin cross metathesis for the preparation of gangliosides and lysogangliosides with homogenous and, if required, artificial sphingoid bases. Advantages of this method are a simplified chromatographic separation by introduction of a phenyl group, the opportunity to use gangliosides heterogeneous in their sphingosine part as educts, and the applicability of the method for the synthesis of lysoganglioside standards. A drawback of the method is that isomerizations can only be suppressed to less than 5%. A direct modification of lysogangliosides by an olefin metathesis is impracticable because the reaction does not tolerate amino groups.

For the synthesis of internal ganglioside standards, we chose a partial synthesis rather than a total synthesis because of the high effort necessary for the latter. Starting materials were obtained by purification of a ganglioside mixture from bovine brain. It was confirmed by ESI-MS that bovine brain gangliosides mainly contain d18:1/18:0- and d20:1/18:0-lipoforms. Usually, the purity of gangliosides is determined by fluorimetric () or photometric (, ) sialic acid determination, sphingoid base determination by HPLC (), GC-flame ionization detection (), or densitometry (). We analyzed the purified ganglioside lipoforms by elemental analysis and used these substances as external standards for fluorimetric and photometric sialic acid determination. The results of the CHN analysis demonstrated that there is residual H2O content of 10–15% in the gangliosides after lyophilization. By drying in vacuum, it can be reduced to 5%. For modification of the fatty acid acyl chain, we followed a chemical and an enzymatic deacylation approach. The results of the chemical deacylation demonstrated that this method is appropriate for the selective deacylation of GM1, but inappropriate for the preparation of oligosialolysogangliosides. The enzymatic deacylation turned out to be more appropriate: yields were in the range of 44–60% for the preparation of lyso-GD1a (8), lyso-GD1b (9), lyso-GT1b (10), and lyso-GQ1b (11). This is comparable to the results of Ando et al. (), who reported yields of 62% resp. 52% for the preparation of lyso-GM1 and lyso-GM2. Due to the occurrence of traces of d18:1/20:0-lipoforms in the starting material, which could not be separated from the d20:1/18:0-lipoforms by RP column chromatography, the prepared d20:1-lyso-GD1b·2NH3 (9) and d20:1-lyso-GT1b·3NH3 (10) contained 3.1% and 4.7%, respectively, of their d18:1-lipoform. Because they do not disturb the mass spectrometric application of the standards, we decided not to remove these minor byproducts. The reacylation of the lysogangliosides was carried out in yields in the range of 19–86%. In general, the reaction works accurately for monosialolysogangliosides and disialolysogangliosides with yields up to 86%. For lyso-GT1b and lyso-GQ1b, the yields drop to 34 and 19%, respectively. An optimization of the reaction conditions for these substrates should be performed in the future.

15/11/1986 · Total synthesis of gangliosides GM1 and GM2
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  • Efficient Synthesis of Ganglioside GM2 for Use in …

    GM1-synthase is responsible for the synthesis of GM1/GD1b from GM2/GD2 in the ganglioside biosynthetic pathway

  • 02/10/1997 · Efficient Synthesis of Ganglioside GM2 ..

    Structure of GM1 ganglioside

  • Total synthesis of the aminopropyl functionalized ganglioside GM 1

    The total synthesis of the methyl glycoside of GM1 (1b) has been accomplished

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Synthesis of ganglioside GM1 containing a …

In the past, ganglioside patterns have been largely determined by TLC followed by densitometric quantification (, ). Within recent years, ganglioside determinations by mass spectrometric methods have been increasingly applied (). In addition to ganglioside classes, which are defined by the carbohydrate head group, MS also allows profiling of ganglioside lipoforms () with different structure of acyl chain and sphingoid base. Ganglioside quantification is applied to ganglioside pattern investigation () in food analyses (, ), but is also used in the analysis of lysosomal storage diseases () and in quantitative imaging MS (). Lysogangliosides play a role in the pathogenesis of gangliosidoses. Elevated levels of lyso-GM2 and lyso-GA2 are present in the brains of patients with GM2 gangliosidoses (), and elevated levels of lyso-GM1 and lyso-GA1 are present in patients with GM1 gangliosidosis (). Both substances are potential biomarkers for these diseases (), and the lysoganglioside standards prepared in this work can be used for their quantitative analysis.

Synthesis of a Pseudo Tetrasaccharide Mimic of Ganglioside GM1

Gangliosides are sialic acid-containing glycosphingolipids (GSLs). They can be found in vertebrates and, with a few exceptions, not in invertebrates (). Gangliosides are especially abundant in neuronal tissues, where their content is one to two orders of magnitude higher than in extraneural tissues (). In the brain, gangliosides, together with other GSLs, are the main glycan carriers (80% of the total glycan mass in adult rat brain) (). The main gangliosides in adult mammalian brain are GM1 (), GD1a, GD1b, GT1b, 9-O-Ac-GT1b, and GQ1b (). They contain mostly C18- and C20-sphingosine acylated with stearic acid, which constitutes more than 80% of the total ganglioside fatty acid content in the nervous system (). In mammals, C20-sphingsosine-containing gangliosides can only be found in significant amounts in the nervous system (). In contrast to adult brain, different GSL and ganglioside series are expressed in the developing nervous system ().

Synthesis of a Fluorescent Ganglioside GM1 Derivative …

All chemicals were of analytical grade or the highest purity available. Water (H2O) used for buffers and solutions was purified by an ultrapure H2O system (EASYpure UV/UF D8612, Werner Reinstwassersysteme, Leverkusen, Germany). Solvents used in reactions of oxygen- and moisture-sensitive compounds were in anhydrous form. 1-Propanol, methanol (MeOH), pyridine, and acetic anhydride were degassed before use. The native mixture of bovine brain gangliosides, Cronassial®, which consists of 21% GM1, 40% GD1a, 16% GD1b, 19% GT1b, and 4% other gangliosides (), was available in our lab. Sphingolipid ceramide N-deacylase (SCDase) and β-galactosidase from bovine testes were from Sigma-Aldrich (Schnelldorf, Germany). Triton™ X-100, sodium taurodeoxycholate, Grubbs catalyst 2nd generation, Hoveyda-Grubbs catalyst 2nd generation, and Stewart-Grubbs catalyst were also from Sigma-Aldrich. For normal phase (NP) column chromatography, silica gel 60 (0.040–0.063 mm or 0.015–0.040 mm) from Merck (Darmstadt, Germany) was used. For desalting and reversed phase (RP) column chromatography, LiChroprep® RP-18 (0.040–0.063 mm) from Merck was used. For TLC analysis, high-performance TLC (HPTLC) silica gel 60 F254 and HPTLC silica gel 60 RP-18 plates from Merck were used. For anion-exchange chromatography, DEAE Sephadex™ A-25 from Amersham Pharmacia Biotech AB (Uppsala, Sweden) was used.

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