Synthetic Glycoforms Reveal Carbohydrate‐Dependent Bioactivity of Human Saposin D

Graf, Christopher G. F.; Schulz, Christian; Schmälzlein, Marina; Heinlein, Christian; Mönnich, Manuel; Perkams, Lukas; Püttner, Markus; Boos, Irene; Hessefort, Markus; Sanchez, Jose Nelson Lombana; Weyand, Michael; Steegborn, Clemens; Breiden, Bernadette; Ross, Kerstin; Schwarzmann, Günter; Sandhoff, Konrad; Unverzagt, Carlo

doi:10.1002/anie.201701362

Cited by 31 publications

(21 citation statements)

References 40 publications

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“…BMP is an intermediate of the phosphatidylglycerol catabolism and can enrich in ILV membranes to reach 40-60 mol% of their phospholipid content [8,53,54], mainly due to its slow catabolism. It can generate a negative zeta potential on the surfaces of ILVs [10], which electrostatically attracts positively charged hydrolases and SAPs to the sphingolipid-substrate carrying ILV-membranes, speeding up their catabolic rates [8,55,56] ( Figure 1).…”

Section: Maturation Of Ilvs and Regulation Of Gg Catabolism At Ilv Sumentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

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Section: Maturation Of Ilvs and Regulation Of Gg Catabolism At Ilv Sumentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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“…Much to our delight, the application of the glycosylamine 25 derived from chitobiose (Supporting Information) led to the smooth formation of glycopeptide 27 a (56 %, entry 6). Use of the complex‐type nonasaccharide amine 26 , which we synthesized from the corresponding glycosyl azide (Supporting Information) was also successful and delivered complex oligosaccharyl decapeptide 28 a in a yield of 21 % after HPLC purification (entry 7). These results emphasize the general feasibility of the one‐pot deprotection/N‐glycosylation protocol for chemoselective synthesis of N‐glycopeptides from aspartic thioacid‐containing peptides.…”

Section: Methodsmentioning

confidence: 99%

A Tripeptide Approach to the Solid‐Phase Synthesis of Peptide Thioacids and N‐Glycopeptides

Schöwe

Keiper

Unverzagt

et al. 2019

Chemistry A European J

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A general and robust method for the incorporation of aspartates with a thioacid side chain into peptides has been developed. Pseudoproline tripeptides served as building blocks for the efficient fluorenylmethyloxycarbonyl (Fmoc) solid‐phase synthesis of thioacid‐containing peptides. These peptides were readily converted to complex N‐glycopeptides by using a fast and chemoselective one‐pot deprotection/ligation procedure. Furthermore, a novel side reaction that can lead to site‐selective peptide cleavage using thioacids (CUT) was discovered and studied in detail.

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“…After purification by flash chromatography, the yields for the core fucosylated compounds 26 – 33 were generally high (76–83 %) and the observed α/β‐ratio exceeded 99:1. For selective removal of the benzyl groups in the presence of an azide, an oxidative debenzylation was carried out by using either Na 2 S 2 O 4 /NaBrO 3 or the recently established NBS as a more controllable source for bromine radicals. After cleavage of the base‐labile protecting groups and acetylation, the core fucosylated N‐glycan azides G9 – G16 were obtained in good yields.…”

Section: Methodsmentioning

confidence: 99%

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

et al. 2018

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The occurrence of α1,6‐linked core fucose on the N‐glycans of mammalian glycoproteins is involved in tumor progression and reduces the bioactivity of antibodies in antibody‐dependent cell‐mediated cytotoxicity (ADCC). Since core‐fucosylated N‐glycans are difficult to isolate from natural sources, only chemical or enzymatic synthesis can provide the desired compounds for biological studies. A general drawback of chemical α‐fucosylation is that the chemical assembly of α1,6‐linked fucosides is not stereospecific. A robust and general method for the α‐selective fucosylation of acceptors with primary hydroxy groups in α/β ratios exceeding 99:1 was developed. The high selectivities result from the interplay of an optimized protecting group pattern of the fucosyl donors in combination with the activation principle and the reaction conditions. Selective deprotection yielded versatile azides of all mammalian complex‐type core‐fucosylated N‐glycans with 2‐4 antennae and optional bisecting GlcNAc.

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Synthetic Glycoforms Reveal Carbohydrate‐Dependent Bioactivity of Human Saposin D

Cited by 31 publications

References 40 publications

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

A Tripeptide Approach to the Solid‐Phase Synthesis of Peptide Thioacids and N‐Glycopeptides

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

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