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LC-MS/MS characterization of xyloside-primed glycosaminoglycans with cytotoxic properties reveals structural diversity and novel glycan modifications

Journal article
Authors Andrea Persson
Alejandro Gomez Toledo
Egor Vorontsov
Waqas Nasir
D. Willen
Fredrik Noborn
U. Ellervik
K. Mani
Jonas Nilsson
Göran Larson
Published in Journal of Biological Chemistry
Volume 293
Issue 26
Pages 10202-10219
ISSN 0021-9258
Publication year 2018
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Core Facilities, Proteomics
Pages 10202-10219
Language en
Links dx.doi.org/10.1074/jbc.RA118.002971
Keywords cancer, chondroitin sulfate, dermatan sulfate, glycosaminoglycan, mass spectrometry (MS), glycan, protein linkage region, heparan-sulfate oligosaccharides, electrospray, mass-spectrometry, beta-d-xylosides, chondroitin sulfate, hnk-1, sulfotransferase, compositional analysis, liquid-chromatography, keratan, sulfate, cultured-cells, Biochemistry & Molecular Biology
Subject categories Biochemistry and Molecular Biology

Abstract

Structural characterization of glycosaminoglycans remains a challenge but is essential for determining structure-function relationships between glycosaminoglycans and the biomolecules with which they interact and for gaining insight into the biosynthesis of glycosaminoglycans. We have recently reported that xyloside-primed chondroitin/dermatan sulfate derived from a human breast carcinoma cell line, HCC70, has cytotoxic effects and shown that it differs in disaccharide composition from nontoxic chondroitin/dermatan sulfate derived from a human breast fibroblast cell line, CCD-1095Sk. To further investigate the structural requirements for the cytotoxic effect, we developed a novel LC-MS/MS approach based on reversed-phase dibutylamine ion-pairing chromatography and negative-mode higher-energy collision dissociation and used it in combination with cell growth studies and disaccharide fingerprinting. This strategy enabled detailed structural characterization of linkage regions, internal oligosaccharides, and nonreducing ends, revealing not only differences between xyloside-primed chondroitin/dermatan sulfate from HCC70 cells and CCD-1095Sk cells, but also sialylation of the linkage region and previously undescribed methylation and sulfation of the nonreducing ends. Although the xyloside-primed chondroitin/dermatan sulfate from HCC70 cells was less complex in terms of presence and distribution of iduronic acid than that from CCD-1095Sk cells, both glucuronic acid and iduronic acid appeared to be essential for the cytotoxic effect. Our data have moved us one step closer to understanding the structure of the cytotoxic chondroitin/dermatan sulfate from HCC70 cells primed on xylosides and demonstrate the suitability of the LC-MS/MS approach for structural characterization of glycosaminoglycans.

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