Heparan Sulfate Containing Unsubstituted Glucosamine Residues: BIOSYNTHESIS AND HEPARANASE-INHIBITORY ACTIVITY* |
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Authors: | Satomi Nadanaka Eko Purunomo Naoko Takeda Jun-ichi Tamura Hiroshi Kitagawa |
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Institution: | From the ‡Department of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.;the §Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyamacho-Minami, Tottori 680-8552, Japan, and ;the ¶Department of Regional Environment, Faculty of Regional Sciences, Tottori University, Tottori, Tottori 680-8551, Japan |
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Abstract: | Degradation of heparan sulfate (HS) in the extracellular matrix by heparanase is linked to the processes of tumor invasion and metastasis. Thus, a heparanase inhibitor can be a potential anticancer drug. Because HS with unsubstituted glucosamine residues accumulates in heparanase-expressing breast cancer cells, we assumed that these HS structures are resistant to heparanase and can therefore be utilized as a heparanase inhibitor. As expected, chemically synthetic HS-tetrasaccharides containing unsubstituted glucosamine residues, GlcAβ1–4GlcNH3+(6-O-sulfate)α1–4GlcAβ1–4GlcNH3+(6-O-sulfate), inhibited heparanase activity and suppressed invasion of breast cancer cells in vitro. Bifunctional NDST-1 (N-deacetylase/N-sulfotransferase-1) catalyzes the modification of N-acetylglucosamine residues within HS chains, and the balance of N-deacetylase and N-sulfotransferase activities of NDST-1 is thought to be a determinant of the generation of unsubstituted glucosamine. We also report here that EXTL3 (exostosin-like 3) controls N-sulfotransferase activity of NDST-1 by forming a complex with NDST-1 and contributes to generation of unsubstituted glucosamine residues. |
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Keywords: | Glycobiology Glycosaminoglycan Glycosidase Heparan Sulfate Heparanase Proteoglycan Proteoglycan Synthesis |
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