title: Heparan sulfate containing unsubstituted glucosamine residues: biosynthesis and heparanase-inhibitory activity.
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.
authors.affiliation: From the Department of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Nadanaka
authors.affiliation: From the Department of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Hyogo 658-8558, Japan.
authors.forename: Eko
authors.initials: E
authors.lastname: Purunomo
authors.affiliation: the Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyamacho-Minami, Tottori 680-8552, Japan, and.
authors.forename: Naoko
authors.initials: N
authors.lastname: Takeda
authors.affiliation: 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.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Tamura
authors.affiliation: From the Department of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Hyogo 658-8558, Japan, kitagawa@kobepharma-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005944:Glucosamine / Q000378:metabolism*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015238:Sulfotransferases / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D005944:Glucosamine; D005966:Glucuronidase; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D017351:N-Acetylglucosaminyltransferases; D015238:Sulfotransferases; D000099175:Heparanase; C110774:EXTL3 protein, human; C484685:Extl3 protein, mouse; C021350:heparitin sulfotransferase
keywords: Glycobiology; Glycosaminoglycan; Glycosidase; Heparan Sulfate; Heparanase; Proteoglycan; Proteoglycan Synthesis
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