| Biosynthesis of heparan sulfate in EXT1-deficient cells. | |
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MedLine Citation:
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PMID: 20377530 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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HS (heparan sulfate) is synthesized by HS co-polymerases encoded by the EXT1 and EXT2 genes (exostosin 1 and 2), which are known as causative genes for hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumours. It has been thought that the hetero-oligomeric EXT1-EXT2 complex is the biologically relevant form of the polymerase and that targeted deletion of either EXT1 or EXT2 leads to a complete lack of HS synthesis. In the present paper we show, unexpectedly, that two distinct cell lines defective in EXT1 expression indeed produce small but significant amounts of HS chains. The HS chains produced without the aid of EXT1 were shorter than HS chains formed in concert with EXT1 and EXT2. In addition, biosynthesis of HS in EXT1-defective cells was notably blocked by knockdown of either EXT2 or EXTL2 (EXT-like), but not of EXTL3. Then, to examine the roles of EXTL2 in the biosynthesis of HS in EXT1-deficient cells, we focused on the GlcNAc (N-aetylglucosamine) transferase activity of EXTL2, which is involved in the initiation of HS chains by transferring the first GlcNAc to the linkage region. Although EXT2 alone synthesized no heparan polymers on the synthetic linkage region analogue GlcUAbeta1-3Galbeta1-O-C2H4NH-benzyloxycarbonyl, marked polymerization by EXT2 alone was demonstrated on GlcNAcalpha1-4GlcUAbeta1-3Galbeta1-O-C2H4N-benzyloxycarbonyl (where GlcUA is glucuronic acid and Gal is galactose), which was generated by transferring a GlcNAc residue using recombinant EXTL2 on to GlcUAbeta1-3Galbeta1-O-C2H4NH-benzyloxycarbonyl. These findings indicate that the transfer of the first GlcNAc residue to the linkage region by EXTL2 is critically required for the biosynthesis of HS in cells deficient in EXT1. |
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Authors:
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Megumi Okada; Satomi Nadanaka; Naoko Shoji; Jun-Ichi Tamura; Hiroshi Kitagawa |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-27 |
Journal Detail:
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Title: The Biochemical journal Volume: 428 ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-27 Completed Date: 2010-07-23 Revised Date: 2010-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 463-71 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Heparitin Sulfate / biosynthesis* Humans Mice N-Acetylglucosaminyltransferases / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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9050-30-0/Heparitin Sulfate; EC 2.4.1.-/N-Acetylglucosaminyltransferases; EC 2.4.1.224/exostosin-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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