2006 Fiscal Year Final Research Report Summary
Scenario of the biosynthesis of glycosaminoglycans
| Project/Area Number |
14082207
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Hokkaido University (2006)
Kobe Pharmaceutical University (2002-2005) |
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Principal Investigator |
SUGAHARA Kazuyuki Hokkaido University, Faculty of Advanced LifeScience, Professor (60154449)
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| Project Period (FY) |
2002 – 2006
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| Keywords | chondroitin sulfate / heparan sulfate / chondroitin synthase / proteoglycan / chondroitin polymerizing factor / glycosyltransferase / EXT tumor suppressor gene / glycosaminoglycan |
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| Research Abstract |
Sulfated glycosaminoglycans, which are side polysaccharide chains of proteoglycans, can be largely classified into a heparan sulfate type and a chondroitin sulfate type, and regulate functions of a wide variety of signaling protein molecules. However, the biosynthetic mechanism of these glycans had not been well understood before this project was launched. Therefore, the aim of this project was to clarify the scenario of the biosynthesis of sulfated glycosaminoglycans. During the project period, we clarified various aspects of the biosynthetic mechanism including the chain initiation, elongation, polymerization and the regulation of the chain length using the in vivo and in vitro systems of human, fly and nematode, and accomplished the aim of the project. The results included identification of glycosyltransferases, sulfotransferases and regulatory factors as well as molecular interactions of these ensymes and factors. Furthermore, it was demonstrated that chondroitin is essential in the cell division of C. elegans by the RNAi approach using the RNAs of the chondroitin synthase and the chondroitin polymerizing factor of the namatode. A human genetic disease caused by a deficiency of a chondroitin 6-O-sulfotransferase was discovered. On the other hand we clarified the molecular mechanism whereby the neurite outgrowth of mouse hippocampal neurons is promoted by pleiotrophin and hepatocyte growth factor through specific interactions with chondoitin sulfate chains in the extracellular matrices. It was also proved that chondroitin sulfate plays a role as a receptor for virus infection. The sugar sequences required for the interactions with a growth factor pleiotrohin and a few cytokines were also revealed. These results have started influencing considerably not only the glycobiology field but also other related fields. The on-going analysis of the GlcAT-I-KO and EXTL2-KO-mice will also confirm the importance of the functions of these sulfated glycosaminoglycan chains.
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[Journal Article] Expression of rib-1, a Caenorhabditis elegans Homolog of the Human Tumor Suppressor EXT Genes is indispensable for heparan sulfate synthesis and embryonic morphogenesis.2007
Author(s)
Kitagawa, H., Izumikawa, T., Mizuguchi, S., Dejima, K., Nomura, K. H., Egusa, N., Taniguchi, F., Tamura, J., Gengyo-Ando, K., Mitani, S., Nomura, K., Sugahara, K.
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Journal Title
J. Biol. Chem. 282 (11)
Pages: 8533-8544
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Biosynthesis of heparin and heparan sulfate.2005
Author(s)
Mizumoto, S., Kitagawa, H., Sugahara, K.
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Journal Title
Chemistry and Biology of Heparin and Heparan sulfate (Garg, H. G., Linhardt, R. J., and Hales, C. A., eds. ), Elsevier, Oxford, UK. 40
Description
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[Journal Article] Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement.2004
Author(s)
Thiele, H., Sakano, M., Kitagawa, H., Sugahara, K,. Rajab, A., Hohne, W., Leschik, G, Nurnberg, P., Mundlos, S.
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Journal Title
Proc. Natl. Acad. Sci. USA 101 (27)
Pages: 10155-10160
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Nematode chondroitin polymerizing factor showing cell/organ-specific expression is indispensable for chondroitin synthesis and embryonic cell division.2004
Author(s)
Izumikawa, T., Kitagawa, H., Mizuguchi, S., Nomura, K. H., Nomura, K., Tamura, J., Gengyo-Ando, K., Mitani, S., Sugahara, K.
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Journal Title
J. Biol. Chem. 279 (51)
Pages: 53755-53761
Description
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[Journal Article] Molecular cloning and expression of a second chondroitin N-acetylgalactosaminyltransferase involved in the biosynthetic initiation and elongation of chondroitin/dermatan sulfate.2003
Author(s)
Uyama, T., Kitagawa, H., Tanaka, J., Tamura, J., Ogawa, T., Sugahara K
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Journal Title
J. Biol. Chem. 278 (5)
Pages: 3072-3078
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Crystal structure of an 1, 4-N-acetylhexosaminyltransferase (EXTL2), a member of the exostosin gene family involved in heparan sulfate biosynthesis.2003
Author(s)
Pedersen, L. C., Dong, J., Taniguchi, F., Kitagawa, H., Krahn, J., Pedersen, L. G., Sugahara, K., Negishi, M.
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Journal Title
J. Biol. Chem. 278 (16)
Pages: 14420-14428
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heterogeneity of the chondroitin sulfate portion of phosphacan/6B4 proteoglycan regulates its binding affinity for pleiotrophin/HB-GAM.2003
Author(s)
Maeda, N., He, J., Yajima, Y, Mikami, T., Sugahara. K., Yabe, T.
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Journal Title
J. Biol. Chem. 278 (37)
Pages: 35805-35811
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate2003
Author(s)
Sugahara, K., Mikami, T., Uyama, U., Mizuguchi, S., Nomura, K., Kitagawa, H.
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Journal Title
Curr. Opin. Struct. Biol. 13(5)
Pages: 612-620
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Recognition of glycosaminoglycans by midkine.2003
Author(s)
Muramatsu, T., Muramatsu, H., Kaneda, N., Sugahara, K.
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Journal Title
Methods in Enzymol., (Lee, Y. C., and . Lee R. T. eds. ), Academic Press, New York 363
Pages: 11
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Oversulfated chondroitin/dermatan sulfates containing GlcA 1/IdoA 1-3GalNAc(4, 6-O-disulfate)interact with L- and P-selectin and chemokines.2002
Author(s)
Kawashima, H., Atarashi, K., Hirose, M., Hirose, J., Yamada, S., Sugahara, K., Miyasaka, M.
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Journal Title
J. Biol. Chem. 277 (15)
Pages: 12921-12930
Description
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