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Journal of Biochemistry Advance Access originally published online on March 26, 2008
Journal of Biochemistry 2008 144(1):7-14; doi:10.1093/jb/mvn040
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© 2008 The Japanese Biochemical Society

JB Minireviews-New Paradigm in Glycobiology

Heparan Sulphate Biosynthesis and Disease

Satomi Nadanaka1 and Hiroshi Kitagawa1,2,*

1Department of Biochemistry, Kobe Pharmaceutical University, Kobe 658-8558; and 2CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

*To whom correspondence should be addressed. Tel: +81 (78) 441 7570, Fax: +81 (78) 441 7569, E-mail: kitagawa{at}kobepharma-u.ac.jp

Received January 18, 2008; Accepted February 13, 2008


  Abstract

Proteoglycans carrying heparan sulphate (HS) chains are ubiquitously expressed at cell surfaces and in extra-cellular matrices, and HS chains interact with numerous proteins, including growth factors, morphogens and extra-cellular-matrix proteins. These interactions form the basis of HS-related biological phenomena. Thus, the biosynthesis of HS regulates key events in embryonic development and homeostasis, and deranged HS biosynthesis could cause diseases. EXT1 and EXT2 genes encoding the polymerase responsible for HS biosynthesis are known as causative genes of hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by the formation of multiple cartilaginous tumours. In this review, we will summarize HS biosynthesis in several model animals, the effects on cellular functions by alteration of HS biosynthesis, and HS-associated diseases. This review suggests that HS biosynthetic enzymes would be potential candidates for drug targets in various diseases.

Key Words: glycosyltransferase, heparan sulphate, hereditary multiple exostoses, proteoglycan, tumour-suppressor gene

Abbreviations: Aβ, amyloid β-peptide; AD, Alzheimer's disease; APP, amyloid precursor protein; BACE1, β-site amyloid precursor protein-cleaving enzyme 1; EXT, exostosin; FGFs, fibroblast growth factors; GlcAT, glucuronyltransferase; GlcNAcT, N-acetylglucosaminyltransferase; {alpha}-GalNAcT, {alpha}-1,4-N-acetylgalactosaminyltransferase; Hh, Hedgehog; HME, hereditary multiple exostoses; HS, heparan sulphate; Ihh, Indian hedgehog; LDL, low-density lipoprotein; LDLR, LDL receptor; LRP, LDL-related protein; Ndst, GlcNAc N-deacetylase/N-sulphotransferase; PG, proteoglycan; PTH, parathyroid hormone; PTHrP, PTH-related peptide; TRL, triglyceride-rich lipoprotein; VEGF, vascular endothelial growth factor; Wg, Wingless


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