KEGG   PATHWAY: rn00534
Entry
rn00534                     Pathway                                
Name
Glycosaminoglycan biosynthesis - heparan sulfate / heparin
Description
Heparan sulfate (HS) and heparin (Hep) are glycosaminoglycans with repeating disaccharide units that consist of alternating residues of alpha-D-glucosamine (GlcN) and uronic acid, the latter being either beta-D-glucuronic acid (GlcA) or alpha-L-iduronic acid (IdoA). In these sugar residues, sulfation modification may be performed at various positions. Structural studies show that Hep possesses a higher degree of sulfation than HS. The biosynthesis of HS/Hep occurs with the addition of the first GlcNAc residue by EXTL3 glycosyltransferase after completion of tetrasaccharide linkage region attached to serine residue of a core protein. The chain polymeraization is then catalyzed by EXT1 and EXT2 transferases. As the chain polymerizes, HS/Hep undergoes a series of modification reactions including N-deacetylation, N-sulfation, epimerization, and subsequently O-sulfation. As final products of biosynthesis, HS is present in the form of hepran sulfate proteoglycan (HSPG) whereas Hep exists as a sugar chain without a core protein. The proteoglycan families with HS, as well as CS (chondroitin sulfate), DS (dermatan sulfate), and KS (keratan sulfate), are composed of two main types depending on the subcellular locations: cell membrane and extracellular matrix [BR:ko00535]. HS/Hep has been shown to bind to a variety of molecules, such as growth factors, chemokines, morphogens, and extracellular matrix components [BR:ko00536].
Class
Metabolism; Glycan biosynthesis and metabolism
Pathway map
rn00534  Glycosaminoglycan biosynthesis - heparan sulfate / heparin
rn00534

Module
M00057  Glycosaminoglycan biosynthesis, linkage tetrasaccharide [PATH:rn00534]
M00059  Glycosaminoglycan biosynthesis, heparan sulfate backbone [PATH:rn00534]
Other DBs
GO: 0030210
Reaction
R05925   
R05926   
R05927   
R05928   
R05930   
R05935   
R05936   
R10138   
R10139   
Compound
C00033  Acetate
C00053  3'-Phosphoadenylyl sulfate
C00054  Adenosine 3',5'-bisphosphate
G00157   
G00162   
G00163   
G00164   
Reference
  Authors
Kim BT, Kitagawa H, Tamura J, Saito T, Kusche-Gullberg M, Lindahl U, Sugahara K
  Title
Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis.
  Journal
Proc Natl Acad Sci U S A 98:7176-81 (2001)
DOI:10.1073/pnas.131188498
Reference
  Authors
Kitagawa H, Shimakawa H, Sugahara K
  Title
The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate.
  Journal
J Biol Chem 274:13933-7 (1999)
DOI:10.1074/jbc.274.20.13933
Reference
PMID:9756849
  Authors
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K
  Title
The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.
  Journal
J Biol Chem 273:26265-8 (1998)
DOI:10.1074/jbc.273.41.26265
Reference
  Authors
Li JP, Gong F, El Darwish K, Jalkanen M, Lindahl U.
  Title
Characterization of the D-glucuronyl C5-epimerase involved in the biosynthesis of heparin and heparan sulfate.
  Journal
J Biol Chem 276:20069-77 (2001)
DOI:10.1074/jbc.M011783200
Reference
  Authors
Habuchi O
  Title
Diversity and functions of glycosaminoglycan sulfotransferases.
  Journal
Biochim Biophys Acta 1474:115-27 (2000)
DOI:10.1016/S0304-4165(00)00016-7
Reference
PMID:9151776
  Authors
Rosenberg RD, Shworak NW, Liu J, Schwartz JJ, Zhang L
  Title
Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated?
  Journal
J Clin Invest 99:2062-70 (1997)
DOI:10.1172/JCI119377
Reference
PMID:9988768
  Authors
Liu J, Shworak NW, Sinay P, Schwartz JJ, Zhang L, Fritze LM, Rosenberg RD
  Title
Expression of heparan sulfate D-glucosaminyl 3-O-sulfotransferase isoforms reveals novel substrate specificities.
  Journal
J Biol Chem 274:5185-92 (1999)
DOI:10.1074/jbc.274.8.5185
Reference
  Authors
Shukla D, Liu J, Blaiklock P, Shworak NW, Bai X, Esko JD, Cohen GH, Eisenberg RJ, Rosenberg RD, Spear PG
  Title
A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry.
  Journal
Cell 99:13-22 (1999)
DOI:10.1016/S0092-8674(00)80058-6
Reference
  Authors
Moon AF, Edavettal SC, Krahn JM, Munoz EM, Negishi M, Linhardt RJ, Liu J, Pedersen LC
  Title
Structural analysis of the sulfotransferase (3-o-sulfotransferase isoform 3) involved in the biosynthesis of an entry receptor for herpes simplex virus 1.
  Journal
J Biol Chem 279:45185-93 (2004)
DOI:10.1074/jbc.M405013200
Reference
  Authors
Chen J, Liu J
  Title
Characterization of the structure of antithrombin-binding heparan sulfate generated by heparan sulfate 3-O-sulfotransferase 5.
  Journal
Biochim Biophys Acta 1725:190-200 (2005)
DOI:10.1016/j.bbagen.2005.06.012
Related
pathway
rn00531  Glycosaminoglycan degradation
rn00532  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate
KO pathway
ko00534   
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