KEGG   PATHWAY: hsa00534Help
Entry
hsa00534                    Pathway                                

Name
Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Glycosaminoglycan biosynthesis - heparan sulfate / heparin
hsa00534

All organismsOrtholog table
Module
Glycosaminoglycan biosynthesis, heparan sulfate backbone [PATH:hsa00534]
Disease
H00122  
Multiple exostoses
H00802  
Ehlers-Danlos syndrome (EDS)
Organism
Homo sapiens (human) [GN:hsa]
Gene
64131  
XYLT1; xylosyltransferase I [KO:K00771] [EC:2.4.2.26]
64132  
XYLT2; xylosyltransferase II [KO:K00771] [EC:2.4.2.26]
11285  
B4GALT7; xylosylprotein beta 1,4-galactosyltransferase, polypeptide 7 [KO:K00733] [EC:2.4.1.133]
126792  
B3GALT6; UDP-Gal:betaGal beta 1,3-galactosyltransferase polypeptide 6 [KO:K00734] [EC:2.4.1.134]
26229  
B3GAT3; beta-1,3-glucuronyltransferase 3 (glucuronosyltransferase I) [KO:K10158] [EC:2.4.1.135]
2135  
EXTL2; exostosin-like glycosyltransferase 2 [KO:K02369] [EC:2.4.1.223]
2137  
EXTL3; exostosin-like glycosyltransferase 3 [KO:K02370] [EC:2.4.1.224 2.4.1.223]
2134  
EXTL1; exostosin-like glycosyltransferase 1 [KO:K02368] [EC:2.4.1.224]
2131  
EXT1; exostosin glycosyltransferase 1 [KO:K02366] [EC:2.4.1.225 2.4.1.224]
2132  
EXT2; exostosin glycosyltransferase 2 [KO:K02367] [EC:2.4.1.225 2.4.1.224]
3340  
NDST1; N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 1 [KO:K02576] [EC:2.8.2.- 3.1.1.-]
8509  
NDST2; N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 2 [KO:K02577] [EC:2.8.2.- 3.1.1.-]
9348  
NDST3; N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3 [KO:K02578] [EC:2.8.2.- 3.1.1.-]
64579  
NDST4; N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4 [KO:K02579] [EC:2.8.2.- 3.1.1.-]
26035  
GLCE; glucuronic acid epimerase [KO:K01793] [EC:5.1.3.17]
9653  
HS2ST1; heparan sulfate 2-O-sulfotransferase 1 [KO:K02513] [EC:2.8.2.-]
9394  
HS6ST1; heparan sulfate 6-O-sulfotransferase 1 [KO:K02514] [EC:2.8.2.-]
90161  
HS6ST2; heparan sulfate 6-O-sulfotransferase 2 [KO:K08102] [EC:2.8.2.-]
266722  
HS6ST3; heparan sulfate 6-O-sulfotransferase 3 [KO:K08103] [EC:2.8.2.-]
9957  
HS3ST1; heparan sulfate (glucosamine) 3-O-sulfotransferase 1 [KO:K01024] [EC:2.8.2.23]
9956  
HS3ST2; heparan sulfate (glucosamine) 3-O-sulfotransferase 2 [KO:K07808] [EC:2.8.2.29]
9953  
HS3ST3B1; heparan sulfate (glucosamine) 3-O-sulfotransferase 3B1 [KO:K07809] [EC:2.8.2.30]
9955  
HS3ST3A1; heparan sulfate (glucosamine) 3-O-sulfotransferase 3A1 [KO:K07809] [EC:2.8.2.30]
222537  
HS3ST5; heparan sulfate (glucosamine) 3-O-sulfotransferase 5 [KO:K08104] [EC:2.8.2.23]
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)
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)
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)
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)
Reference
  Authors
Habuchi O
  Title
Diversity and functions of glycosaminoglycan sulfotransferases.
  Journal
Biochim Biophys Acta 1474:115-27 (2000)
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)
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)
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)
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)
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)
KO pathway
 

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