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
hsa00534  Glycosaminoglycan biosynthesis - heparan sulfate / heparin
hsa00534

Ortholog table
Module
hsa_M00059  Glycosaminoglycan biosynthesis, heparan sulfate backbone [PATH:hsa00534]
Disease
H00122  Multiple exostoses
H00494  Desbuquois syndrome
H00802  Ehlers-Danlos syndrome (EDS)
H01494  Spondyloepimetaphyseal dysplasia with joint laxity type (SEMD-JL)
H01496  Spondyloocular syndrome (SOS)
H01498  Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects (JDSSDHD)
Organism
Homo sapiens (human) [GN:hsa]
Gene
64131  XYLT1; xylosyltransferase 1 [KO:K00771] [EC:2.4.2.26]
64132  XYLT2; xylosyltransferase 2 [KO:K00771] [EC:2.4.2.26]
11285  B4GALT7; beta-1,4-galactosyltransferase 7 [KO:K00733] [EC:2.4.1.133]
126792  B3GALT6; beta-1,3-galactosyltransferase 6 [KO:K00734] [EC:2.4.1.134]
26229  B3GAT3; beta-1,3-glucuronyltransferase 3 [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 and N-sulfotransferase 1 [KO:K02576] [EC:2.8.2.- 3.1.1.-]
8509  NDST2; N-deacetylase and N-sulfotransferase 2 [KO:K02577] [EC:2.8.2.- 3.1.1.-]
9348  NDST3; N-deacetylase and N-sulfotransferase 3 [KO:K02578] [EC:2.8.2.- 3.1.1.-]
64579  NDST4; N-deacetylase and N-sulfotransferase 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-sulfotransferase 1 [KO:K01024] [EC:2.8.2.23]
9956  HS3ST2; heparan sulfate-glucosamine 3-sulfotransferase 2 [KO:K07808] [EC:2.8.2.29]
9953  HS3ST3B1; heparan sulfate-glucosamine 3-sulfotransferase 3B1 [KO:K07809] [EC:2.8.2.30]
9955  HS3ST3A1; heparan sulfate-glucosamine 3-sulfotransferase 3A1 [KO:K07809] [EC:2.8.2.30]
222537  HS3ST5; heparan sulfate-glucosamine 3-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)
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
KO pathway
ko00534   

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