Glycosaminoglycan metabolism (Homo sapiens)

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22, 80, 1291330, 37, 4544, 11650117, 12246, 62677, 10429, 11218, 51, 53, 9085020, 95, 105, 14074, 89, 1377811, 69, 14285, 115, 12141, 55, 56, 128, 13017, 12035, 8839, 11749, 9315, 10923, 40, 58, 111, 12682, 11811, 69, 14249, 93513558685, 115, 12130, 37, 4599, 102, 10316, 66, 97, 98, 106...28, 77, 8323, 40, 58, 111, 12627, 32, 33, 48, 54...2, 21, 1272, 21, 127110, 13330, 37, 4574, 89, 13746, 6259101, 13420, 95, 105, 1402, 21, 127131231, 73, 9442, 79, 8411438, 125, 1316, 75, 96516, 97, 1133, 14, 19, 36, 60...26, 12313713672, 13670, 10012523, 40, 58, 111, 12643, 47, 6335, 886865, 91, 9225, 71, 132, 1411046, 62117, 12220, 34, 57, 105, 1381, 9, 87642, 21, 1274, 24, 76, 139110, 1334, 24, 76, 13952, 81HA receptors HA receptors EXT1EXT2 IDS dimer HAHARHYAL2 HPSE dimer Golgi lumenbHEXA cytosolGUSB tetramer ARSBCa2+ bHEXA Golgi lumenlysosomal lumenHAHARHYAL2SLC9A1 UDPH+D2,4,4CHST15H2OSO4GlcA-Gal-Gal-Xyl-CS proteinsCSE-PGHSPGsHAS1,2,3UDP-GlcASLC9A1GlcA-b1,3-GlcNAclinker chainEXT2 SO4beta-xylosidaseUDPCS GlcA tranferasesHAHARHYAL2UDP-sugarsGal-glycan-proteinHMMR DSEKeratanGalchondroitinUDP-GlcAL-Iduronic acidCSPGsUDPATPH2OHYAL1HMMR L-AspGlcAHS core proteinsUDPUDP-GalC4S/C6S chainsHSPGsCHST3,7Ca2+ L-Iduronic acidH2OSTAB2UDPH2OchondroitinHeparanHAHARHYAL2SLC9A1PAPSS1,2SGSHH2OUDP-xylEXT1EXT2SLC35D2Heparan sulfate chainUDP-GalGlcNAcGlcA-Gal-Gal-Xyl-proteinsHeparanSGSHUDPUDP-GlcACoA-SHUDP-GalHS3ST1SLC9A1 SO4CSPGsCoA-SHHSHeparan sulfate chainUDP-sugarsUDPCSGALNACTHS core proteinsCHST14ChEBI63515 chainH2OD-xyloseGALNS oligomerUDPGal-GlcNAcHEXBHSIDSPAPGUSB H2ON-glycan-proteinCHST2,5,6UDPPAPSHyaluronanPAPSCD44 Heparan sulfate chainUMPPAPH2OPAPSD4S-PGsLYVE1 HS/HPIN-PGsPAPSbHEXAAPSPAPHS3ST sulfotransferasesH2OB3GAT dimersChondroitin chainsChEBI63517 chainGlcAUDPHeparan sulfate chainSO4PAPSH2OGalNAcKeratanPAPSD2,4UDP-GalBGALkeratan sulfate 1,4-beta-D-galactosidaseCS/DS core proteinsH2OH2OKSPGH2OChEBI63516 chainH2OHS/HPIN-PGsOxA-ARSB ABCC5NAGLUGlcNAc-GlcA-GlcNAcAc-CoAKSPGHSSO4OxA-GNSIDS dimerPAPSH2OST3GAL1-4,6Gal-GlcNAcHS6STsUSTPAPSUDP-GlcNAcHPSE2SO4PAPCHEBI63868 chainHPSEPAPSNAGLUIDUAPAPH+HA receptorsGlcNAcHeparan sulfate chainHYAL2 B3GNT1,2,3,4,7IDUAATPUDP-GalC4S-PGUDP-GalNAcHS2ST1NDSTsGlcNAcHPSE dimerHEXA H2OHeparan chainKSPGHA polymerGlcA-Gal-Gal-Xyl-HS proteinsCH3COO-HPSEHeparan sulfate chainUDPAc-CoAGAG core proteinsH2OHEXA Gal-Gal-Xyl-proteinsGlcNAc-Gal-GlcNAcKS core proteinsCD44 xylosyl-core proteinsHSSO4HEXBPAPKeratanCa2+ HeparanUDPD2,4,4CHST1DSPGsBGALPAPSCSPGsUDPHeparanB4GALT1-6 homodimerschondroitinHGSNAT oligomerHeparan sulfate chainHS3STsSO4B3GALT6B4GALT7UDPH2OGal-Xyl-proteinsPAPH2ODSPGsCS GalNAc tranferasesH2OUDP-GlcNAcSLC26A1,2GalDSPGsSLC35B2,3ARSBCa2+STAB2HYAL1H2OPAPbHEXAADPH2OHYAL2 HYAL2HSKSPGHS/HPIN-PGsHeparan sulfate chainPAPSC6S-PGChEBI63519 chainH2OCS/HS precursorChondroitin chainCMPGXYLTsGlcA-b1,3-GlcNAcPAPHEXBIdoA-GalNAcGalHEXBGalNAcHeparan chainIDSCHST9,11,12,13Heparan-PGsPPiUDP-GlcACMP-SAH2OPAPEXT1 GUSB tetramerGlcNAcUDP-GlcNAcKeratanUMPUDPUDP-GalNAcLYVE1 GLCEGlcNAc


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Glycosaminoglycans (GAGs) are long, unbranched polysaccharides containing a repeating disaccharide unit composed of a hexosamine (either N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc)) and a uronic acid (glucuronate or iduronate). They can be heavily sulfated. GAGs are located primarily in the extracellular matrix (ECM) and on cell membranes, acting as a lubricating fluid for joints and as part of signalling processes. They have structural roles in connective tissue, cartilage, bone and blood vessels (Esko et al. 2009). GAGs are degraded in the lysosome as part of their natural turnover. Defects in the lysosomal enzymes responsible for the metabolism of membrane-associated GAGs lead to lysosomal storage diseases called mucopolysaccharidoses (MPS). MPSs are characterised by the accumulation of GAGs in lysosomes resulting in chronic, progressively debilitating disorders that in many instances lead to severe psychomotor retardation and premature death (Cantz & Gehler 1976, Clarke 2008). The biosynthesis and breakdown of the main GAGs (hyaluronate, keratan sulfate, chondroitin sulfate, dermatan sulfate and heparan sulfate) is described here.

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  95. Knudson W, Chow G, Knudson CB.; ''CD44-mediated uptake and degradation of hyaluronan.''; PubMed Europe PMC Scholia
  96. Ohtake S, Kimata K, Habuchi O.; ''A unique nonreducing terminal modification of chondroitin sulfate by N-acetylgalactosamine 4-sulfate 6-o-sulfotransferase.''; PubMed Europe PMC Scholia
  97. Levy-Adam F, Miao HQ, Heinrikson RL, Vlodavsky I, Ilan N.; ''Heterodimer formation is essential for heparanase enzymatic activity.''; PubMed Europe PMC Scholia
  98. Tsutsumi K, Shimakawa H, Kitagawa H, Sugahara K.; ''Functional expression and genomic structure of human chondroitin 6-sulfotransferase.''; PubMed Europe PMC Scholia
  99. Wang C, Entwistle J, Hou G, Li Q, Turley EA.; ''The characterization of a human RHAMM cDNA: conservation of the hyaluronan-binding domains.''; PubMed Europe PMC Scholia
  100. Ouzzine M, Gulberti S, Netter P, Magdalou J, Fournel-Gigleux S.; ''Structure/function of the human Ga1beta1,3-glucuronosyltransferase. Dimerization and functional activity are mediated by two crucial cysteine residues.''; PubMed Europe PMC Scholia
  101. Kang HG, Evers MR, Xia G, Baenziger JU, Schachner M.; ''Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases.''; PubMed Europe PMC Scholia
  102. Oshima A, Kyle JW, Miller RD, Hoffmann JW, Powell PP, Grubb JH, Sly WS, Tropak M, Guise KS, Gravel RA.; ''Cloning, sequencing, and expression of cDNA for human beta-glucuronidase.''; PubMed Europe PMC Scholia
  103. Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, Mollica F, Lüdecke HJ, Sayli BS, Pazzaglia UE, Mortier G, Hamel B, Conrad EU, Matsushita M, Raskind WH, Willems PJ.; ''Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.''; PubMed Europe PMC Scholia
  104. Stern R.; ''Hyaluronan catabolism: a new metabolic pathway.''; PubMed Europe PMC Scholia
  105. Takagaki K, Nakamura T, Endo M.; ''Demonstration of an endo-beta-galactosidase and an endo-beta-xylosidase that degrade the proteoglycan linkage region.''; PubMed Europe PMC Scholia
  106. Hansske B, Thiel C, Lübke T, Hasilik M, Höning S, Peters V, Heidemann PH, Hoffmann GF, Berger EG, von Figura K, Körner C.; ''Deficiency of UDP-galactose:N-acetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId.''; PubMed Europe PMC Scholia
  107. Lo NW, Shaper JH, Pevsner J, Shaper NL.; ''The expanding beta 4-galactosyltransferase gene family: messages from the databanks.''; PubMed Europe PMC Scholia
  108. Okuda T, Mita S, Yamauchi S, Matsubara T, Yagi F, Yamamori D, Fukuta M, Kuroiwa A, Matsuda Y, Habuchi O.; ''Molecular cloning, expression, and chromosomal mapping of human chondroitin 4-sulfotransferase, whose expression pattern in human tissues is different from that of chondroitin 6-sulfotransferase.''; PubMed Europe PMC Scholia
  109. Hiraoka N, Nakagawa H, Ong E, Akama TO, Fukuda MN, Fukuda M.; ''Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family.''; PubMed Europe PMC Scholia
  110. Frost GI, Csóka AB, Wong T, Stern R.; ''Purification, cloning, and expression of human plasma hyaluronidase.''; PubMed Europe PMC Scholia
  111. Shang J, Qiu R, Wang J, Liu J, Zhou R, Ding H, Yang S, Zhang S, Jin C.; ''Molecular cloning and expression of Galbeta1,3GalNAc alpha2, 3-sialyltransferase from human fetal liver.''; PubMed Europe PMC Scholia
  112. Kamiyama S, Sasaki N, Goda E, Ui-Tei K, Saigo K, Narimatsu H, Jigami Y, Kannagi R, Irimura T, Nishihara S.; ''Molecular cloning and characterization of a novel 3'-phosphoadenosine 5'-phosphosulfate transporter, PAPST2.''; PubMed Europe PMC Scholia
  113. Akama TO, Misra AK, Hindsgaul O, Fukuda MN.; ''Enzymatic synthesis in vitro of the disulfated disaccharide unit of corneal keratan sulfate.''; PubMed Europe PMC Scholia
  114. Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T, Sakai S, Sugiyama Y, Enomoto H, Okada Y, Inoue S.; ''KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.''; PubMed Europe PMC Scholia
  115. Faiyaz ul Haque M, King LM, Krakow D, Cantor RM, Rusiniak ME, Swank RT, Superti-Furga A, Haque S, Abbas H, Ahmad W, Ahmad M, Cohn DH.; ''Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse.''; PubMed Europe PMC Scholia
  116. Tian J, Ling L, Shboul M, Lee H, O'Connor B, Merriman B, Nelson SF, Cool S, Ababneh OH, Al-Hadidy A, Masri A, Hamamy H, Reversade B.; ''Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling.''; PubMed Europe PMC Scholia
  117. Sakaguchi H, Kitagawa H, Sugahara K.; ''Functional expression and genomic structure of human N-acetylglucosamine-6-O-sulfotransferase that transfers sulfate to beta-N-acetylglucosamine at the nonreducing end of an N-acetyllactosamine sequence.''; PubMed Europe PMC Scholia
  118. Clarke LA.; ''The mucopolysaccharidoses: a success of molecular medicine.''; PubMed Europe PMC Scholia
  119. Daly SB, Urquhart JE, Hilton E, McKenzie EA, Kammerer RA, Lewis M, Kerr B, Stuart H, Donnai D, Long DA, Burgu B, Aydogdu O, Derbent M, Garcia-Minaur S, Reardon W, Gener B, Shalev S, Smith R, Woolf AS, Black GC, Newman WG.; ''Mutations in HPSE2 cause urofacial syndrome.''; PubMed Europe PMC Scholia
  120. Smeds E, Feta A, Kusche-Gullberg M.; ''Target selection of heparan sulfate hexuronic acid 2-O-sulfotransferase.''; PubMed Europe PMC Scholia
  121. Habuchi H, Tanaka M, Habuchi O, Yoshida K, Suzuki H, Ban K, Kimata K.; ''The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine.''; PubMed Europe PMC Scholia
  122. Ozeran JD, Westley J, Schwartz NB.; ''Identification and partial purification of PAPS translocase.''; PubMed Europe PMC Scholia
  123. Lee-Chen GJ, Lin SP, Tang YF, Chin YW.; ''Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity.''; PubMed Europe PMC Scholia
  124. Pacheco B, Malmström A, Maccarana M.; ''Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate.''; PubMed Europe PMC Scholia
  125. Wilson PJ, Morris CP, Anson DS, Occhiodoro T, Bielicki J, Clements PR, Hopwood JJ.; ''Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA.''; PubMed Europe PMC Scholia
  126. Li Y, Laue K, Temtamy S, Aglan M, Kotan LD, Yigit G, Canan H, Pawlik B, Nürnberg G, Wakeling EL, Quarrell OW, Baessmann I, Lanktree MB, Yilmaz M, Hegele RA, Amr K, May KW, Nürnberg P, Topaloglu AK, Hammerschmidt M, Wollnik B.; ''Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of BMP signaling.''; PubMed Europe PMC Scholia
  127. Zheng H, Li Y, Ji C, Li J, Zhang J, Yin G, Xu J, Ye X, Wu M, Zou X, Gu S, Xie Y, Mao Y.; ''Characterization of a cDNA encoding a protein with limited similarity to beta1, 3-N-acetylglucosaminyltransferase.''; PubMed Europe PMC Scholia
  128. Fukuda S, Tomatsu S, Masue M, Sukegawa K, Iwata H, Ogawa T, Nakashima Y, Hori T, Yamagishi A, Hanyu Y.; ''Mucopolysaccharidosis type IVA. N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases.''; PubMed Europe PMC Scholia
  129. Silbert JE, Sugumaran G.; ''Biosynthesis of chondroitin/dermatan sulfate.''; PubMed Europe PMC Scholia
  130. Dixon J, Loftus SK, Gladwin AJ, Scambler PJ, Wasmuth JJ, Dixon MJ.; ''Cloning of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene from the Treacher Collins syndrome candidate region at 5q32-q33.1.''; PubMed Europe PMC Scholia
  131. Bai X, Zhou D, Brown JR, Crawford BE, Hennet T, Esko JD.; ''Biosynthesis of the linkage region of glycosaminoglycans: cloning and activity of galactosyltransferase II, the sixth member of the beta 1,3-galactosyltransferase family (beta 3GalT6).''; PubMed Europe PMC Scholia
  132. Toyoshima M, Nakajima M.; ''Human heparanase. Purification, characterization, cloning, and expression.''; PubMed Europe PMC Scholia
  133. Mishima M, Wakabayashi S, Kojima C.; ''Solution structure of the cytoplasmic region of Na+/H+ exchanger 1 complexed with essential cofactor calcineurin B homologous protein 1.''; PubMed Europe PMC Scholia
  134. Okajima T, Fukumoto S, Miyazaki H, Ishida H, Kiso M, Furukawa K, Urano T, Furukawa K.; ''Molecular cloning of a novel alpha2,3-sialyltransferase (ST3Gal VI) that sialylates type II lactosamine structures on glycoproteins and glycolipids.''; PubMed Europe PMC Scholia
  135. Maccarana M, Olander B, Malmström J, Tiedemann K, Aebersold R, Lindahl U, Li JP, Malmström A.; ''Biosynthesis of dermatan sulfate: chondroitin-glucuronate C5-epimerase is identical to SART2.''; PubMed Europe PMC Scholia
  136. Schaub BE, Berger B, Berger EG, Rohrer J.; ''Transition of galactosyltransferase 1 from trans-Golgi cisterna to the trans-Golgi network is signal mediated.''; PubMed Europe PMC Scholia
  137. Jedrzejas MJ, Stern R.; ''Structures of vertebrate hyaluronidases and their unique enzymatic mechanism of hydrolysis.''; PubMed Europe PMC Scholia
  138. Yada T, Sato T, Kaseyama H, Gotoh M, Iwasaki H, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Watanabe H, Narimatsu H, Kimata K.; ''Chondroitin sulfate synthase-3. Molecular cloning and characterization.''; PubMed Europe PMC Scholia
  139. Evers MR, Xia G, Kang HG, Schachner M, Baenziger JU.; ''Molecular cloning and characterization of a dermatan-specific N-acetylgalactosamine 4-O-sulfotransferase.''; PubMed Europe PMC Scholia
  140. Harris EN, Weigel JA, Weigel PH.; ''The human hyaluronan receptor for endocytosis (HARE/Stabilin-2) is a systemic clearance receptor for heparin.''; PubMed Europe PMC Scholia
  141. Durand S, Feldhammer M, Bonneil E, Thibault P, Pshezhetsky AV.; ''Analysis of the biogenesis of heparan sulfate acetyl-CoA:alpha-glucosaminide N-acetyltransferase provides insights into the mechanism underlying its complete deficiency in mucopolysaccharidosis IIIC.''; PubMed Europe PMC Scholia
  142. Gorham SD, Cantz M.; ''Arylsulphatase B, an exo-sulphatase for chondroitin 4-sulphate tetrasaccharide.''; PubMed Europe PMC Scholia
  143. Winchester B.; ''Lysosomal metabolism of glycoproteins.''; PubMed Europe PMC Scholia
  144. Xia G, Chen J, Tiwari V, Ju W, Li JP, Malmstrom A, Shukla D, Liu J.; ''Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1.''; PubMed Europe PMC Scholia
  145. Weber B, Blanch L, Clements PR, Scott HS, Hopwood JJ.; ''Cloning and expression of the gene involved in Sanfilippo B syndrome (mucopolysaccharidosis III B).''; PubMed Europe PMC Scholia
  146. Gotoh M, Yada T, Sato T, Akashima T, Iwasaki H, Mochizuki H, Inaba N, Togayachi A, Kudo T, Watanabe H, Kimata K, Narimatsu H.; ''Molecular cloning and characterization of a novel chondroitin sulfate glucuronyltransferase that transfers glucuronic acid to N-acetylgalactosamine.''; PubMed Europe PMC Scholia
  147. Lee JK, Bhakta S, Rosen SD, Hemmerich S.; ''Cloning and characterization of a mammalian N-acetylglucosamine-6-sulfotransferase that is highly restricted to intestinal tissue.''; PubMed Europe PMC Scholia
  148. Masue M, Sukegawa K, Orii T, Hashimoto T.; ''N-acetylgalactosamine-6-sulfate sulfatase in human placenta: purification and characteristics.''; PubMed Europe PMC Scholia
  149. Robertson DA, Freeman C, Morris CP, Hopwood JJ.; ''A cDNA clone for human glucosamine-6-sulphatase reveals differences between arylsulphatases and non-arylsulphatases.''; PubMed Europe PMC Scholia
  150. Lederkremer GZ.; ''Glycoprotein folding, quality control and ER-associated degradation.''; PubMed Europe PMC Scholia
  151. Hrebícek M, Mrázová L, Seyrantepe V, Durand S, Roslin NM, Nosková L, Hartmannová H, Ivánek R, Cízkova A, Poupetová H, Sikora J, Urinovská J, Stranecký V, Zeman J, Lepage P, Roquis D, Verner A, Ausseil J, Beesley CE, Maire I, Poorthuis BJ, van de Kamp J, van Diggelen OP, Wevers RA, Hudson TJ, Fujiwara TM, Majewski J, Morgan K, Kmoch S, Pshezhetsky AV.; ''Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome).''; PubMed Europe PMC Scholia
  152. Lim CT, Horwitz AL.; ''Purification and properties of human N-acetylgalactosamine-6-sulfate sulfatase.''; PubMed Europe PMC Scholia
  153. Götting C, Kuhn J, Zahn R, Brinkmann T, Kleesiek K.; ''Molecular cloning and expression of human UDP-d-Xylose:proteoglycan core protein beta-d-xylosyltransferase and its first isoform XT-II.''; PubMed Europe PMC Scholia
  154. Lepperdinger G, Strobl B, Kreil G.; ''HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114622view16:08, 25 January 2021ReactomeTeamReactome version 75
113070view11:13, 2 November 2020ReactomeTeamReactome version 74
112305view15:22, 9 October 2020ReactomeTeamReactome version 73
101203view11:10, 1 November 2018ReactomeTeamreactome version 66
100741view20:34, 31 October 2018ReactomeTeamreactome version 65
100285view19:11, 31 October 2018ReactomeTeamreactome version 64
99831view15:55, 31 October 2018ReactomeTeamreactome version 63
99388view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93758view13:34, 16 August 2017ReactomeTeamreactome version 61
93280view11:19, 9 August 2017ReactomeTeamreactome version 61
87154view18:58, 18 July 2016MkutmonOntology Term : 'glycosaminoglycan metabolic pathway' added !
86359view09:16, 11 July 2016ReactomeTeamreactome version 56
83349view10:56, 18 November 2015ReactomeTeamVersion54
81509view13:02, 21 August 2015ReactomeTeamVersion53
76981view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76686view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76013view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75721view11:08, 10 June 2014ReactomeTeamReactome 48 Update
74718view08:47, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABCC5ProteinO15440 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
APSMetaboliteCHEBI:17709 (ChEBI)
ARSB Ca2+ComplexREACT_122486 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
B3GALT6ProteinQ96L58 (Uniprot-TrEMBL)
B3GAT dimersComplexREACT_122746 (Reactome)
B3GNT1,2,3,4,7ProteinREACT_121781 (Reactome)
B4GALT1-6 homodimersComplexREACT_26591 (Reactome)
B4GALT7ProteinQ9UBV7 (Uniprot-TrEMBL)
BGALProteinREACT_165100 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
C4S-PGProteinREACT_124101 (Reactome)
C4S/C6S chainsMetaboliteREACT_122110 (Reactome)
C6S-PGProteinREACT_121500 (Reactome)
CD44 ProteinP16070 (Uniprot-TrEMBL)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
CHEBI 63868 chainMetaboliteCHEBI:63868 (ChEBI)
CHST14ProteinQ8NCH0 (Uniprot-TrEMBL)
CHST15ProteinQ7LFX5 (Uniprot-TrEMBL)
CHST1ProteinO43916 (Uniprot-TrEMBL)
CHST2,5,6ProteinREACT_123312 (Reactome)
CHST3,7ProteinREACT_125232 (Reactome)
CHST9,11,12,13ProteinREACT_125490 (Reactome)
CMP-SAMetaboliteCHEBI:16556 (ChEBI)
CMPMetaboliteCHEBI:17361 (ChEBI)
CS GalNAc tranferasesProteinREACT_124285 (Reactome)
CS GlcA tranferasesProteinREACT_124292 (Reactome)
CS/DS core proteinsProteinREACT_124137 (Reactome)
CS/HS precursorMetaboliteCHEBI:63505 (ChEBI)
CSE-PGProteinREACT_123649 (Reactome)
CSGALNACTProteinREACT_125395 (Reactome)
CSPGsProteinREACT_123227 (Reactome)
CSPGsProteinREACT_124804 (Reactome)
CSPGsProteinREACT_124864 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
ChEBI 63515 chainMetaboliteCHEBI:63515 (ChEBI)
ChEBI 63516 chainMetaboliteCHEBI:63516 (ChEBI)
ChEBI 63517 chainMetaboliteCHEBI:63517 (ChEBI)
ChEBI 63519 chainMetaboliteCHEBI:63519 (ChEBI)
Chondroitin chainMetaboliteCHEBI:63511 (ChEBI)
Chondroitin chainsMetaboliteREACT_121412 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
D-xyloseMetaboliteCHEBI:15936 (ChEBI)
D2,4,4ProteinREACT_122418 (Reactome)
D2,4,4ProteinREACT_124659 (Reactome)
D2,4ProteinREACT_125480 (Reactome)
D4S-PGsProteinREACT_124915 (Reactome)
DSEProteinQ9UL01 (Uniprot-TrEMBL)
DSPGsProteinREACT_121927 (Reactome)
DSPGsProteinREACT_122485 (Reactome)
DSPGsProteinREACT_122660 (Reactome)
EXT1 EXT2ComplexREACT_122567 (Reactome)
EXT1 ProteinQ16394 (Uniprot-TrEMBL)
EXT2 ProteinQ93063 (Uniprot-TrEMBL)
GAG core proteinsProteinREACT_124694 (Reactome)
GALNS oligomerREACT_121429 (Reactome)
GLCEProteinO94923 (Uniprot-TrEMBL)
GUSB ProteinP08236 (Uniprot-TrEMBL)
GUSB tetramerComplexREACT_125084 (Reactome)
GXYLTsProteinREACT_122530 (Reactome)
Gal-Gal-Xyl-proteinsProteinREACT_125558 (Reactome)
Gal-GlcNAcMetaboliteCHEBI:63850 (ChEBI)
Gal-GlcNAcMetaboliteCHEBI:63853 (ChEBI)
Gal-Xyl-proteinsProteinREACT_125578 (Reactome)
Gal-glycan-proteinProteinREACT_122582 (Reactome)
GalMetaboliteCHEBI:28061 (ChEBI)
GalMetaboliteCHEBI:63846 (ChEBI)
GalNAcMetaboliteCHEBI:28037 (ChEBI)
GlcA-Gal-Gal-Xyl-CS proteinsProteinREACT_124761 (Reactome)
GlcA-Gal-Gal-Xyl-HS proteinsProteinREACT_124611 (Reactome)
GlcA-Gal-Gal-Xyl-proteinsProteinREACT_123660 (Reactome)
GlcA-b1,3-GlcNAcMetaboliteCHEBI:64024 (ChEBI)
GlcAMetaboliteCHEBI:4178 (ChEBI)
GlcNAc-Gal-GlcNAcMetaboliteCHEBI:63852 (ChEBI)
GlcNAc-GlcA-GlcNAcREACT_125048 (Reactome)
GlcNAcMetaboliteCHEBI:17411 (ChEBI)
GlcNAcMetaboliteCHEBI:63851 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HA

HAR HYAL2

SLC9A1
ComplexREACT_124260 (Reactome)
HA

HAR

HYAL2
ComplexREACT_124024 (Reactome)
HA polymerREACT_122338 (Reactome)
HA receptorsProteinREACT_124198 (Reactome)
HAS1,2,3ProteinREACT_121848 (Reactome)
HEXA ProteinP06865 (Uniprot-TrEMBL)
HEXBProteinP07686 (Uniprot-TrEMBL)
HGSNAT oligomerREACT_124887 (Reactome)
HMMR ProteinO75330 (Uniprot-TrEMBL)
HPSE dimerComplexREACT_122933 (Reactome)
HPSE2ProteinQ8WWQ2 (Uniprot-TrEMBL)
HPSEProteinQ9Y251 (Uniprot-TrEMBL)
HS core proteinsProteinREACT_123905 (Reactome)
HS core proteinsProteinREACT_124689 (Reactome)
HS/HPIN-PGsProteinREACT_122772 (Reactome)
HS/HPIN-PGsProteinREACT_124554 (Reactome)
HS/HPIN-PGsProteinREACT_125265 (Reactome)
HS2ST1ProteinQ7LGA3 (Uniprot-TrEMBL)
HS3ST sulfotransferasesProteinREACT_161535 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
HS3ST1ProteinO14792 (Uniprot-TrEMBL)
HS3STsProteinREACT_123150 (Reactome)
HS6STsProteinREACT_124907 (Reactome)
HSPGsProteinREACT_122831 (Reactome)
HSPGsProteinREACT_124539 (Reactome)
HSProteinREACT_121587 (Reactome)
HSProteinREACT_122101 (Reactome)
HSProteinREACT_123398 (Reactome)
HSProteinREACT_123421 (Reactome)
HSProteinREACT_123903 (Reactome)
HYAL1ProteinQ12794 (Uniprot-TrEMBL)
HYAL2 ProteinQ12891 (Uniprot-TrEMBL)
HYAL2ProteinQ12891 (Uniprot-TrEMBL)
Heparan chainMetaboliteCHEBI:63645 (ChEBI)
Heparan chainMetaboliteCHEBI:63811 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63666 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63805 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63806 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63807 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63808 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63809 (ChEBI)
Heparan sulfate chainMetaboliteCHEBI:63810 (ChEBI)
Heparan-PGsProteinREACT_124579 (Reactome)
HeparanProteinREACT_122863 (Reactome)
HeparanProteinREACT_123848 (Reactome)
HeparanProteinREACT_125452 (Reactome)
HeparanProteinREACT_125688 (Reactome)
HyaluronanREACT_124014 (Reactome)
IDS dimerComplexREACT_121563 (Reactome)
IDSProteinP22304 (Uniprot-TrEMBL)
IDUAProteinP35475 (Uniprot-TrEMBL)
IdoA-GalNAcMetaboliteCHEBI:63873 (ChEBI)
KS core proteinsProteinREACT_125390 (Reactome)
KSPGProteinREACT_121812 (Reactome)
KSPGProteinREACT_121901 (Reactome)
KSPGProteinREACT_123146 (Reactome)
KSPGProteinREACT_125462 (Reactome)
KeratanProteinREACT_122716 (Reactome)
KeratanProteinREACT_123317 (Reactome)
KeratanProteinREACT_123640 (Reactome)
KeratanProteinREACT_124854 (Reactome)
L-AspMetaboliteCHEBI:17053 (ChEBI)
L-Iduronic acidMetaboliteCHEBI:28481 (ChEBI)
LYVE1 ProteinQ9Y5Y7 (Uniprot-TrEMBL)
N-glycan-proteinProteinREACT_122505 (Reactome)
NAGLUProteinP54802 (Uniprot-TrEMBL)
NDSTsProteinREACT_123253 (Reactome)
OxA-ARSB ProteinP15848 (Uniprot-TrEMBL)
OxA-GNSProteinP15586 (Uniprot-TrEMBL)
PAPMetaboliteCHEBI:17985 (ChEBI)
PAPSMetaboliteCHEBI:17980 (ChEBI)
PAPSS1,2ProteinREACT_7300 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
REACT_121659 (Reactome)
REACT_122218 (Reactome)
REACT_123492 (Reactome)
SGSHProteinP51688 (Uniprot-TrEMBL)
SLC26A1,2ProteinREACT_19980 (Reactome)
SLC35B2,3ProteinREACT_164729 (Reactome)
SLC35D2ProteinQ76EJ3 (Uniprot-TrEMBL)
SLC9A1 ProteinP19634 (Uniprot-TrEMBL)
SLC9A1ProteinP19634 (Uniprot-TrEMBL)
SO4MetaboliteCHEBI:16189 (ChEBI)
ST3GAL1-4,6ProteinREACT_121515 (Reactome)
STAB2ProteinQ8WWQ8 (Uniprot-TrEMBL)
UDP-GalMetaboliteCHEBI:18307 (ChEBI)
UDP-GalNAcMetaboliteCHEBI:16650 (ChEBI)
UDP-GlcAMetaboliteCHEBI:17200 (ChEBI)
UDP-GlcNAcMetaboliteCHEBI:16264 (ChEBI)
UDP-sugarsMetaboliteREACT_23127 (Reactome)
UDP-sugarsMetaboliteREACT_23247 (Reactome)
UDP-xylMetaboliteCHEBI:16082 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UMPMetaboliteCHEBI:16695 (ChEBI)
USTProteinQ9Y2C2 (Uniprot-TrEMBL)
bHEXAComplexREACT_117569 (Reactome)
beta-xylosidaseREACT_124529 (Reactome)
chondroitinProteinREACT_121656 (Reactome)
chondroitinProteinREACT_121869 (Reactome)
chondroitinProteinREACT_122176 (Reactome)
keratan sulfate 1,4-beta-D-galactosidaseREACT_124590 (Reactome)
linker chainMetaboliteCHEBI:63503 (ChEBI)
xylosyl-core proteinsProteinREACT_124300 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ABCC5mim-catalysisREACT_121051 (Reactome)
ADPArrowREACT_6792 (Reactome)
APSArrowREACT_6767 (Reactome)
APSREACT_6792 (Reactome)
ARSB Ca2+mim-catalysisREACT_120889 (Reactome)
ARSB Ca2+mim-catalysisREACT_121276 (Reactome)
ATPREACT_6767 (Reactome)
ATPREACT_6792 (Reactome)
Ac-CoAREACT_121010 (Reactome)
Ac-CoAREACT_121194 (Reactome)
ArrowREACT_120971 (Reactome)
B3GALT6mim-catalysisREACT_121213 (Reactome)
B3GAT dimersmim-catalysisREACT_120897 (Reactome)
B3GNT1,2,3,4,7mim-catalysisREACT_121143 (Reactome)
B4GALT1-6 homodimersmim-catalysisREACT_120770 (Reactome)
B4GALT1-6 homodimersmim-catalysisREACT_120893 (Reactome)
B4GALT1-6 homodimersmim-catalysisREACT_120962 (Reactome)
B4GALT7mim-catalysisREACT_121136 (Reactome)
BGALmim-catalysisREACT_120986 (Reactome)
BGALmim-catalysisREACT_121086 (Reactome)
C4S-PGArrowREACT_121270 (Reactome)
C4S-PGREACT_120940 (Reactome)
C4S/C6S chainsArrowREACT_121272 (Reactome)
C4S/C6S chainsREACT_120889 (Reactome)
C6S-PGArrowREACT_120725 (Reactome)
CH3COO-ArrowREACT_121110 (Reactome)
CHEBI 63868 chainArrowREACT_121062 (Reactome)
CHST14mim-catalysisREACT_120903 (Reactome)
CHST15mim-catalysisREACT_120940 (Reactome)
CHST1mim-catalysisREACT_121317 (Reactome)
CHST2,5,6mim-catalysisREACT_121283 (Reactome)
CHST3,7mim-catalysisREACT_120725 (Reactome)
CHST9,11,12,13mim-catalysisREACT_121270 (Reactome)
CMP-SAREACT_121285 (Reactome)
CMPArrowREACT_121285 (Reactome)
CS GalNAc tranferasesmim-catalysisREACT_121192 (Reactome)
CS GlcA tranferasesmim-catalysisREACT_120993 (Reactome)
CS/DS core proteinsArrowREACT_121041 (Reactome)
CS/DS core proteinsArrowREACT_121272 (Reactome)
CS/HS precursorArrowREACT_120723 (Reactome)
CS/HS precursorREACT_121353 (Reactome)
CSE-PGArrowREACT_120940 (Reactome)
CSGALNACTmim-catalysisREACT_120769 (Reactome)
CSPGsArrowREACT_120855 (Reactome)
CSPGsREACT_120855 (Reactome)
CSPGsREACT_121272 (Reactome)
ChEBI 63516 chainArrowREACT_120781 (Reactome)
ChEBI 63516 chainREACT_121316 (Reactome)
ChEBI 63517 chainArrowREACT_121276 (Reactome)
ChEBI 63517 chainREACT_120781 (Reactome)
ChEBI 63519 chainArrowREACT_121041 (Reactome)
ChEBI 63519 chainREACT_121276 (Reactome)
Chondroitin chainArrowREACT_120889 (Reactome)
Chondroitin chainsREACT_121345 (Reactome)
CoA-SHArrowREACT_121010 (Reactome)
CoA-SHArrowREACT_121194 (Reactome)
D-xyloseArrowREACT_121086 (Reactome)
D2,4,4ArrowREACT_120903 (Reactome)
D2,4,4REACT_121041 (Reactome)
D2,4ArrowREACT_120932 (Reactome)
D2,4REACT_120903 (Reactome)
D4S-PGsREACT_120932 (Reactome)
DSEmim-catalysisREACT_120814 (Reactome)
DSPGsArrowREACT_120855 (Reactome)
DSPGsREACT_120855 (Reactome)
EXT1 EXT2mim-catalysisREACT_120936 (Reactome)
EXT1 EXT2mim-catalysisREACT_121050 (Reactome)
EXT1 EXT2mim-catalysisREACT_121277 (Reactome)
EXT1 EXT2mim-catalysisREACT_121320 (Reactome)
GAG core proteinsREACT_120955 (Reactome)
GALNS oligomermim-catalysisREACT_121094 (Reactome)
GLCEmim-catalysisREACT_120794 (Reactome)
GLCEmim-catalysisREACT_120946 (Reactome)
GUSB tetramermim-catalysisREACT_120758 (Reactome)
GUSB tetramermim-catalysisREACT_121043 (Reactome)
GUSB tetramermim-catalysisREACT_121353 (Reactome)
GXYLTsmim-catalysisREACT_120955 (Reactome)
Gal-Gal-Xyl-proteinsArrowREACT_121213 (Reactome)
Gal-Gal-Xyl-proteinsREACT_120897 (Reactome)
Gal-GlcNAcArrowREACT_120972 (Reactome)
Gal-GlcNAcArrowREACT_121094 (Reactome)
Gal-GlcNAcREACT_120986 (Reactome)
Gal-Xyl-proteinsArrowREACT_121136 (Reactome)
Gal-Xyl-proteinsREACT_121213 (Reactome)
Gal-glycan-proteinArrowREACT_120962 (Reactome)
Gal-glycan-proteinREACT_121143 (Reactome)
GalArrowREACT_120986 (Reactome)
GalArrowREACT_121072 (Reactome)
GalArrowREACT_121086 (Reactome)
GalNAcArrowREACT_120972 (Reactome)
GalNAcArrowREACT_121316 (Reactome)
GalREACT_121094 (Reactome)
GlcA-Gal-Gal-Xyl-CS proteinsREACT_120769 (Reactome)
GlcA-Gal-Gal-Xyl-HS proteinsREACT_121277 (Reactome)
GlcA-Gal-Gal-Xyl-proteinsArrowREACT_120897 (Reactome)
GlcA-b1,3-GlcNAcArrowREACT_121200 (Reactome)
GlcA-b1,3-GlcNAcREACT_120758 (Reactome)
GlcAArrowREACT_120758 (Reactome)
GlcAArrowREACT_121043 (Reactome)
GlcAArrowREACT_121138 (Reactome)
GlcAArrowREACT_121353 (Reactome)
GlcAREACT_121138 (Reactome)
GlcNAc-Gal-GlcNAcArrowREACT_120828 (Reactome)
GlcNAc-Gal-GlcNAcREACT_120972 (Reactome)
GlcNAc-GlcA-GlcNAcArrowREACT_121043 (Reactome)
GlcNAc-GlcA-GlcNAcREACT_121200 (Reactome)
GlcNAcArrowREACT_120723 (Reactome)
GlcNAcArrowREACT_120758 (Reactome)
GlcNAcArrowREACT_120986 (Reactome)
GlcNAcArrowREACT_121018 (Reactome)
GlcNAcArrowREACT_121138 (Reactome)
GlcNAcArrowREACT_121200 (Reactome)
GlcNAcREACT_120828 (Reactome)
GlcNAcREACT_121138 (Reactome)
H+ArrowREACT_19330 (Reactome)
H+REACT_19330 (Reactome)
H2OREACT_120723 (Reactome)
H2OREACT_120758 (Reactome)
H2OREACT_120763 (Reactome)
H2OREACT_120781 (Reactome)
H2OREACT_120828 (Reactome)
H2OREACT_120889 (Reactome)
H2OREACT_120961 (Reactome)
H2OREACT_120972 (Reactome)
H2OREACT_120986 (Reactome)
H2OREACT_121018 (Reactome)
H2OREACT_121041 (Reactome)
H2OREACT_121043 (Reactome)
H2OREACT_121062 (Reactome)
H2OREACT_121072 (Reactome)
H2OREACT_121086 (Reactome)
H2OREACT_121094 (Reactome)
H2OREACT_121110 (Reactome)
H2OREACT_121137 (Reactome)
H2OREACT_121158 (Reactome)
H2OREACT_121160 (Reactome)
H2OREACT_121200 (Reactome)
H2OREACT_121272 (Reactome)
H2OREACT_121274 (Reactome)
H2OREACT_121276 (Reactome)
H2OREACT_121316 (Reactome)
H2OREACT_121335 (Reactome)
H2OREACT_121345 (Reactome)
H2OREACT_121353 (Reactome)
HA

HAR HYAL2

SLC9A1
ArrowREACT_120971 (Reactome)
HA

HAR HYAL2

SLC9A1
mim-catalysisREACT_120971 (Reactome)
HA

HAR

HYAL2
REACT_120879 (Reactome)
HA receptorsREACT_120787 (Reactome)
HAS1,2,3mim-catalysisREACT_121109 (Reactome)
HGSNAT oligomermim-catalysisREACT_121010 (Reactome)
HGSNAT oligomermim-catalysisREACT_121194 (Reactome)
HPSE dimermim-catalysisREACT_121335 (Reactome)
HPSE2mim-catalysisREACT_120961 (Reactome)
HS core proteinsArrowREACT_120961 (Reactome)
HS core proteinsArrowREACT_121335 (Reactome)
HS/HPIN-PGsArrowREACT_120849 (Reactome)
HS/HPIN-PGsREACT_120961 (Reactome)
HS/HPIN-PGsREACT_121335 (Reactome)
HS2ST1mim-catalysisREACT_120904 (Reactome)
HS3ST sulfotransferasesmim-catalysisREACT_120741 (Reactome)
HS3STsmim-catalysisREACT_120839 (Reactome)
HS6STsmim-catalysisREACT_120849 (Reactome)
HSArrowREACT_120741 (Reactome)
HSArrowREACT_120811 (Reactome)
HSArrowREACT_120839 (Reactome)
HSArrowREACT_120904 (Reactome)
HSREACT_120741 (Reactome)
HSREACT_120839 (Reactome)
HSREACT_120849 (Reactome)
HSREACT_120904 (Reactome)
HYAL1mim-catalysisREACT_121183 (Reactome)
HYAL1mim-catalysisREACT_121345 (Reactome)
HYAL2REACT_120787 (Reactome)
Heparan chainArrowREACT_121158 (Reactome)
Heparan chainArrowREACT_121194 (Reactome)
Heparan chainREACT_120723 (Reactome)
Heparan chainREACT_121194 (Reactome)
Heparan sulfate chainArrowREACT_120763 (Reactome)
Heparan sulfate chainArrowREACT_120961 (Reactome)
Heparan sulfate chainArrowREACT_121010 (Reactome)
Heparan sulfate chainArrowREACT_121018 (Reactome)
Heparan sulfate chainArrowREACT_121137 (Reactome)
Heparan sulfate chainArrowREACT_121160 (Reactome)
Heparan sulfate chainArrowREACT_121274 (Reactome)
Heparan sulfate chainArrowREACT_121335 (Reactome)
Heparan sulfate chainREACT_120763 (Reactome)
Heparan sulfate chainREACT_121010 (Reactome)
Heparan sulfate chainREACT_121018 (Reactome)
Heparan sulfate chainREACT_121137 (Reactome)
Heparan sulfate chainREACT_121158 (Reactome)
Heparan sulfate chainREACT_121160 (Reactome)
Heparan sulfate chainREACT_121274 (Reactome)
Heparan-PGsArrowREACT_121277 (Reactome)
Heparan-PGsREACT_121320 (Reactome)
HeparanArrowREACT_120936 (Reactome)
HeparanArrowREACT_121050 (Reactome)
HeparanArrowREACT_121110 (Reactome)
HeparanArrowREACT_121320 (Reactome)
HeparanREACT_120811 (Reactome)
HeparanREACT_120936 (Reactome)
HeparanREACT_121050 (Reactome)
HeparanREACT_121110 (Reactome)
HyaluronanREACT_120787 (Reactome)
IDS dimermim-catalysisREACT_120781 (Reactome)
IDS dimermim-catalysisREACT_121160 (Reactome)
IDUAmim-catalysisREACT_120763 (Reactome)
IDUAmim-catalysisREACT_121062 (Reactome)
IDUAmim-catalysisREACT_121137 (Reactome)
IdoA-GalNAcArrowREACT_121316 (Reactome)
IdoA-GalNAcREACT_121062 (Reactome)
KS core proteinsArrowREACT_121072 (Reactome)
KSPGArrowREACT_121283 (Reactome)
KSPGArrowREACT_121317 (Reactome)
KSPGREACT_121072 (Reactome)
KSPGREACT_121317 (Reactome)
KeratanArrowREACT_120770 (Reactome)
KeratanArrowREACT_120893 (Reactome)
KeratanArrowREACT_121143 (Reactome)
KeratanArrowREACT_121285 (Reactome)
KeratanREACT_120770 (Reactome)
KeratanREACT_120893 (Reactome)
KeratanREACT_121283 (Reactome)
KeratanREACT_121285 (Reactome)
L-AspTBarREACT_121353 (Reactome)
L-Iduronic acidArrowREACT_120763 (Reactome)
L-Iduronic acidArrowREACT_121062 (Reactome)
L-Iduronic acidArrowREACT_121137 (Reactome)
N-glycan-proteinREACT_120962 (Reactome)
NAGLUmim-catalysisREACT_120723 (Reactome)
NAGLUmim-catalysisREACT_121018 (Reactome)
NDSTsmim-catalysisREACT_120811 (Reactome)
NDSTsmim-catalysisREACT_121110 (Reactome)
OxA-GNSmim-catalysisREACT_120828 (Reactome)
PAPArrowREACT_120725 (Reactome)
PAPArrowREACT_120741 (Reactome)
PAPArrowREACT_120811 (Reactome)
PAPArrowREACT_120839 (Reactome)
PAPArrowREACT_120849 (Reactome)
PAPArrowREACT_120903 (Reactome)
PAPArrowREACT_120904 (Reactome)
PAPArrowREACT_120932 (Reactome)
PAPArrowREACT_120940 (Reactome)
PAPArrowREACT_121270 (Reactome)
PAPArrowREACT_121283 (Reactome)
PAPArrowREACT_121317 (Reactome)
PAPSArrowREACT_6792 (Reactome)
PAPSREACT_120725 (Reactome)
PAPSREACT_120741 (Reactome)
PAPSREACT_120811 (Reactome)
PAPSREACT_120839 (Reactome)
PAPSREACT_120849 (Reactome)
PAPSREACT_120903 (Reactome)
PAPSREACT_120904 (Reactome)
PAPSREACT_120932 (Reactome)
PAPSREACT_120940 (Reactome)
PAPSREACT_121270 (Reactome)
PAPSREACT_121283 (Reactome)
PAPSREACT_121317 (Reactome)
PAPSS1,2mim-catalysisREACT_6767 (Reactome)
PAPSS1,2mim-catalysisREACT_6792 (Reactome)
PPiArrowREACT_6767 (Reactome)
REACT_120723 (Reactome) Alpha-N-acetylglucosaminidase (NAGLU) also hydrolyses another non-reducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from an 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause Mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920), also known as Sanfilippo syndrome type B (Beesley et al. 2005).
REACT_120725 (Reactome) Carbohydrate sulfotransferases 3 and 7 (CHST3 and 7) catalyse the transfer of sulfate from PAPS to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin (Tsutsumi et al. 1998, Kitagawa et al. 2000).
REACT_120741 (Reactome) Heparan sulfate 3-O-sulfotransferase1 (HS3ST1) transfers sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS. HS3ST1 is the rate limiting enzyme for synthesis of anticoagulant heparan sulfate. Unlike the other members of the HS3ST family, it is probably located in the Golgi lumen (Shworak et al. 1997).
REACT_120758 (Reactome) The tetrameric lysosomal enzyme beta-glucuronidase hydrolyses glucuronate from the HA disaccharide (Oshima et al. 1987) resulting in the single sugars glucuronic acid and N-acetylglucosamine. These single sugars can exit the lysosome by an unknown mechanism. L-aspartic acid is an inhibitor of enzyme activity (Kreamer et al. 2001).
REACT_120763 (Reactome) An L-iduronic acid residue can be cleaved from either heparan sulfate or dermatan sulfate by the lysosomal enzyme alpha-L-iduronidase (IDUA) (Scott et al. 1991). Defects in IDUA are the cause of mucopolysaccharidosis type IH (MPS IH, Hurler syndrome, MIM:607014), mucopolysaccharidosis IH/S (MPSIH/S, HurlerScheie syndrome, MIM:607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM:607016) (LeeChen et al. 1999).
REACT_120769 (Reactome) Chondroitin sulfate N-acetylgalactosaminyltransferases 1 and 2 (CSGALNACT1 and 2) (Uyama et al. 2002, Gotoh et al. 2002) transfer N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the glucuronate (GlcA) residue of the linker sequence. This first addition to the linker determines this GAG to be chondroitin. Chondroitin is comprised of the repeating disaccharide unit GalNAc-GlcA.
REACT_120770 (Reactome) The family of beta 4-galactosyltransferases (B4GALTs) is composed by at least six known members with different Km and acceptor specifities (Guo et al. 2001) that probably originated by gene duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures, in this case, to elongate a branched chain of keratan. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006).
REACT_120781 (Reactome) Iduronate 2-sulfatase (IDS) hydrolyses 2-sulfate groups from L-iduronate 2-sulfate units of dermatan sulfate in the lysosome. Defects in IDS are the cause of mucopolysaccharidosis type II (MPSII, MIM:309900), also called Hunter syndrome (Wilson et al. 1990).
REACT_120787 (Reactome) HA receptors mediate the uptake of HA into cells. CD44 consists of four functional domains, the extracellular distal domain being the HA-binding region (Culty et al. 1990, Asher & Bignami 1992). The receptor for hyaluronan mediated motility (RHAMM, also called HMMR) can bind HA but not heparin or chondroitin sulfate (Assmann et al. 1998, Wang et al. 1996). Lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1) removes HA from the lymphatic system (Banerji et al. 1999). It is present mainly on lymphatic endothelial cells but also in liver sinusoids. Hyaluronan receptor for endocytosis (HARE, stabilin-2, STAB2) binds to and mediates endocytosis of HA (Harris et al. 2007, Harris et al. 2004). HARE can also bind other glycosaminoglycans such as heparin (Harris et al. 2008).
High molecular weight HA is tethered to the cell surface by HA receptors and the GPI-linked hyaluronidase 2 (HYAL2) to form a HA:HAR:HYAL2 complex in the plasma membrane that localizes to caveolae (invaginations of the plasma membrane composed of cholesterol and gangliosides and rich in caveolin and flotillin).
REACT_120794 (Reactome) As the sulfate content rises, so does the iduronic acid:glucuronic acid ratio. Once glucosamine is sulfated, glucuronic acid (GlcA) is epimerised to iduronic acid (IdoA). The enzyme glucuronyl C5-epimerase (GLCE) mediates this reaction, evidence of function and cellular location coming from mouse studies (Li et al. 2001, Crawford et al. 2001). The distinction between HS and heparin is fairly arbritary but generally, low-sulfated and GlcA-rich polysaccharides are called HS and high-sulfated and IdoA-rich polysaccharides are called heparin. It can be argued that this structure can now be called either heparan sulfate-PG or heparin-PG.
REACT_120811 (Reactome) The bifunctional enzymes heparan sulfate N-deacetylases/N-sulfotransferases 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. 1995, Duncan et al. 2006, Aikawa & Esko 1999, Aikawa et al. 2001). Once GlcNAc is deacetylated to glucosamine, the NDST enzymes can sulfate it on position 2 (N).
REACT_120814 (Reactome) The glucuronate (GlcA) moiety of chondroitin sulfate (CS) can undergo C-5 epimerization to change into an iduronic acid (IdoA) moiety, thus changing the polymer composition and creating dermatan sulfate (DS). Dermatan-sulfate epimerase (DSE) mediates this reaction (Tiedemann et al. 2001).
REACT_120828 (Reactome) N-acetylglucosamine 6-sulfatase (GNS) is a lysosomal enzyme which degrades glycosaminoglycans such as heparan sulfate and keratan sulfate. GNS shows strong sequence similarity to other sulphatases such as the family of arylsulfatases and the conversion to 3-oxo-alanine (formylglycine, FGly) of a cysteine residue is critical for catalytic activity, based on this similarity (Robertson et al. 1992, Robertson et al. 1988). Defects in GNS are the cause of mucopolysaccharidosis type IIID (MPSIIID, MIM:252940), also called Sanfilippo D syndrome (Valstar et al. 2010).
REACT_120839 (Reactome) Heparan sulfate 3-O-sulfotransferases (HS3ST2-6) transfer sulfate to the 3-OH position on glucosamine (GlcN) residues of heparan sulfate (HS) to form 3-O-sulfated HS (Shworak et al. 1999, Xia et al. 2002). HS3ST2-6 do not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.
REACT_120849 (Reactome) Heparan-sulfate 6-O-sulfotransferases 1 and 2 (HS3ST1-2) (Habuchi et al. 1998, Habuchi et al. 2003 respectively) catalyze the transfer of sulfate to C6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate. A third member HS3ST3 that may also mediate this reaction has been characterised in mouse (Habuchi et al. 2000) but remains uncharacterised in humans. It can be argued that this structure can now be called either heparan sulfate- or heparin-PG.
REACT_120855 (Reactome) As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell or autophagy from inside the cell (Winchester 2005).
REACT_120879 (Reactome) Hyaluronidases are only active in acidic environments. HYAL2 can interact with the Na+-H+ exchanger NHE1 which can create an acidic microenvironment in the caveolae. Extracellular Na+ ions are exchanged for protons which creates the acidic conditions required for the activity of HYAL2.
REACT_120889 (Reactome) Arylsulfatase B (ARSB) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate (or 6-sulfate) units (GalNAc 4-sulfate or GalNAc 6-sulfate) within chondroitin sulfate (Gorham & Cantz 1978). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in ARSB are the cause of mucopolysaccharidosis type VI (MPSVI) (MIM:253200, also called Maroteaux-Lamy syndrome (Wicker et al. 1991). ARSB activity is defective in multiple sulfatase deficiency (MSD) (MIM:272200) (Schmidt et al. 1995).
REACT_120893 (Reactome) The family of beta 4-galactosyltransferases (B4GALTs) is composed by at least six known members with different Km and acceptor specifities (Guo et al. 2001) and probably originated by duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures, either to begin, or in this case, to elongate keratan chains. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006).
REACT_120897 (Reactome) B3GAT1 (Kitagawa et al. 1998), 2 (Marcos et al. 2002) and 3 (Ouzzine et al. 2000) transfer a glucuronate residue via a beta1,3-linkage to a terminal galactose. The B3GATs are homodimeric and require manganese as a cofactor (Kakuda et al. 2004, Ouzzine et al. 2000). The tetrasaccharide linker is now complete, ready to accept further hexosamine additions. The type of hexosamine added is critical in determining which glycosaminoglycan (GAG) is formed.
REACT_120903 (Reactome) Important functional domains in dermatan sulfate (DS) are generated by the action of an epimerase (which converts D-glucuronic acid into its epimer L-iduronic acid) together with 4-O-sulfation. These domains are named 4-O-sulfated iduronic acid blocks (Pachebo et al. 2009).
REACT_120904 (Reactome) Human heparan sulfate L-iduronyl 2-O-sulfotransferase 1 (HS2ST1) mediates the transfer of sulfate from PAPS to the C2-position of iduronate (and glucuronate with lesser preference) (Smeds et al. 2010) residues in heparan sulfate chains (Rong et al. 2000).
REACT_120932 (Reactome) Uronyl 2-sulfotransferase (UST) catalyzes the transfer of sulfate from PAPS to position 2 of iduronyl residues in dermatan sulfate (Kobayashi et al. 1999).
REACT_120936 (Reactome) Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. The next addition mediated by these enzymes is that of glucuronate. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001).
REACT_120940 (Reactome) Carbohydrate sulfotransferase 15 (CHST15) catalyses the transfer of sulfate from PAPS to the C-6 hydroxyl group of the GalNAc 4-sulfate residue of chondroitin 4-sulfate (C4S) (Ohtake et al. 2003).
REACT_120946 (Reactome) As the sulfate content rises, so does the iduronic acid:glucuronic acid ratio. Once glucosamine is sulfated, glucuronic acid (GlcA) is epimerised to iduronic acid (IdoA). The enzyme glucuronyl C5-epimerase (GLCE) mediates this reaction, evidence of function and cellular location coming from mouse studies (Li et al. 2001, Crawford et al. 2001). The distinction between HS and heparin is fairly arbritary but generally, low-sulfated and GlcA-rich polysaccharides are called HS and high-sulfated and IdoA-rich polysaccharides are called heparin. It can be argued that this structure can now be called either heparan sulfate-PG or heparin-PG.
REACT_120955 (Reactome) Xylosyltransferase 1 (XYLT1) catalyses the initial step in the tetrasaccharide linkage required for glycosaminoglycan biosynthesis. This reaction can take place in the Golgi apparatus and endoplasmic reticulum (not shown here). XYLT1 mediates the transfer of xylose from the active nucleotide sugar UDP-xylose to specific serine hydroxy groups in the core protein. A C-terminal DxD motif on the enzyme is thought to be critical for activity (Muller et al. 2005, Goetting et al. 2004). Xylosyltransferase 2 (XYLT2) belongs to the XYLT family, displaying 55% amino acid sequence homology to XYLT1, whose activity has yet to be demonstrated (Goetting et al. 2000).
REACT_120961 (Reactome) Heparanase 2 (HPSE2) (McKenzie et al. 2000) is a membrane-bound endoglycosidase that cleaves heparan sulfate (HS) from its HS proteoglycan (HSPG), either in the extracellular matrix or the basement membranes of cells. Defects in HPSE2 are the cause of urofacial syndrome (UFS) (MIM:236730) (Daly et al. 2010, Pang et al. 2010).
REACT_120962 (Reactome) The family of beta 4-galactosyltransferases (B4GALTs) is composed of at least six known members with different Km and acceptor specifities (Guo et al. 2001) that probably originated by gene duplication (Lo et al. 1998). They mediate the transfer of galactose to N-glycan structures which form the beginning of keratan sulfate biosynthesis. B4GALT1 is associated with Congenital Disorder of Glycosylation of type IId (Hansske et al. 2002), and is expressed as two splicing isoforms of which only one is localizated in the Golgi system (Lopez et al. 1991, Schaub et al. 2006).
REACT_120971 (Reactome) In acidic conditions, hyaluronidase 2 (HYAL2), a membrane-anchored protein, hydrolyses high molecular weight HA into approximately 20kDa (50 disaccharide unit) fragments (Lepperdinger et al. 1998, Jedrzejas & Stern 2005).
REACT_120972 (Reactome) Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991).
REACT_120986 (Reactome) Beta-galactosidase (GLB1) can cleave terminal galactose residues from glycosaminoglycans such as keratan sulfate (KS) (Asp et al. 1969). Defects in GLB1 cause the lysosomal storage diseases GM1gangliosidosis (Yoshida et al. 1991) and Morquio syndrome type B (Oshima et al. 1991).
REACT_120993 (Reactome) A glucuronate moiety is added to the chondroitin chain by dual-activity enzymes, the chondroitin sulfate synthases 1-3 (CHSY1, CHPF and CHSY3 respectively) (Kitagawa et al. 2001, Yada et al. 2003, Yada et al. 2003b). They possess both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. These three enzymes require divalent metals as cofactors, manganese producing the highest activities. Another candidate enzyme, chondroitin sulfate glucuronyltransferase (CHPF2) possess only beta-1,3-glucuronic acid transferase activity (Izumikawa et al. 2008, Gotoh et al. 2002). Defects in CHSY1 cause Temtamy preaxial brachydactyly syndrome (TPBS) (MIM:605282) (Tian et al. 2010, Li et al. 2010).
REACT_120998 (Reactome) Once chondroitin sulfate proteoglycans (CSPGs) are formed (can be either C4S-PG, C6S-PG or CSE-PG), they are secreted out into the extracellular matrix (ECM) via the trans-golgi network (Fransson et al. 2000).
REACT_121010 (Reactome) Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) acetylates the non-reducing terminal alpha-glucosamine residue of heparan sulfate. This is a critical reaction for the degradation of heparan sulfate because there is no enzyme that can act on the unacetylated glucosamine molecule. The mechanism by which HGSNAT uses cytosolic acetyl-CoA to transfer the acetyl group to the lysosomal luminal substrate is unknown (Fan et al. 2006). A catalytically inactive 77kDa precursor is transported to the lysosome and is cleaved into a 29kDa N-terminal alpha-chain and a 48kDa C-terminal beta-chain, which are assembled into active 440kDa oligomers in the lysosomal membrane (Durand et al. 2010). Defects in HGSNAT cause mucopolysaccharidosis type IIIC (MPSIIIC, MIM:252930), also called Sanfilippo C syndrome (Fan et al. 2006, Hrebicek et al. 2006).
REACT_121018 (Reactome) Alpha-N-acetylglucosaminidase (NAGLU) hydrolyses the non-reducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from a 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause of mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920) also known as Sanfilippo syndrome type B (Beesley et al. 2005).
REACT_121021 (Reactome) Depending on the nature of the core protein HS-GAGs are attached to, they will either translocate to the cell surface or be secreted into the extracellular matrix (ECM). Here, HS-GAGs are shown to translocate to the cell surface (Kjellen & Lindahl, 1991). The mechanism of transfer from the Golgi apparatus to the cell surface and beyond is unknown but most likely involves the trans-Golgi network.
REACT_121041 (Reactome) Dermatan sulfate (DS) is thought to be hydrolysed from its dermatan sulfate proteoglycan (DSPG) by an unknown human beta-xylosidase. The reaction shown here is based on studies of a rabbit lysosomal enzyme fraction assay (Takagaki et al. 1988). DSPG can have many DS chains attached to it; this example shows the hydrolysis of one DS chain from DSPG.
REACT_121043 (Reactome)
REACT_121050 (Reactome) Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. Heparan is synthesized once GlcNAc is transferred to this sequence. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001).
REACT_121051 (Reactome) As hyaluronan (HA) is synthesised, it is continually extruded from the cell by the ABC transporter C5 (ABCC5), also called multidrug resistance-associated protein 5 (MRP5) (Schulz et al. 2007).
REACT_121062 (Reactome) The lysosomal enzyme alpha-L-iduronidase (IDUA) hydrolyzes the nonreducing terminal iduronide glycosidic bond in heparan sulfate and dermatan sulfate (Scott et al. 1991). Defects in IDUA cause mucopolysaccharidosis type IH (MIM:607014, also called Hurler syndrome), mucopolysaccharidosis type IH/S (MIM:607015, also called HurlerScheie syndrome) and mucopolysaccharidosis type IS (MIM:607016, also called Scheie syndrome) (Scott et al. 1993).
REACT_121072 (Reactome) Keratan sulfate (KS) is cleaved from its KS proteoglycan (KSPG) by an as yet unknown beta-galactosidase. It performs a similar function to beta-galactosidase GLB1 (Asp et al. 1969). A simplified version of KS is used to demonstrate cleavage reactions.
REACT_121086 (Reactome) Beta-galactosidase (GLB1) can cleave terminal galactose residues from the linker chain sequence of glycosaminoglycans (Asp et al. 1969). Defects in GLB1 causes the lysosomal storage diseases GM1 gangliosidosis (Yoshida et al. 1991) and Morquio syndrome B (Oshima et al. 1991).
REACT_121094 (Reactome) N-acetylgalactosamine 6-sulfate sulfatase (GALNS) hydrolyses sulfate from galactose 6-sulfate units of keratan sulfate (KS, shown here) and sulfate from N-acetyl-D-galactosamine 6-sulfate units of chondroitin sulfate (CS, not shown) (Lim & Horwitz 1981, Masue et al. 1991). The conversion to 3-oxoalanine (C-formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in GALNS cause mucopolysaccharidosis type IVA (MPSIVA, MIM:253000), also called Morquio A syndrome, a lysosomal storage disease characterized by intracellular accumulation of KS and CS (Fukuda et al. 1992).
REACT_121109 (Reactome) The integral membrane dual-action glycosyltransferase proteins hyaluronan synthases 1-3 (HAS1-3) (Shyjan et al. 1996, Watanabe & Yamaguchi 1996, Spicer et al. 1997 respectively) mediate the polymerisation of glucuronic acid (GlcA) with N-acetylglucosamine (GlcNAc) to form hyaluronan (HA). The resulting polymer has the arrangement [-4GlcA-1,3GlcNAc-]n and can be as large as 10 miilion Da.
REACT_121110 (Reactome) The bifunctional enzymes heparan sulfate N-deacetylase/N-sulfotransferase 1-4 (NDST1-4) catalyse both the N-deacetylation and the N-sulfation of N-acetylglucosamine (GlcNAc) of heparan (Dixon et al. 1995, Duncan et al. 2006, Aikawa & Esko 1999, Aikawa et al. 2001). The N-deacetylation of a GlcNAc residue to a glucosamine residue is shown here.
REACT_121136 (Reactome) Beta-1,4-galactosyltransferase 7 (B4GALT7) adds galactose to beta-xyloside in a beta-1,4 linkage creating the second addition to the tetrasaccharide linker, the precursor required for glycosaminoglycan synthesis (Almeida et al. 1999). Defects in B4GALT7 cause Ehlers-Danlos syndrome progeroid type (EDSP) (MIM:130070) (Okajima et al. 1999).
REACT_121137 (Reactome) An L-iduronic acid residue can be cleaved from either heparan sulfate or dermatan sulfate by the lysosomal enzyme alpha-L-iduronidase (IDUA) (Scott et al. 1991). Defects in IDUA are the cause of mucopolysaccharidosis type IH (MPS IH, Hurler syndrome, MIM:607014), mucopolysaccharidosis IH/S (MPSIH/S, HurlerScheie syndrome, MIM:607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM:607016) (LeeChen et al. 1999).
REACT_121138 (Reactome) Glucuronate and N-acetylglucosamine exit the lysosome into the cytosol, ready for reuse in GAG biosynthesis. The mechanism of translocation is unknown (for reviews see Stern 2004, Stern 2003).
REACT_121143 (Reactome) The UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase family (B3GNTs) consists of 9 members in humans (Kolbinger et al, 1998; Shiraishi et al, 2001; Togayachi et al, 2001; Iwai et al, 2002; Huang et al, 2004; Ishida et al, 2005; Zheng et al, 2004). Members 1,2,3,4 and 7 can catalyse the addition of N-acetylglucosamine (GlcNAc) to the galactosyl residue of the sachharide chain in a beta-1,3 linkage to form a structure called Keratan-proteoglycan (PG).
REACT_121158 (Reactome) Alpha-N-acetylglucosaminidase (NAGLU) also hydrolyses another nonreducing, terminal N-acetyl-D-glucosamine residue from heparan sulfate. The active form of the enzyme (77kDa) is derived from an 82kDa precursor (Weber et al. 1996). Defects in NAGLU cause Mucopolysaccharidosis type IIIB (MPSIIIB, MIM:252920), also known as Sanfilippo syndrome type B (Beesley et al. 2005).
REACT_121160 (Reactome) Iduronate 2sulfatase (IDS) hydrolyses 2-sulfate groups from Liduronate 2-sulfate units of heparan sulfate. Defects in IDS are the cause of mucopolysaccharidosis type II (MPSII, MIM:309900), also called Hunter syndrome (Wilson et al. 1990).
REACT_121178 (Reactome) Once formed, keratan sulfate proteoglycans (KSPGs) are secreted from the cell into the extracellular matrix (ECM) by an unknown translocation mechanism (Funderburgh 2000). KSPG can bind with many cell surface and extracellular proteins.
REACT_121181 (Reactome) The smallest fragments HYAL2 can generate are 20kDa (approximately 50 disaccharide unit) HA fragments. These fragments are internalized and delivered to lysosomes (Knudson et al. 2002, Erickson & Stern 2012) where another hyalurindase, HYAL1, can degrade them further.
REACT_121183 (Reactome) In the acid environment of the lysosome, hyaluronidase 1 (HYAL1) is able to hydrolyse large 20kDa HA fragments (approximately 50 disaccharide units) to 800 Da fragments (2 disaccharide units).
REACT_121192 (Reactome) An N-acetylgalactosamine (GalNAc) moiety is added to the chondroitin chain by dual-activity enzymes, the chondroitin sulfate synthases 1-3 (CHSY1, CHPF and CHSY3 respectively) (Kitagawa et al. 2001, Yada et al. 2003, Yada et al. 2003b). They possess both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity, the latter activity used in this reaction. These three enzymes require divalent metals as cofactors, manganese producing the highest activities. The repeated disaccharide units of GlcA-GalNAc identify this glycosaminoglycan as chondroitin.
REACT_121194 (Reactome) Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) acetylates another non-reducing terminal alpha-glucosamine residue of heparan sulfate. This is a critical reaction for the degradation of heparan sulfate because there is no enzyme that can act on the unacetylated glucosamine molecule. The mechanism by which HGSNAT uses cytosolic acetyl-CoA to transfer the acetyl group to the lysosomal luminal substrate is unknown (Fan et al. 2006). A catalytically inactive 77kDa precursor is transported to the lysosome and is cleaved into a 29kDa N-terminal alpha-chain and a 48kDa C-terminal beta-chain, which are assembled into active 440kDa oligomers in the lysosomal membrane (Durand et al. 2010). Defects in HGSNAT cause mucopolysaccharidosis type IIIC (MPSIIIC, MIM:252930), also called Sanfilippo C syndrome (Fan et al. 2006, Hrebicek et al. 2006).
REACT_121200 (Reactome) Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991).
REACT_121213 (Reactome) Beta-1,3-galactosyltransferase 6 (B3GALT6) transfers a second galactose to the tetrasaccharide linker. Although it can act on substrates with a terminal beta-linked galactose residue, it prefers galactose-beta-1,4-xylose (Bai et al. 2001). B3GALT6 requires manganese as a cofactor (Zhou et al. 1999).
REACT_121270 (Reactome) Carbohydrate sulfotransferase9, 11, 12 and 13 (CHST9, 11, 12 and 13) catalyse the transfer of sulfate from PAPS to position 4 of the N-acetylgalactosamine (GalNAc) residue of chondroitin (Kang et al. 2001, Okuda et al. 2000, Hiraoka et al. 2000, Kang et al. 2002 respectively).
REACT_121272 (Reactome) Chondroitin sulfate (CS) is hydrolysed from its chondroitin sulfate proteoglycan (CSPG) by an unknown human beta-xylosidase. The reaction shown here is based on studies of a rabbit lysosomal enzyme fraction assay (Takagaki et al. 1988). CSPG can have many CS chains attached to it; this example shows the hydrolysis of one CS chain from CSPG.
REACT_121274 (Reactome) N-sulphoglucosamine sulphohydrolase (SGSH) hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (Scott et al. 1995). Defects in SGSH cause mucopolysaccharidosis type IIIA (MPSIIIA, MIM:252900), also called Sanfilippo syndrome A (Weber et al. 1997).
REACT_121276 (Reactome) Arylsulfatase B (ARSB) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate units within dermatan sulfate (DS; Gorham & Cantz 1978). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue in eukaryotes, is critical for catalytic activity, based on similarity to the prototypical arylsulfatase ARSA (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in ARSB are the cause of mucopolysaccharidosis type VI (MPSVI) (MIM:253200, also called Maroteaux-Lamy syndrome (Wicker et al. 1991). ARSB activity is defective in multiple sulfatase deficiency (MSD) (MIM:272200) (Schmidt et al. 1995).
REACT_121277 (Reactome) Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. Heparan is synthesized once GlcNAc is transferred to this sequence. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001).
REACT_121283 (Reactome) Carbohydrate sulfotransferases 2, 5 and 6 (CHST2, 5 and 6) catalyse the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues within keratan-like molecules (Sakaguchi et al. 2000, Lee et al. 1999, Akama et al. 2002).
REACT_121285 (Reactome) The human genes ST3GAL1-4 and 6 encode for sialyltransferase1-4 and 6 respectively (Shang et al. 1999, Kim et al. 1996, Kitagawa and Paulson, 1993, Basu et al. 1993, Okajima et al. 1999). They add a sialyl residue to the growing keratan chain, blocking any further chain elongation.
REACT_121303 (Reactome) As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell or autophagy from inside the cell (Winchester 2005).
REACT_121316 (Reactome) Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine (GalNAc) from glucosaminoglycans (GAGs) and any other molecules containing a terminal GalNAc. There are two forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 gangliosides in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991).
REACT_121317 (Reactome) Carbohydrate sulfotransferase 1 (CHST1, keratan sulfate Gal-6 sulfotransferase) mediates the sulfation of galactose (Gal) on position 6 in keratan sulfate proteoglycans (KSPGs) (Fukuta et al. 1997).
REACT_121320 (Reactome) Exostosin1 and 2 (EXT1 and 2) are dual-specificity enzymes which catalyse the addition of N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to the GAG-protein linker sequence. The next addition mediated by these enzymes is that of glucuronate. EXT1 and 2 form a heterodimer which translocates to the Golgi apparatus from the ER membrane (McCormick et al. 2000). Defects in EXT1 or 2 cause the hereditary bone disorders multiple exostoses type 1 (MIM:133700) and 2 (MIM:133701) (Wuyts et al. 1998, Bernard et al. 2001).
REACT_121335 (Reactome) Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate (HS) from its HS proteoglycan (HSPG) (Toyoshima & Nakajima 1999). The formation of a heterodimer of 8kDa and 50kDa subunits cleaved from the 65kDa form is required for enzyme activity (Levy-Adam et al. 2003) and this proteolytic cleavage occurs in the lysosome (Goldshmidt et al. 2002). Acidic conditions within the lysosome optimises HPSE activity.
REACT_121341 (Reactome) Various forms of dermatan sulfate are excreted from the cell once formed. The mechanism of transport is unknown but most likely involves the trans-golgi network (Silbert & Sugumaran 2002).
REACT_121345 (Reactome) Hyaluronidase 1 (HYAL1) hydrolyses 1-4 linkages between GalNAc and D-glucuronate residues in chondroitin (or dermatan). It also hydrolyses this linkage in hyaluronate, another glycosaminoglycan (GAG) composed of repeating disaccharide units but the only one which is non-sulfated (Frost et al. 1997). There are five human hyaluronidases (HYALs, endo-beta-acetyl-hexosaminidases), HYAL1-4, and PH-20 (Jedrzejas & Stern 2005).
REACT_121353 (Reactome) The tetrameric lysosomal enzyme beta-glucuronidase hydrolyses glucuronate from heparan or the linker chain (Oshima et al. 1987). L-aspartic acid is an inhibitor of enzyme activity (Kreamer et al. 2001).
REACT_121392 (Reactome) As part of the natural turnover of GAGs, extracellular KSPGs translocate to the lysosome to be degraded. The translocation process is unsure but could be either endocytosis from outside the cell and/or autophagy from inside the cell (Winchester 2005).
REACT_19330 (Reactome) The SLC26A1 and 2 genes encode proteins that facilitate sulfate uptake into cells. The mechanism by which these transporters work is unclear but may be enhanced by extracellular halides or acidic pH environments, cotransporting protons electroneutrally. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) (Regeer et al. 2003) which can transport sulfate and oxalate across the basolateral membrane of epithelial cells. It is most abundantly expressed in the liver and kidney, with lower levels expressed in many other parts of the body. SLC26A2 is ubiquitously expressed and encodes a sulfate transporter (Diastrophic dysplasia protein, DTD, DTDST) (Hastbacka et al. 1994). This transporter provides sulfate for proteoglycan sulfation which is needed for cartilage development. Defects in SLC26A2 are implicated in the pathogenesis of several human chondrodysplasias.
REACT_22255 (Reactome) The human gene SLC35B2 encodes the adenosine 3'-phospho 5'-phosphosulfate transporter 1 (PAPST1) (Ozeran et al. 1996, Kamiyama et al. 2003). In human tissues, PAPST1 is highly expressed in the placenta and pancreas and present at lower levels in the colon and heart. The human gene SLC35B3 encodes a human PAPS transporter gene that is closely related to PAPST1. Called PAPST2, it is predominantly expressed in the colon (Kamiyama et al. 2006).
REACT_22287 (Reactome) The human gene SLC35D2 encodes the UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose transporter (UGTREL8; homolog of Fringe connection protein 1, HFRC1). It resides on the Golgi membrane where it mediates the transport of nucleotide sugars such as UDP-GlcNAc and UDP-glucose into the Golgi lumen in exchange for UMP (Suda et al. 2004, Ishida et al. 2005).
REACT_6767 (Reactome) In the first step of PAPS biosynthesis, ATP and sulfate react to form adenylyl sulfate (APS) and pyrophosphate (PPi), catalysed by the bifunctional enzymes PAPS synthases 1 and 2 (PAPSS1 and 2). PAPSS2 is essential for the sulfation of proteoglycans, a necessary post-translational modification. Defective PAPSS2 results in undersulfation of proteoglycans which causes spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA; MIM:612847), a bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Mutations resulting in SEMD-PA include S438*, T48R and R329* (Ahmad et al. 1998, ul Haque et al. 1998, Noordam et al. 2009).
REACT_6792 (Reactome) In the second step of PAPS biosynthesis, adenylyl sulfate (APS) is phosphorylated to 3'-phosphoadenylyl sulfate (PAPS), catalysed by the bifunctional enzymes PAPS synthases 1 and 2 (PAPSS1 and 2). PAPSS2 is essential for the sulfation of proteoglycans, a necessary post-translational modification. Defective PAPSS2 results in undersulfation of proteoglycans which causes spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA; MIM:612847), a bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Mutations resulting in SEMD-PA include S438*, T48R and R329* (Ahmad et al. 1998, ul Haque et al. 1998, Noordam et al. 2009).

SGSHmim-catalysisREACT_121158 (Reactome)
SGSHmim-catalysisREACT_121274 (Reactome)
SLC26A1,2mim-catalysisREACT_19330 (Reactome)
SLC35B2,3mim-catalysisREACT_22255 (Reactome)
SLC35D2mim-catalysisREACT_22287 (Reactome)
SLC9A1REACT_120879 (Reactome)
SO4ArrowREACT_120781 (Reactome)
SO4ArrowREACT_120828 (Reactome)
SO4ArrowREACT_120889 (Reactome)
SO4ArrowREACT_121094 (Reactome)
SO4ArrowREACT_121158 (Reactome)
SO4ArrowREACT_121160 (Reactome)
SO4ArrowREACT_121274 (Reactome)
SO4ArrowREACT_121276 (Reactome)
SO4ArrowREACT_19330 (Reactome)
SO4REACT_19330 (Reactome)
SO4REACT_6767 (Reactome)
ST3GAL1-4,6mim-catalysisREACT_121285 (Reactome)
UDP-GalNAcREACT_120769 (Reactome)
UDP-GalNAcREACT_121192 (Reactome)
UDP-GalREACT_120770 (Reactome)
UDP-GalREACT_120893 (Reactome)
UDP-GalREACT_120962 (Reactome)
UDP-GalREACT_121136 (Reactome)
UDP-GalREACT_121213 (Reactome)
UDP-GlcAREACT_120897 (Reactome)
UDP-GlcAREACT_120936 (Reactome)
UDP-GlcAREACT_120993 (Reactome)
UDP-GlcAREACT_121320 (Reactome)
UDP-GlcNAcREACT_121050 (Reactome)
UDP-GlcNAcREACT_121143 (Reactome)
UDP-GlcNAcREACT_121277 (Reactome)
UDP-sugarsArrowREACT_22287 (Reactome)
UDP-sugarsREACT_22287 (Reactome)
UDP-xylREACT_120955 (Reactome)
UDPArrowREACT_120769 (Reactome)
UDPArrowREACT_120770 (Reactome)
UDPArrowREACT_120893 (Reactome)
UDPArrowREACT_120897 (Reactome)
UDPArrowREACT_120936 (Reactome)
UDPArrowREACT_120955 (Reactome)
UDPArrowREACT_120962 (Reactome)
UDPArrowREACT_120993 (Reactome)
UDPArrowREACT_121050 (Reactome)
UDPArrowREACT_121136 (Reactome)
UDPArrowREACT_121143 (Reactome)
UDPArrowREACT_121192 (Reactome)
UDPArrowREACT_121213 (Reactome)
UDPArrowREACT_121277 (Reactome)
UDPArrowREACT_121320 (Reactome)
UMPArrowREACT_22287 (Reactome)
UMPREACT_22287 (Reactome)
USTmim-catalysisREACT_120932 (Reactome)
bHEXAmim-catalysisREACT_120972 (Reactome)
bHEXAmim-catalysisREACT_121200 (Reactome)
bHEXAmim-catalysisREACT_121316 (Reactome)
beta-xylosidasemim-catalysisREACT_121041 (Reactome)
beta-xylosidasemim-catalysisREACT_121272 (Reactome)
chondroitinArrowREACT_120769 (Reactome)
chondroitinArrowREACT_120993 (Reactome)
chondroitinArrowREACT_121192 (Reactome)
chondroitinREACT_120725 (Reactome)
chondroitinREACT_120993 (Reactome)
chondroitinREACT_121192 (Reactome)
chondroitinREACT_121270 (Reactome)
keratan sulfate 1,4-beta-D-galactosidasemim-catalysisREACT_121072 (Reactome)
linker chainArrowREACT_121353 (Reactome)
linker chainREACT_121086 (Reactome)
xylosyl-core proteinsArrowREACT_120955 (Reactome)
xylosyl-core proteinsREACT_121136 (Reactome)
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