Note: a dashed line (without arrowheads) between two compound names is meant to imply that the two names are just different instantiations of the same compound -- i.e. one may be a specific name and the other a general name, or they may both represent the same compound in different stages of a polymerization-type pathway. This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Carbohydrates Biosynthesis → Polysaccharides Biosynthesis → Glycosaminoglycans Biosynthesis|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
Chondroitin sulfate is a sulfated glycosaminoglycan composed of alternating units of sulfated N-acetyl-β-D-galactosamine and β-D-glucuronate residues. The N-acetyl-β-D-galactosamine residues are substituted to varying degrees with sulfate linked to 4- and/or 6-hydroxyl positions, forming N-acetyl-β-D-galactosamine 4-sulfate, N-acetyl-β-D-galactosamine 6-O-sulfate or N-acetyl-D-galactosamine 4,6-bissulfate, and to a lesser extent the uronic acid residues may be substituted with sulfate at the 2-hydroxyl position forming 2-O-sulfo-β-D-glucuronate. The uronic acid residues may also be substituted with sulfate at the 3-hydroxyl positions, although this substitution is quite rare.
The following names have been used to define different sulfation states:
The term "chondroitin sulfate B" has been used in the past to refer to dermatan sulfate, but is not used any more.
The chondroitin chains vary in size up to a hundred or more disaccharide repeating units. They are usually found attached to assorted core proteins as part of a proteoglycan complex. Chondroitin sulfate is a major component of connective tissue matrix (such as skin and cartilage), but is also found on cell surface and basement membranes and in intracellular granules of certain cells. Functions in matrix locations are mainly structural, while functions in membranes are mainly as receptors.
Chondroitin sulfate chains are synthesized in situ on the protein chain. They are attached to the core protein via a specific tetrasaccharide known as the "glycoaminoglycan-protein linkage region", which is formed by sequential stepwise additions of the sugar residues to specific core proteins. The synthesis of the linkage region is described in glycoaminoglycan-protein linkage region biosynthesis, and the polymerization of the chondroitin chain is described in chondroitin and dermatan biosynthesis.
About This Pathway
This pathway describes the later modifications of the chondroitin chain. These modifications include the sulfation of the β-D-glucuronate and N-acetyl-β-D-galactosamine residues at different positions by a number of sulfotransferases with strict specificities.
The sulfation of N-acetyl-β-D-galactosamine at the 4-hydroxyl position is catalyzed by three enzymes encoded by the CHST11, CHST12 and CHST13 genes [Yamauchi00, Hiraoka00, Kang02]. The sulfation of N-acetyl-β-D-galactosamine at the 6-hydroxyl position is catalyzed by enzymes encoded by the CHST3 and CHST7 genes [Tsutsumi98, Fukuta98, Kitagawa00, Bhakta00]. Another enzyme, encoded by CHST15, catalyzes the sulfation at the C6 position of residues already sulfated at the C4 position [Ohtake01].
Superpathways: chondroitin sulfate biosynthesis
Bhakta00: Bhakta S, Bartes A, Bowman KG, Kao WM, Polsky I, Lee JK, Cook BN, Bruehl RE, Rosen SD, Bertozzi CR, Hemmerich S (2000). "Sulfation of N-acetylglucosamine by chondroitin 6-sulfotransferase 2 (GST-5)." J Biol Chem 275(51);40226-34. PMID: 10956661
Hiraoka00: Hiraoka N, Nakagawa H, Ong E, Akama TO, Fukuda MN, Fukuda M (2000). "Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family." J Biol Chem 275(26);20188-96. PMID: 10781601
Kang02: Kang HG, Evers MR, Xia G, Baenziger JU, Schachner M (2002). "Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases." J Biol Chem 277(38);34766-72. PMID: 12080076
Kobayashi99: Kobayashi M, Sugumaran G, Liu J, Shworak NW, Silbert JE, Rosenberg RD (1999). "Molecular cloning and characterization of a human uronyl 2-sulfotransferase that sulfates iduronyl and glucuronyl residues in dermatan/chondroitin sulfate." J Biol Chem 274(15);10474-80. PMID: 10187838
Ohtake01: Ohtake S, Ito Y, Fukuta M, Habuchi O (2001). "Human N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase cDNA is related to human B cell recombination activating gene-associated gene." J Biol Chem 276(47);43894-900. PMID: 11572857
Yamauchi00: Yamauchi S, Mita S, Matsubara T, Fukuta M, Habuchi H, Kimata K, Habuchi O (2000). "Molecular cloning and expression of chondroitin 4-sulfotransferase." J Biol Chem 275(12);8975-81. PMID: 10722746
Gotoh02: Gotoh M, Sato T, Akashima T, Iwasaki H, Kameyama A, Mochizuki H, Yada T, Inaba N, Zhang Y, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Nishihara S, Watanabe H, Kimata K, Narimatsu H (2002). "Enzymatic synthesis of chondroitin with a novel chondroitin sulfate N-acetylgalactosaminyltransferase that transfers N-acetylgalactosamine to glucuronic acid in initiation and elongation of chondroitin sulfate synthesis." J Biol Chem 277(41);38189-96. PMID: 12163485
Hermanns08: Hermanns P, Unger S, Rossi A, Perez-Aytes A, Cortina H, Bonafe L, Boccone L, Setzu V, Dutoit M, Sangiorgi L, Pecora F, Reicherter K, Nishimura G, Spranger J, Zabel B, Superti-Furga A (2008). "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis." Am J Hum Genet 82(6);1368-74. PMID: 18513679
Izumikawa07: Izumikawa T, Uyama T, Okuura Y, Sugahara K, Kitagawa H (2007). "Involvement of chondroitin sulfate synthase-3 (chondroitin synthase-2) in chondroitin polymerization through its interaction with chondroitin synthase-1 or chondroitin-polymerizing factor." Biochem J 403(3);545-52. PMID: 17253960
Izumikawa08: Izumikawa T, Koike T, Shiozawa S, Sugahara K, Tamura J, Kitagawa H (2008). "Identification of chondroitin sulfate glucuronyltransferase as chondroitin synthase-3 involved in chondroitin polymerization: chondroitin polymerization is achieved by multiple enzyme complexes consisting of chondroitin synthase family members." J Biol Chem 283(17);11396-406. PMID: 18316376
Kitagawa03: Kitagawa H, Izumikawa T, Uyama T, Sugahara K (2003). "Molecular cloning of a chondroitin polymerizing factor that cooperates with chondroitin synthase for chondroitin polymerization." J Biol Chem 278(26);23666-71. PMID: 12716890
Mikami03: Mikami T, Mizumoto S, Kago N, Kitagawa H, Sugahara K (2003). "Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor: implication of differential roles in dermatan sulfate biosynthesis." J Biol Chem 278(38);36115-27. PMID: 12847091
Okuda00: Okuda T, Mita S, Yamauchi S, Matsubara T, Yagi F, Yamamori D, Fukuta M, Kuroiwa A, Matsuda Y, Habuchi O (2000). "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." J Biochem 128(5);763-70. PMID: 11056388
Sato03: Sato T, Gotoh M, Kiyohara K, Akashima T, Iwasaki H, Kameyama A, Mochizuki H, Yada T, Inaba N, Togayachi A, Kudo T, Asada M, Watanabe H, Imamura T, Kimata K, Narimatsu H (2003). "Differential roles of two N-acetylgalactosaminyltransferases, CSGalNAcT-1, and a novel enzyme, CSGalNAcT-2. Initiation and elongation in synthesis of chondroitin sulfate." J Biol Chem 278(5);3063-71. PMID: 12446672
Thiele04: Thiele H, Sakano M, Kitagawa H, Sugahara K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S (2004). "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement." Proc Natl Acad Sci U S A 101(27);10155-60. PMID: 15215498
Uchimura00: Uchimura K, Fasakhany F, Kadomatsu K, Matsukawa T, Yamakawa T, Kurosawa N, Muramatsu T (2000). "Diversity of N-acetylglucosamine-6-O-sulfotransferases: molecular cloning of a novel enzyme with different distribution and specificities." Biochem Biophys Res Commun 274(2);291-6. PMID: 10913333
Uyama02: Uyama T, Kitagawa H, Tamura Ji J, Sugahara K (2002). "Molecular cloning and expression of human chondroitin N-acetylgalactosaminyltransferase: the key enzyme for chain initiation and elongation of chondroitin/dermatan sulfate on the protein linkage region tetrasaccharide shared by heparin/heparan sulfate." J Biol Chem 277(11);8841-6. PMID: 11788602
Uyama03: Uyama T, Kitagawa H, Tanaka J, Tamura J, Ogawa T, Sugahara K (2003). "Molecular cloning and expression of a second chondroitin N-acetylgalactosaminyltransferase involved in the initiation and elongation of chondroitin/dermatan sulfate." J Biol Chem 278(5);3072-8. PMID: 12433924
Verkoczy98: Verkoczy LK, Marsden PA, Berinstein NL (1998). "hBRAG, a novel B cell lineage cDNA encoding a type II transmembrane glycoprotein potentially involved in the regulation of recombination activating gene 1 (RAG1)." Eur J Immunol 28(9);2839-53. PMID: 9754571
Yada03: Yada T, Gotoh M, Sato T, Shionyu M, Go M, Kaseyama H, Iwasaki H, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Watanabe H, Narimatsu H, Kimata K (2003). "Chondroitin sulfate synthase-2. Molecular cloning and characterization of a novel human glycosyltransferase homologous to chondroitin sulfate glucuronyltransferase, which has dual enzymatic activities." J Biol Chem 278(32);30235-47. PMID: 12761225
Yada03a: Yada T, Sato T, Kaseyama H, Gotoh M, Iwasaki H, Kikuchi N, Kwon YD, Togayachi A, Kudo T, Watanabe H, Narimatsu H, Kimata K (2003). "Chondroitin sulfate synthase-3. Molecular cloning and characterization." J Biol Chem 278(41);39711-25. PMID: 12907687
Yamauchi99: Yamauchi S, Hirahara Y, Usui H, Takeda Y, Hoshino M, Fukuta M, Kimura JH, Habuchi O (1999). "Purification and characterization of chondroitin 4-sulfotransferase from the culture medium of a rat chondrosarcoma cell line." J Biol Chem 274(4);2456-63. PMID: 9891016
Yuki00: Yuki M, Yoshinaga K, Yamakawa H, Sakurada K, Sato S, Yajima A, Horii A (2000). "Structure, expression and mutational analysis of the hBRAG gene on 10q in the frequently deleted region in human endometrial cancer." Oncol Rep 7(6);1339-42. PMID: 11032940
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