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. 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-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.
About This Pathway
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.
The linkage region may be extended into mutiple kinds of glycosaminoglycans. However, the addition of an N-acetyl-β-D-galactosamine residue prevents the formation of heparin or heparan sulfate and commits the molecule to become chondroitin or dermatan. This reaction is catalyzed by the enzyme chondroitin sulfate N-acetylgalactosaminyltransferase. Humans have two isoforms of this enzyme, encoded by the CSGALNACT1 and CSGALNACT2 genes [Uyama02, Kitagawa03, Uyama03].
Once the linkage region has been formed and committed, the polymerzation of the chondroitin/dermatan chain proceeds by the alternate addition of β-D-glucuronate and N-acetyl-α-D-galactosamine from activated precursors to the non-reducing end of the elongating chain. The addition of both residues is catalyzed by the bifunctional chondroitin sulfate synthases. Humans possess three isoforms of this bifunctional enzyme (CHSY1, CHPF and CHSY3), plus an additional enzyme that can catalyze only the addition of β-D-glucuronate (CHPF2) [Kitagawa01, Yada03, Gotoh02]. It has been suggested that chondroitin polymerization is achieved by multiple combinations of the different enzymes and that each combination may play a unique role in the biosynthesis of chondroitin or dermatan sulfate [Izumikawa07, Izumikawa08].
Further control over the exact nature of the chondroitin sulfate is determined by the modifications performed during the later part of the pathway. 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 modifications are performed by several types and isoforms of enzymes, and the exact combination depends on the environment and type of the cell that produces the molecule.
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, Kitagawa00a, Bhakta00]. Another enzyme, encoded by CHST15, catalyzes the sulfation at the C6 position of residues already sulfated at the C4 position [Ohtake01].
The very first reaction in this pathway, the addition of a xylose molecule to a serine residue of the core protein, is performed at the endoplasmic reticulum. The rest of the pathway occurs at the Golgi apparatus.
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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
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Amado99: Amado M, Almeida R, Schwientek T, Clausen H (1999). "Identification and characterization of large galactosyltransferase gene families: galactosyltransferases for all functions." Biochim Biophys Acta 1473(1);35-53. PMID: 10580128
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Cebo02: Cebo C, Durier V, Lagant P, Maes E, Florea D, Lefebvre T, Strecker G, Vergoten G, Zanetta JP (2002). "Function and molecular modeling of the interaction between human interleukin 6 and its HNK-1 oligosaccharide ligands." J Biol Chem 277(14);12246-52. PMID: 11788581
Condac07: Condac E, Silasi-Mansat R, Kosanke S, Schoeb T, Towner R, Lupu F, Cummings RD, Hinsdale ME (2007). "Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis." Proc Natl Acad Sci U S A 104(22);9416-21. PMID: 17517600
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Gotoh02a: 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
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Kakuda05: Kakuda S, Sato Y, Tonoyama Y, Oka S, Kawasaki T (2005). "Different acceptor specificities of two glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate." Glycobiology 15(2);203-10. PMID: 15470230
Kitagawa01a: Kitagawa H, Taoka M, Tone Y, Sugahara K (2001). "Human glycosaminoglycan glucuronyltransferase I gene and a related processed pseudogene: genomic structure, chromosomal mapping and characterization." Biochem J 358(Pt 3);539-46. PMID: 11535117
Kitagawa98: Kitagawa H, Tone Y, Tamura J, Neumann KW, Ogawa T, Oka S, Kawasaki T, Sugahara K (1998). "Molecular cloning and expression of glucuronyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans." J Biol Chem 273(12);6615-8. PMID: 9506957
Kuhn01: Kuhn J, Gotting C, Schnolzer M, Kempf T, Brinkmann T, Kleesiek K (2001). "First isolation of human UDP-D-xylose: proteoglycan core protein beta-D-xylosyltransferase secreted from cultured JAR choriocarcinoma cells." J Biol Chem 276(7);4940-7. PMID: 11087729
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