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MetaCyc Pathway: chondroitin sulfate biosynthesis

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
Superpathways

Some taxa known to possess this pathway include ? : Homo sapiens

Expected Taxonomic Range: Metazoa

Summary:
General Background

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:

Chondroitin sulfate A contains β-D-glucuronate and N-acetyl-β-D-galactosamine 4-sulfate

Chondroitin sulfate C contains β-D-glucuronate and N-acetyl-β-D-galactosamine 6-O-sulfate

Chondroitin sulfate D contains 2-O-sulfo-β-D-glucuronate and N-acetyl-β-D-galactosamine 6-O-sulfate

Chondroitin sulfate E contains β-D-glucuronate and N-acetyl-D-galactosamine 4,6-bissulfate

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, Kitagawa00, Bhakta00]. Another enzyme, encoded by CHST15, catalyzes the sulfation at the C6 position of residues already sulfated at the C4 position [Ohtake01].

The C2 position of β-D-glucuronate residues is also often sulfated in a reaction catalyzed by uronyl 2-sulfotransferase, encoded by the UST gene [Kobayashi99].

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.

Subpathways: glycoaminoglycan-protein linkage region biosynthesis , chondroitin and dermatan biosynthesis , chondroitin sulfate biosynthesis (late stages)

Credits:
Created 06-Aug-2010 by Caspi R , SRI International


References

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

Casu89: Casu, B. (1989). "in Heparin: Chemical and Biological Properties, Clinical Applications." Lane, D. A., and Lindahl, U., Eds, pp 25-49, CRC Press, Boca Raton, FL.

Fukuta98: Fukuta M, Kobayashi Y, Uchimura K, Kimata K, Habuchi O (1998). "Molecular cloning and expression of human chondroitin 6-sulfotransferase." Biochim Biophys Acta 1399(1);57-61. PMID: 9714738

Gatti79: Gatti, G., Casu, B., Hamer, G. K., Pelin, A. S. (1979). Macromolecules 12:1001-1007.

Gotoh02: Gotoh M, Yada T, Sato T, Akashima T, Iwasaki H, Mochizuki H, Inaba N, Togayachi A, Kudo T, Watanabe H, Kimata K, Narimatsu H (2002). "Molecular cloning and characterization of a novel chondroitin sulfate glucuronyltransferase that transfers glucuronic acid to N-acetylgalactosamine." J Biol Chem 277(41);38179-88. PMID: 12145278

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

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

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

Kitagawa00: Kitagawa H, Fujita M, Ito N, Sugahara K (2000). "Molecular cloning and expression of a novel chondroitin 6-O-sulfotransferase." J Biol Chem 275(28);21075-80. PMID: 10781596

Kitagawa01: Kitagawa H, Uyama T, Sugahara K (2001). "Molecular cloning and expression of a human chondroitin synthase." J Biol Chem 276(42);38721-6. PMID: 11514575

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

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

Murphy04: Murphy KJ, Merry CL, Lyon M, Thompson JE, Roberts IS, Gallagher JT (2004). "A new model for the domain structure of heparan sulfate based on the novel specificity of K5 lyase." J Biol Chem 279(26);27239-45. PMID: 15047699

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

Rosenberg97: Rosenberg RD, Shworak NW, Liu J, Schwartz JJ, Zhang L (1997). "Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated?." J Clin Invest 99(9);2062-70. PMID: 9151776

Silbert02: Silbert JE, Sugumaran G (2002). "Biosynthesis of chondroitin/dermatan sulfate." IUBMB Life 54(4);177-86. PMID: 12512856

Trowbridge02: Trowbridge JM, Gallo RL (2002). "Dermatan sulfate: new functions from an old glycosaminoglycan." Glycobiology 12(9);117R-25R. PMID: 12213784

Tsutsumi98: Tsutsumi K, Shimakawa H, Kitagawa H, Sugahara K (1998). "Functional expression and genomic structure of human chondroitin 6-sulfotransferase." FEBS Lett 441(2);235-41. PMID: 9883891

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

Yada03: 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

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Almeida99: Almeida R, Levery SB, Mandel U, Kresse H, Schwientek T, Bennett EP, Clausen H (1999). "Cloning and expression of a proteoglycan UDP-galactose:beta-xylose beta1,4-galactosyltransferase I. A seventh member of the human beta4-galactosyltransferase gene family." J Biol Chem 274(37);26165-71. PMID: 10473568

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

Andersson96: Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (1996). "A "double adaptor" method for improved shotgun library construction." Anal Biochem 236(1);107-13. PMID: 8619474

Bai01: Bai X, Zhou D, Brown JR, Crawford BE, Hennet T, Esko JD (2001). "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)." J Biol Chem 276(51);48189-95. PMID: 11551958

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

Condac09: Condac E, Dale GL, Bender-Neal D, Ferencz B, Towner R, Hinsdale ME (2009). "Xylosyltransferase II is a significant contributor of circulating xylosyltransferase levels and platelets constitute an important source of xylosyltransferase in serum." Glycobiology 19(8);829-33. PMID: 19389916

Cuellar07: Cuellar K, Chuong H, Hubbell SM, Hinsdale ME (2007). "Biosynthesis of chondroitin and heparan sulfate in chinese hamster ovary cells depends on xylosyltransferase II." J Biol Chem 282(8);5195-200. PMID: 17189266

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

Gotting00: Gotting C, Kuhn J, Zahn R, Brinkmann T, Kleesiek K (2000). "Molecular cloning and expression of human UDP-d-Xylose:proteoglycan core protein beta-d-xylosyltransferase and its first isoform XT-II." J Mol Biol 304(4);517-28. PMID: 11099377

Gotting04: Gotting C, Muller S, Schottler M, Schon S, Prante C, Brinkmann T, Kuhn J, Kleesiek K (2004). "Analysis of the DXD motifs in human xylosyltransferase I required for enzyme activity." J Biol Chem 279(41);42566-73. PMID: 15294915

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

Kakuda04: Kakuda S, Oka S, Kawasaki T (2004). "Purification and characterization of two recombinant human glucuronyltransferases involved in the biosynthesis of HNK-1 carbohydrate in Escherichia coli." Protein Expr Purif 35(1);111-9. PMID: 15039073

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

Kuroiwa00: Kuroiwa A, Matsuda Y, Okajima T, Furukawa K (2000). "Assignment of human xylosylprotein beta-1,4-galactosyltransferase gene (B4GALT7) to human chromosome 5q35.2-->q35.3 by in situ hybridization." Cytogenet Cell Genet 89(1-2);8-9. PMID: 10894925

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Marcos02: Marcos I, Galan JJ, Borrego S, Antinolo G (2002). "Cloning, characterization, and chromosome mapping of the human GlcAT-S gene." J Hum Genet 47(12);677-80. PMID: 12522689

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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