Proteoglycan biosynthesis (WP4784)

Homo sapiens

Proteoglycan (PG) synthesis is a complex mechanism that can be divided in four main steps. Core protein synthesis occurs in the rough endoplasmic reticulum (RER). Once PG core protein has been synthesized, it moves from the RER to the Golgi apparatus where the first sugar of glycosaminoalycan (GAG) chain is added on Ser residues. GAG synthesis continues by glycosyltransferases that transfer sugar moieties from UDP-sugars to GAG chains. UDP-sugars are synthesized in the cytoplasm and are translocated in the Golgi apparatus by an antiporter with UMP. Then UDP, the by-product of glycosyltransferase reactions, is hydrolyzed to UMP and phosphate by calcium activated nucleotidase 1 (CANT1). Chondroitin, dermatan and heparan sulfate synthesis starts on a Ser residue of the PG core protein with the formation of a tetrasaccharide linkage region composed of a xylose (Xyl), two galactoses (Gal) and a glucuronic acid (GlcUA). After tetrasaccharide synthesis, GAG chain elongation continues through the binding of specific saccharides defining chondroitin sulfate, dermatan sulfate and heparan sulfate. Specific enzymes are involved in this process and mutations in their gene cause different types of skeletal dysplasia (indicated in red boxes). The third step is GAG sulfation. Sulfate enters in cells through the SLC26A2 transporter and it is activated to 30-phosphoadenosine 50-phosphosulfate (PAPS) by PAPS synthase (PAPSS) in the cytosol. Through a PAPS transporter (PAPST), PAPS moves to Golgi apparatus where it is used as sulfate donor by sulfotransferases to sulfate GAGs. This reaction also produces phosphoadenosine phosphate (PAP), that is hydrolyzed into AMP and phosphate by a Golgi resident phosphoadenosine phosphate phosphatase (gPAPP). Once synthesized, PGs are secreted in extracellular space. Sulfation of GAGs is an important step in PG synthesis determining PG properties. Inorganic sulfate enters in cells through a sulfate/chloride antiporter named SLC26A2, but a small amount of sulfate could be derived from sulfur-containing amino acid metabolism. To be used by Golgi sulfotransferases, sulfate is activated to 30-phosphoadenosine 50-phosphosulfate (PAPS), the universal sulfate donor, by PAPS synthase (PAPSS2). The by-product of sulfotransferase reactions, phosphoadenosine phosphate (PAP), is hydrolyzed by a Golgi resident phosphoadenosine phosphate phosphatase (gPAPP) in order to prevent feedback inhibition of these reactions. Linked with a dotted arrow to the GeneProduct nodes are skeletal dysplasias caused by mutation in the respective gene. For further details, see [].


Ritchie Lee , Kristina Hanspers , Egon Willighagen , Andreas Zankl , and Eric Weitz


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Homo sapiens


Skeletal Dysplasia


Disease Ontology

brachyolmia diastrophic dysplasia hereditary multiple exostoses multiple epiphyseal dysplasia 7 multiple epiphyseal dysplasia 4 Desbuquois dysplasia achondrogenesis type IB trichorhinophalangeal syndrome type I atelosteogenesis

Pathway Ontology

classic metabolic pathway


Label Type Compact URI Comment
UDP xylose Metabolite chebi:16082
PAPS Metabolite chebi:17980
Sulfate ion (SO42-) Metabolite chebi:16189
Uridine diphosphateglucuronic acid Metabolite chebi:17200
Xylose Metabolite chebi:18222
PO4(.2-) Metabolite chebi:29932
Galactose Metabolite chebi:28260
UDP Metabolite chebi:17659
Chloride Metabolite chebi:17996
UMP Metabolite chebi:16695
Phosphoadenosine phosphate Metabolite chebi:17985
ADENOSINE MONOPHOSPHATE Metabolite chebi:16027
D-glucuronic acid Metabolite chebi:4178
N-Acetylgalactosamine Metabolite chebi:28800
UDP galactose Metabolite chebi:18307
Sulfate ion (SO42-) Metabolite chebi:16189
Chloride Metabolite chebi:17996
PAPS Metabolite chebi:17980
Galactose Metabolite chebi:28260
UDP galactose Metabolite chebi:18307
N-Acetylgalactosamine Metabolite chebi:28800
N-acetylglucosamines Metabolite chebi:59640
D-glucuronic acid Metabolite chebi:4178
D-glucuronic acid Metabolite chebi:4178
L-Iduronic acid Metabolite chebi:24769
N-Acetylgalactosamine Metabolite chebi:28800
N-Acetylgalactosamine Metabolite chebi:28800
N-acetylglucosamines Metabolite chebi:59640
CSGALNACT1 GeneProduct ensembl:ENSG00000147408
SLC35B2 GeneProduct ensembl:ENSG00000157593
B3GALT6 GeneProduct ensembl:ENSG00000176022
IMPAD1 GeneProduct ensembl:ENSG00000104331
B4GALT7 GeneProduct ensembl:ENSG00000027847
CHSY1 GeneProduct ensembl:ENSG00000131873
PAPSS2 GeneProduct ensembl:ENSG00000198682
EXT2 GeneProduct ensembl:ENSG00000151348
XYLT1 GeneProduct ensembl:ENSG00000103489
CHST3 GeneProduct ensembl:ENSG00000122863
SLC26A2 GeneProduct ensembl:ENSG00000155850
XYLT2 GeneProduct ensembl:ENSG00000015532
EXTL3 GeneProduct ensembl:ENSG00000012232
B3GAT3 GeneProduct ensembl:ENSG00000149541
CHST14 GeneProduct ensembl:ENSG00000169105
SLC35B3 GeneProduct ensembl:ENSG00000124786
EXT1 GeneProduct ensembl:ENSG00000182197
CANT1 GeneProduct ensembl:ENSG00000171302


  1. Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Hästbacka J, Kaitila I, Sistonen P, de la Chapelle A. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8056–9. PubMed Europe PMC Scholia
  2. Molecular cloning and expression of a human chondroitin synthase. Kitagawa H, Uyama T, Sugahara K. J Biol Chem. 2001 Oct 19;276(42):38721–6. PubMed Europe PMC Scholia
  3. 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. Uyama T, Kitagawa H, Tamura Ji J ichi, Sugahara K. J Biol Chem. 2002 Mar 15;277(11):8841–6. PubMed Europe PMC Scholia
  4. Differential roles of two N-acetylgalactosaminyltransferases, CSGalNAcT-1, and a novel enzyme, CSGalNAcT-2. Initiation and elongation in synthesis of chondroitin sulfate. Sato T, Gotoh M, Kiyohara K, Akashima T, Iwasaki H, Kameyama A, et al. J Biol Chem. 2003 Jan 31;278(5):3063–71. PubMed Europe PMC Scholia
  5. Molecular cloning and identification of 3’-phosphoadenosine 5’-phosphosulfate transporter. Kamiyama S, Suda T, Ueda R, Suzuki M, Okubo R, Kikuchi N, et al. J Biol Chem. 2003 Jul 11;278(28):25958–63. PubMed Europe PMC Scholia
  6. Molecular cloning of a chondroitin polymerizing factor that cooperates with chondroitin synthase for chondroitin polymerization. Kitagawa H, Izumikawa T, Uyama T, Sugahara K. J Biol Chem. 2003 Jun 27;278(26):23666–71. PubMed Europe PMC Scholia
  7. Molecular cloning and characterization of a novel 3’-phosphoadenosine 5’-phosphosulfate transporter, PAPST2. Kamiyama S, Sasaki N, Goda E, Ui-Tei K, Saigo K, Narimatsu H, et al. J Biol Chem. 2006 Apr 21;281(16):10945–53. PubMed Europe PMC Scholia
  8. Involvement of chondroitin sulfate synthase-3 (chondroitin synthase-2) in chondroitin polymerization through its interaction with chondroitin synthase-1 or chondroitin-polymerizing factor. Izumikawa T, Uyama T, Okuura Y, Sugahara K, Kitagawa H. Biochem J. 2007 May 1;403(3):545–52. PubMed Europe PMC Scholia
  9. 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. Izumikawa T, Koike T, Shiozawa S, Sugahara K, Tamura J ichi, Kitagawa H. J Biol Chem. 2008 Apr 25;283(17):11396–406. PubMed Europe PMC Scholia
  10. A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation. Frederick JP, Tafari AT, Wu SM, Megosh LC, Chiou ST, Irving RP, et al. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11605–12. PubMed Europe PMC Scholia
  11. Metabolism of cartilage proteoglycans in health and disease. Vynios DH. Biomed Res Int. 2014;2014:452315. PubMed Europe PMC Scholia
  12. Human genetic disorders and knockout mice deficient in glycosaminoglycan. Mizumoto S, Yamada S, Sugahara K. Biomed Res Int. 2014;2014:495764. PubMed Europe PMC Scholia
  13. Determinants of Glycosaminoglycan (GAG) Structure. Prydz K. Biomolecules. 2015 Aug 21;5(3):2003–22. PubMed Europe PMC Scholia
  14. Glycosaminoglycans: Sorting determinants in intracellular protein traffic. Mihov D, Spiess M. Int J Biochem Cell Biol. 2015 Nov;68:87–91. PubMed Europe PMC Scholia
  15. Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias. Mizumoto S, Yamada S, Sugahara K. Biomed Res Int. 2015;2015:861752. PubMed Europe PMC Scholia
  16. Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view. Paganini C, Costantini R, Superti-Furga A, Rossi A. FEBS J. 2019 Aug;286(15):3008–32. PubMed Europe PMC Scholia