Proteoglycan biosynthesis (Homo sapiens)

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3151211, 128, 1011, 1211, 1211, 122, 6, 9, 13, 14, 161241, 7122, 6, 9, 13, 14, 164PG core proteinGlcUA-Gal-Gal-Xyl-proteinNewly synthesizedproteoglycanSulfur-containing amino acid metabolismSulfation ofproteoglycanChondroitin sulfateExtracellular spaceGlycosylated proteoglycannCytoplasmGolgi apparatusProteoglycan core synthesized inrough endoplasmic reticulum5EXTL3D-glucuronic acidChlorideIMPAD1XylosePO4(.2-)XYLT1B4GALT7CSGALNACT1N-AcetylgalactosamineB3GAT3UMPUDPCANT1SLC26A2ADENOSINE MONOPHOSPHATECHST14PAPSS2Uridine diphosphateglucuronic acidUDP xyloseCHSY1CHST3UDP galactoseB3GALT6Phosphoadenosine phosphateEXT2SLC35B2EXT1SLC35B3XYLT2PAPSGalactoseSulfate ion (SO42-)Sulfate ion (SO42-)ChloridePAPSGalactoseUDP galactoseGlcUA-Gal-Gal-Xyl-proteinN-AcetylgalactosamineGlcUA-Gal-Gal-Xyl-proteinN-acetylglucosaminesD-glucuronic acidD-glucuronic acidL-Iduronic acidN-AcetylgalactosamineN-AcetylgalactosamineN-acetylglucosaminesNewly synthesizedproteoglycanDermatan sulfateHeparan sulfatennOMIM:600972Achondrogenesis, type IBOMIM:256050Atelosteogenesis, type IIOMIM:615777Desbuquois dysplasia 2OMIM:605822Spondyloocular syndromeOMIM:612847Brachyolmia type 4 with mild epiphyseal and metaphyseal changesOMIM:150230Trichorhinophalangeal syndrome, type IIOMIM:614078Chondrodysplasia with joint dislocations, gPAPP TypeOMIM:222600Diastrophic dysplasiaOMIM:143095Spondyloepiphyseal dysplasia with congenital joint dislocationsOMIM:130070Ehlers-Danlos syndrome, spondylodysplastic type, 1OMIM:605282Temtamy preaxial brachydactyly syndromeOMIM:616615CSGALNACT1 deficiency (joint dislocations and mild skeletal dysplasia)OMIM:226900Epiphyseal dysplasia, multiple, 4OMIM:133700Exostoses, multiple, type IOMIM:617719Epiphyseal dysplasia, multiple, 7OMIM:271640Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fracturesOMIM:251450Desbuquois dysplasia 1OMIM:245600Multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defectsOMIM:601776Ehlers-Danlos syndrome, musculocontractural type, 1OMIM:617425Immunoskeletal dysplasia with neurodevelopmental abnormalities


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 [1].

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  1. 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.''; J Biol Chem, 2006 PubMed Europe PMC Scholia
  2. Kitagawa H, Izumikawa T, Uyama T, Sugahara K; ''Molecular cloning of a chondroitin polymerizing factor that cooperates with chondroitin synthase for chondroitin polymerization.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  3. Paganini C, Costantini R, Superti-Furga A, Rossi A; ''Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view.''; FEBS J, 2019 PubMed Europe PMC Scholia
  4. Hästbacka J, Kaitila I, Sistonen P, de la Chapelle A; ''Diastrophic dysplasia gene maps to the distal long arm of chromosome 5.''; Proc Natl Acad Sci U S A, 1990 PubMed Europe PMC Scholia
  5. Vynios DH; ''Metabolism of cartilage proteoglycans inhealth and disease.''; Biomed Res Int, 2014 PubMed Europe PMC Scholia
  6. 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; ''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, 2003 PubMed Europe PMC Scholia
  7. Kamiyama S, Suda T, Ueda R, Suzuki M, Okubo R, Kikuchi N, Chiba Y, Goto S, Toyoda H, Saigo K, Watanabe M, Narimatsu H, Jigami Y, Nishihara S; ''Molecular cloning and identification of 3'-phosphoadenosine 5'-phosphosulfate transporter.''; J Biol Chem, 2003 PubMed Europe PMC Scholia
  8. Prydz K; ''Determinants of Glycosaminoglycan (GAG)Structure.''; Biomolecules, 2015 PubMed Europe PMC Scholia
  9. Izumikawa T, Uyama T, Okuura Y, Sugahara K, Kitagawa H; ''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, 2007 PubMed Europe PMC Scholia
  10. Mihov D, Spiess M; ''Glycosaminoglycans: Sorting determinants in intracellular protein traffic.''; Int J Biochem Cell Biol, 2015 PubMed Europe PMC Scholia
  11. Mizumoto S, Yamada S, Sugahara K; ''Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias.''; Biomed Res Int, 2015 PubMed Europe PMC Scholia
  12. Mizumoto S, Yamada S, Sugahara K; ''Human genetic disorders and knockout mice deficient in glycosaminoglycan.''; Biomed Res Int, 2014 PubMed Europe PMC Scholia
  13. Kitagawa H, Uyama T, Sugahara K; ''Molecular cloning and expression of a human chondroitin synthase.''; J Biol Chem, 2001 PubMed Europe PMC Scholia
  14. Uyama T, Kitagawa H, Tamura Ji J, Sugahara K; ''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, 2002 PubMed Europe PMC Scholia
  15. Frederick JP, Tafari AT, Wu SM, Megosh LC, Chiou ST, Irving RP, York JD; ''A role for a lithium-inhibited Golgi nucleotidase in skeletal development and sulfation.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC Scholia
  16. Izumikawa T, Koike T, Shiozawa S, Sugahara K, Tamura J, Kitagawa H; ''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, 2008 PubMed Europe PMC Scholia


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128877view00:01, 24 February 2024EweitzStandardize case
128876view23:55, 23 February 2024EweitzSoften disease color
128875view23:46, 23 February 2024EweitzOntology Term : 'trichorhinophalangeal syndrome type I' added !
128874view23:44, 23 February 2024EweitzOntology Term : 'hereditary multiple exostoses' added !
128873view23:43, 23 February 2024EweitzOntology Term : 'brachyolmia' added !
128872view23:42, 23 February 2024EweitzOntology Term : 'diastrophic dysplasia' added !
128871view23:41, 23 February 2024EweitzOntology Term : 'multiple epiphyseal dysplasia 4' added !
128870view23:40, 23 February 2024EweitzOntology Term : 'atelosteogenesis' added !
128869view23:40, 23 February 2024EweitzOntology Term : 'achondrogenesis type IB' added !
128868view23:39, 23 February 2024EweitzOntology Term : 'multiple epiphyseal dysplasia 7' added !
128867view23:39, 23 February 2024EweitzOntology Term : 'Desbuquois dysplasia' added !
128866view22:49, 23 February 2024EweitzModified description
111633view02:45, 1 September 2020AzanklModified description
110986view14:55, 25 June 2020EgonwConverted three mim-conversions to Arrow (they're translocations)
110015view18:37, 12 April 2020EgonwReplaced secondary ChEBI identifiers with a primary identifiers.
109334view23:36, 13 March 2020KhanspersOntology Term : 'classic metabolic pathway' added !
108790view01:08, 30 January 2020RleeModified description
108789view01:06, 30 January 2020RleeNew pathway

External references


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NameTypeDatabase referenceComment
B3GALT6GeneProductENSG00000176022 (Ensembl)
B3GAT3GeneProductENSG00000149541 (Ensembl)
B4GALT7GeneProductENSG00000027847 (Ensembl)
CANT1GeneProductENSG00000171302 (Ensembl)
CHST14GeneProductENSG00000169105 (Ensembl)
CHST3GeneProductENSG00000122863 (Ensembl)
CHSY1GeneProductENSG00000131873 (Ensembl)
CSGALNACT1GeneProductENSG00000147408 (Ensembl)
ChlorideMetaboliteCHEBI:17996 (ChEBI)
D-glucuronic acidMetaboliteCHEBI:4178 (ChEBI)
EXT1GeneProductENSG00000182197 (Ensembl)
EXT2GeneProductENSG00000151348 (Ensembl)
EXTL3GeneProductENSG00000012232 (Ensembl)
GalactoseMetaboliteCHEBI:28260 (ChEBI)
IMPAD1GeneProductENSG00000104331 (Ensembl)
L-Iduronic acidMetaboliteCHEBI:24769 (ChEBI)
N-AcetylgalactosamineMetaboliteCHEBI:28800 (ChEBI)
N-acetylglucosaminesMetaboliteCHEBI:59640 (ChEBI)
PAPSMetaboliteCHEBI:17980 (ChEBI)
PAPSS2GeneProductENSG00000198682 (Ensembl)
PO4(.2-)MetaboliteCHEBI:29932 (ChEBI)
Phosphoadenosine phosphateMetaboliteCHEBI:17985 (ChEBI)
SLC26A2GeneProductENSG00000155850 (Ensembl)
SLC35B2GeneProductENSG00000157593 (Ensembl)
SLC35B3GeneProductENSG00000124786 (Ensembl)
Sulfate ion (SO42-)MetaboliteCHEBI:16189 (ChEBI)
UDP galactoseMetaboliteCHEBI:18307 (ChEBI)
UDP xyloseMetaboliteCHEBI:16082 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UMPMetaboliteCHEBI:16695 (ChEBI)
Uridine diphosphate glucuronic acidMetaboliteCHEBI:17200 (ChEBI)
XYLT1GeneProductENSG00000103489 (Ensembl)
XYLT2GeneProductENSG00000015532 (Ensembl)
XyloseMetaboliteCHEBI:18222 (ChEBI)

Annotated Interactions

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