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
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three heparan sulfate chains are attached to cell surface or extracellular matrix proteins, known as "core proteins". Heparan sulfate binds to diverse protein ligands (known as heparin-binding proteins) and regulates a wide variety of biological activities, including developmental processes, cell adhesion and motility, angiogenesis, blood coagulation and tumour metastasis.
The molecule is built of glycosaminoglycan chains attached to specific serine residues in a core protein. The chains are composed of a simple sugar backbone that is modified to different degrees depending on the cellular conditions. The backbone is built of several types of disaccharide building units with different sulfation patterns and can accomodate over 1,000,000 different sequences built up of up to 200 disaccharide units [Sasisekharan00].
The disaccharide building units are composed of a hexose sugar and a uronic acid. The most common repeating unit, which makes up around 50% of the total disaccharide units in heparan sulfate, is composed of β-D-glucuronate linked to N-acetyl-α-D-glucosamine. In other units β-D-glucuronate may be substituted by α-L-iduronate or its sulfated form α-L-iduronate 2-O-sulfate, and N-acetyl-β-D-glucosamine may be sulfated to α-D-N-sulfoglucosamine, α-D-N-sulfoglucosamine 6-O-sulfate, [heparan sulfate]-α-D-N-sulfoglucosamine 3-O-sulfate or [heparan sulfate]-α-D-N-sulfoglucosamine 3,6-O-bissulfate.
Heparan sulfate chains comprise three different types of domains: S-domains that contain contiguous N-sulfated residues, unmodified N-acetyl-rich regions, and mixed transition zones between the S-domains and the unmodified segments. Only the S-domains have binding capacities for growth factors and other proteins [Gallagher01a]. The structure of heparin is very similar, but its chains are not organized into distinct sulfated and non-sulfated domains [Murphy04].
The synthesis of heparan sulfate takes place in the Golgi apparatus, with the exception of the first reaction, the attachemnt of xylose to the core protein, which takes place within the endoplasmic reticulum.
About This Pathway
The synthesis of heparan sulfate begins with the formation of a tetrasaccharide linkage region on the core protein, as described in glycoaminoglycan-protein linkage region biosynthesis. Once the linkage region is synthesized, a key reaction, catalyzed by EXTL2 and EXTL3, adds an N-acetyl-α-D-glucosamine residue to the linkage region tetrasaccharide. This addition is a molecular switch that prevents the synthesis of chondroitin sulfate or dermatan sulfate on the linkage region. The chain is then elongated by the exostosin complex, a bifunctional protein composed of EXT1 and EXT2 units, that can add both β-D-glucuronate and N-acetyl-α-D-glucosamine in an alternating manner to the nascent chain. Once the basic backbone is synthesized, many enzymes alter the structure.
A key enzyme is the bifunctional heparan sulfate N-deacetylase/N-sulfotransferase (4 isoforms are encoded by NDST1, NDST2, NDST3 and NDST4). The enzyme removes the acetyl groups from [heparan]-N-acetyl-α-D-glucosamine residues in what would become S-regions, and sulfates the free NH2 groups, resulting in [heparan sulfate]-α-D-N-sulfoglucosamine.
Heparosan-N-sulfate-glucuronate 5-epimerase (GLCE) converts β-D-glucuronate residues to α-L-iduronate residues. [Heparan sulfate]-uronosyl-2-O-sulfotransferase 1 (HS2ST1), which interacts with GLCE, transfers a sulfate group to the C2 position of the α-L-iduronate residues.
Finally, a set of 3-O-sulfotransferases and 6-O-sulfotransferases act on the [heparan sulfate]-α-D-N-sulfoglucosamine residues, resulting in formation of the bi-sulfated forms [heparan sulfate]-α-D-N-sulfoglucosamine 3-O-sulfate, [heparan sulfate]-α-D-N-sulfoglucosamine 6-O-sulfate and the triple-sulfated [heparan sulfate]-α-D-N-sulfoglucosamine 3,6-O-bissulfate residues.
Superpathways: heparan sulfate biosynthesis
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
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
Ahn95: Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE (1995). "Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1)." Nat Genet 11(2);137-43. PMID: 7550340
Aikawa01: Aikawa J, Grobe K, Tsujimoto M, Esko JD (2001). "Multiple isozymes of heparan sulfate/heparin GlcNAc N-deacetylase/GlcN N-sulfotransferase. Structure and activity of the fourth member, NDST4." J Biol Chem 276(8);5876-82. PMID: 11087757
Aikawa99: Aikawa J, Esko JD (1999). "Molecular cloning and expression of a third member of the heparan sulfate/heparin GlcNAc N-deacetylase/ N-sulfotransferase family." J Biol Chem 274(5);2690-5. PMID: 9915799
Campbell94: Campbell P, Hannesson HH, Sandback D, Roden L, Lindahl U, Li JP (1994). "Biosynthesis of heparin/heparan sulfate. Purification of the D-glucuronyl C-5 epimerase from bovine liver." J Biol Chem 269(43);26953-8. PMID: 7929434
Crawford01: Crawford BE, Olson SK, Esko JD, Pinhal MA (2001). "Cloning, Golgi localization, and enzyme activity of the full-length heparin/heparan sulfate-glucuronic acid C5-epimerase." J Biol Chem 276(24);21538-43. PMID: 11279150
Dixon95: Dixon J, Loftus SK, Gladwin AJ, Scambler PJ, Wasmuth JJ, Dixon MJ (1995). "Cloning of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene from the Treacher Collins syndrome candidate region at 5q32-q33.1." Genomics 26(2);239-44. PMID: 7601448
Duncan01: Duncan G, McCormick C, Tufaro F (2001). "The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins." J Clin Invest 108(4);511-6. PMID: 11518722
Duncan06: Duncan MB, Liu M, Fox C, Liu J (2006). "Characterization of the N-deacetylase domain from the heparan sulfate N-deacetylase/N-sulfotransferase 2." Biochem Biophys Res Commun 339(4);1232-7. PMID: 16343444
Grobe02: Grobe K, Esko JD (2002). "Regulated translation of heparan sulfate N-acetylglucosamine N-deacetylase/n-sulfotransferase isozymes by structured 5'-untranslated regions and internal ribosome entry sites." J Biol Chem 277(34);30699-706. PMID: 12070138
Habuchi00: Habuchi H, Tanaka M, Habuchi O, Yoshida K, Suzuki H, Ban K, Kimata K (2000). "The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine." J Biol Chem 275(4);2859-68. PMID: 10644753
Habuchi03: Habuchi H, Miyake G, Nogami K, Kuroiwa A, Matsuda Y, Kusche-Gullberg M, Habuchi O, Tanaka M, Kimata K (2003). "Biosynthesis of heparan sulphate with diverse structures and functions: two alternatively spliced forms of human heparan sulphate 6-O-sulphotransferase-2 having different expression patterns and properties." Biochem J 371(Pt 1);131-42. PMID: 12492399
Habuchi95: Habuchi H, Habuchi O, Kimata K (1995). "Purification and characterization of heparan sulfate 6-sulfotransferase from the culture medium of Chinese hamster ovary cells." J Biol Chem 270(8);4172-9. PMID: 7876170
Habuchi98: Habuchi H, Kobayashi M, Kimata K (1998). "Molecular characterization and expression of heparan-sulfate 6-sulfotransferase. Complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells." J Biol Chem 273(15);9208-13. PMID: 9535912
Hernaiz00: Hernaiz M, Liu J, Rosenberg RD, Linhardt RJ (2000). "Enzymatic modification of heparan sulfate on a biochip promotes its interaction with antithrombin III." Biochem Biophys Res Commun 276(1);292-7. PMID: 11006120
Humphries97: Humphries DE, Sullivan BM, Aleixo MD, Stow JL (1997). "Localization of human heparan glucosaminyl N-deacetylase/N-sulphotransferase to the trans-Golgi network." Biochem J 325 ( Pt 2);351-7. PMID: 9230113
Humphries98: Humphries DE, Lanciotti J, Karlinsky JB (1998). "cDNA cloning, genomic organization and chromosomal localization of human heparan glucosaminyl N-deacetylase/N-sulphotransferase-2." Biochem J 332 ( Pt 2);303-7. PMID: 9601056
Jemth03: Jemth P, Smeds E, Do AT, Habuchi H, Kimata K, Lindahl U, Kusche-Gullberg M (2003). "Oligosaccharide library-based assessment of heparan sulfate 6-O-sulfotransferase substrate specificity." J Biol Chem 278(27);24371-6. PMID: 12702732
Kakuta99: Kakuta Y, Sueyoshi T, Negishi M, Pedersen LC (1999). "Crystal structure of the sulfotransferase domain of human heparan sulfate N-deacetylase/ N-sulfotransferase 1." J Biol Chem 274(16);10673-6. PMID: 10196134
Kim01g: Kim BT, Kitagawa H, Tamura J, Saito T, Kusche-Gullberg M, Lindahl U, Sugahara K (2001). "Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha 1,4- N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis." Proc Natl Acad Sci U S A 98(13);7176-81. PMID: 11390981
Kitagawa99: Kitagawa H, Shimakawa H, Sugahara K (1999). "The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate." J Biol Chem 274(20);13933-7. PMID: 10318803
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493