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 N-sulfo-D-glucosamine, α-D-N-sulfoglucosamine 6-O-sulfate, a [heparan sulfate]-α-D-N-sulfoglucosamine 3-O-sulfate or a [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 a [heparan]-N-acetyl-α-D-glucosamine residues in what would become S-regions, and sulfates the free NH2 groups, resulting in a [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 a [heparan sulfate]-α-D-N-sulfoglucosamine residues, resulting in formation of the bi-sulfated forms a [heparan sulfate]-α-D-N-sulfoglucosamine 3-O-sulfate, a [heparan sulfate]-α-D-N-sulfoglucosamine 6-O-sulfate and the triple-sulfated a [heparan sulfate]-α-D-N-sulfoglucosamine 3,6-O-bissulfate residues.
Superpathways: heparan sulfate biosynthesis
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