Heparan Sulfate/Heparin Biosynthesis

Heparin is a highly sulfated variant of heparan sulfate (HS). Whereas heparin is found exclusively in the MC granules, HS is a ubiquitous component of cell surfaces and is also present in the extracellular matrix, predominantly in basement membranes. HS/heparin biosynthesis is a complex process with many different Golgi enzymes involved (). The HS-polymerases EXT1 and EXT2 synthesize a polysaccharide backbone consisting of repeating units of glucuronic acid and N-acetylglucosamine. The first modifying event is the N-deacetylase/N-sulfotransferase (NDST) reaction, where N-acetyl groups of selected N-acetylglucosamine residues are removed and replaced by sulfate groups (). After N-sulfation, the C5-epimerase converts glucuronic acid residues to iduronic acid. Sulfation at the 2-O position of iduronic acid residues and some glucuronic acid is then carried out by a 2-O-sulfotransferase, followed by glucosamine 6-O-sulfation and, more rarely, 3-O-sulfation. Little is known about the organization of the biosynthesis enzymes in the Golgi stacks. It has been suggested that the enzymes together with other yet unidentified components form GAGosomes, molecular machines responsible for elongation as well as modification of the glycosaminoglycan chains (). Different compositions of the GAGosome may result in different modification patterns of the HS chain. In support of the GAGosome concept, several interactions between pairs of HS/heparin biosynthesis enzymes have been demonstrated. For example, the polymerases EXT1 and EXT2 are known to form a functional complex (, ). Interactions have also been demonstrated between the C5-epimerase and the 2-O-sulfotransferase () and between the xylosyltransferase and galactosyltransferase-I (). In addition, we recently demonstrated an interaction between NDST1 and EXT2 that greatly influenced the structure of the polysaccharide formed ().

Biosynthesis of Heparin/Heparan Sulfate

N2 - Heparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response, and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analog of HS, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists, and developmental biologists. In this review, we summarize recent progress toward understanding the interaction between HS and blood-coagulating factors, the biosynthesis of anticoagulant HS and the mechanism of action of HS biosynthetic enzymes. Furthermore, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents.


Biosynthesis of heparin - ScienceDirect

AB - Heparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response, and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analog of HS, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists, and developmental biologists. In this review, we summarize recent progress toward understanding the interaction between HS and blood-coagulating factors, the biosynthesis of anticoagulant HS and the mechanism of action of HS biosynthetic enzymes. Furthermore, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents.