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T1 - Anticoagulant heparan sulfate

KW - Heparan sulfate

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Biosynthesis of Heparin and Heparan Sulfate - …

N2 - Heparan sulfate (HS), a highly sulfated polysaccharide, is biosynthesized through a pathway involving several enzymes. C 5-epimerase (C 5-epi) is a key enzyme in this pathway. C 5-epi is known for being a two-way catalytic enzyme, displaying a "reversible" catalytic mode by converting a glucuronic acid to an iduronic acid residue, and vice versa. Here, we discovered that C 5-epi can also serve as a one-way catalyst to convert a glucuronic acid to an iduronic acid residue, displaying an "irreversible"catalytic mode. Our data indicated that the reversible or irreversible catalytic mode strictly depends on the saccharide substrate structures. The biphasic mode of C 5-epi offers a novel mechanism to regulate the biosynthesis of HS with the desired biological functions.

T1 - Uncovering biphasic catalytic mode of C 5-epimerase in heparan sulfate biosynthesis

Our research goal is to develop a novel method to synthesize anticoagulant Heparin drug and antiviral drugs by targeting the biosynthesis of Heparan Sulfate.

Heparan Sulfate Biosynthesis - Europe PMC Article - …

T1 - Biosynthesis of heparan sulfate proteoglycans of developing chick breast skeletal muscle in vitro

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.

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.

Heparan Sulfate Biosynthesis - Hinke A. B. Multhaupt, …

Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

The composition of heparan sulfate from a variety of tissues across a number of species iswell documented, although perhaps not as well known as those from invertebrates wheretraditional biochemical approaches are more demanding. Moreover, the sequences of all theenzymes that contribute to heparan sulfate biosynthesis are catalogued from a number ofgenomes across the animal kingdom. However, the sheer complexity of heparan sulfatestructures poses interesting questions and problems regarding synthesis. Initiation ischaracterized by the transfer of xylose to a serine acceptor on the core protein. This isfollowed by two galactose units and a glucuronic acid moiety. The completed tetrasaccharideis often referred to as a stem or linker, because it is common to heparan sulfate andchondroitin/dermatan sulfate synthesis (; ). In the case of heparan sulfate, repeating disaccharides ofN-acetylglucosamine and glucuronic acid are added, and in some cases, 50disaccharides or more may follow. The polymerase consists of two proteins, EXT1 and EXT2,that form heterodimeric complexes (). Data suggest that before chain elongation is completed,early modification steps occur. The first is N-deacetylation andN-sulfation, carried out by one of fourN-deacetylases/N-sulfotransferases (NDSTs) (in mammals).Both steps are carried out by a single protein. This is followed by epimerization of uronicacid residues, converting some of them from glucuronic to iduronic acid. Some of theiduronate is then sulfated at the 2-O position. In contrast to the NDSTs,there is a single 5′ epimerase and 2-O-sulfotransferase, reportedly forminga complex with each other (). Next, 6-O-sulfation of glucosamine residues can occur; inmammals, three enzymes are capable of this modification (HS6ST-1, -2, and -3). Finally, andrarely, 3-O-sulfation takes place, but interestingly, seven mammalianenzymes are capable of completing this step ().

In the case of heparin, characteristic of mucosal mast cell granules, chain modification isextensive, so that trisulfated disaccharides can be abundant (; ; ). However, adjacent to the coreprotein (serglycin; ; ), there is a sulfate-poor region, and this appears to be common to all HSPGs(). Incontrast to heparin, however, heparan sulfate of syndecans and glypicans, for example, isnot so extensively modified. Regions of low or no sulfation are interspersed between regionsof high sulfation, and at the junctions between these zones are regions of intermediatesulfation ().Given that the overall pattern of chain modification is held relatively constant within aparticular cell type but may differ between cell types, the control of heparan sulfatesynthesis is clearly complex. Because it is not random, modifications must be regulated. Forexample, it is known that liver-derived heparan sulfate is more highly sulfated than that ofother organs (;). Still,today, there is little information regarding how cells control the pattern of chainmodification. It is known that the activity of NDSTs lay down a template becauseN-sulfation largely determines where further modifications, such asepimerization and 2-O-sulfation, occur (; ). However, even where NDST1and NDST2 are deleted, some 6-O-sulfation takes place (), even thoughN-sulfation may be absent.

17/11/2015 · Divergent Synthesis of Heparan Sulfate Oligosaccharides
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  • MetaCyc heparan sulfate biosynthesis (late stages)

    FULL TEXT Abstract: Heparan sulfate is perhaps the most complex polysaccharide known from animals

  • Heparan sulfate proteoglycans: ..

    01/12/2012 · Heparan sulfate is perhaps the most complex polysaccharide known from animals

  • The Activities of Heparan Sulfate and its Analogue …

    Heparan sulfate is a linear polysaccharide found in all animal tissues

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Chemoenzymatic synthesis of heparan sulfate and …

Previous studies have reported an increase in heparan sulfate glycosaminoglycan (HSGAG) during skeletal muscle differentiation in culture. We have investigated this phenomenon further in relation to the heparan sulfate proteoglycans (HSPG) produced by myogenic cultures. Pulse-chase analysis indicated an approx. 3-fold increase in heparan sulfate synthesis in myotube cultures over that in proliferating or aligning myoblast cultures. Muscle fibroblast culture heparan sulfate synthesis was higher than that of myoblasts but was lower than myotubes. The turnover rates appeared to be the same for all stages of development, with a t 1 2 of approx. 5 h. Enrichment for heparan sulfate by Sepharose CL-4B and DEAE-Sephacel chromatography indicated an increase in the hydrodynamic size of the proteoglycan produced by myotubes over that from myoblasts, with a shift in Kav from 0.14-0.19 to 0.07. Fibroblasts synthesized the smallest proteoglycan, with a Kav of 0.22. All of the proteoglycans contained similar sized glycosaminoglycan chains with an estimated molecular weight of 30 000-40 000. Localization of the heparan sulfate proteoglycan in myotube cultures by trypsin sensitivity indicated much of the intact proteoglycan to be closely associated with the cell surface, while internalized material appeared in a degraded form.

Anticoagulant heparan sulfate: Structural specificity …

Heparan sulfate (HS), a highly sulfated polysaccharide, is biosynthesized through a pathway involving several enzymes. C 5-epimerase (C 5-epi) is a key enzyme in this pathway. C 5-epi is known for being a two-way catalytic enzyme, displaying a "reversible" catalytic mode by converting a glucuronic acid to an iduronic acid residue, and vice versa. Here, we discovered that C 5-epi can also serve as a one-way catalyst to convert a glucuronic acid to an iduronic acid residue, displaying an "irreversible"catalytic mode. Our data indicated that the reversible or irreversible catalytic mode strictly depends on the saccharide substrate structures. The biphasic mode of C 5-epi offers a novel mechanism to regulate the biosynthesis of HS with the desired biological functions.

Heparan Sulfate Biosynthesis - CORE

The importance of the pathological changes in proteoglycans has driven the need to study and design novel chemical tools to control proteoglycan synthesis. Accordingly, we tested the fluorinated analogue of glucosamine (4-fluoro-N-acetyl-glucosamine (4-F-GlcNAc)) on the synthesis of heparan sulfate (HS) and chondroitin sulfate (CS) by murine airway smooth muscle (ASM) cells in the presence of radiolabeled metabolic precursors. Secreted and cell-associated CS and HS were assessed for changes in size by Superose 6 chromatography. Treatment of ASM cells with 4-F-GlcNAc (100 μM) reduced the quantity (by 64.1-76.6%) and decreased the size of HS/CS glycosaminoglycans associated with the cell layer (Kav shifted from 0.30 to 0.45). The quantity of CS secreted into the medium decreased by 65.7-73.0%, and the size showed a Kav shift from 0.30 to 0.50. Treatment of ASM cells with 45 μM and 179 μM 4-F-GlcNAc in the presence of a stimulator of CS synthesis, 4-methylumbelliferyl-β-D-xyloside, reduced the amount of the xyloside-CS chains by 65.4 and 87.0%, respectively. The size of xyloside-CS chains synthesized in the presence of 4-F-GlcNAc were only slightly larger than those with xyloside treatment alone (Kav of 0.55 compared with that of 0.6). The effects of 4-F-GlcNAc to inhibit CS synthesis were not observed with equimolar concentrations of glucosamine. We propose that 4-F-GlcNAc inhibits CS synthesis by inhibiting 4-epimerization of UDP-GlcNAc to UDP-GalNAc, thereby depleting one of the substrates required, whereas HS elongation is inhibited by truncation when the nonreducing terminus of the growing chain is capped with 4-F-GlcNAc.

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