Sulfated and heparin

Veldkamp CT, Peterson FC, Pelzek AJ, Volkman BF. The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin. Protein Sci 2005 14 1071-81. 

Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic variant of the human enzyme a-L-iduronidase. It was approved for general medical use in the USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited disease MPS I. MPS I is caused by a deficiency of a lysosomal a-L-iduronidase, which normally catalyses the hydrolysis of terminal a-L-iduronic acid residues from the glycosaminoglycans dermatan sulfate and heparin sulfate. The deficiency results in accumulation of the glycosaminoglycans throughout the body, causing widespread cell and tissue dysfunction. 

Stnictures 1. Characteristic structural motifs in heparan sulfate and heparin... 

Heparinoid polysaccharides such as heparan sulfate and heparin are able to interact with numerous proteins and influence vital biological processes. Heparinoid mimetics were prepared to reduce the structural complexity of heparinoids and to obtain selectivities. This article summarizes the development of heparinoid mimetics of different classes including representative syntheses and biological activities. Largely simplified compounds with regard to structure and synthetic access are described which maintain or exceed the activity of heparinoid polysaccharides. One of the recipes to increase binding or modify pharmacokinetic parameters was the introduction of hydrophobic groups. 

Subsequent modifications of the polymers involve extensive formation of O-sulfate esters,1903 193 197 N-deacetylation and N-sulfation,198/199 and epimerization at C5.10 In some tissues almost all GluA is epimer-ized.200 The modifications are especially extensive in dermatan, heparan sulfates, and heparin (see also p. 177).196 201 203b The modifications are not random and follow a defined order. N-Deacetylation must precede N-sulfation, and O-sulfation is initiated only after N-sulfation of the entire chain is complete. The modifications occur within the Golgi (see Fig. 20-7) but not all... 

In the following, we summarize briefly findings on the CPL fragments from dermatan sulfate, chondroitin sulfate, heparan sulfate, and heparin. 

Oligosaccharide Fragments Isolated from the Carbohydrate-Protein Linkage-Region of Heparan Sulfate and Heparin Proteoglycans... 

Figure 2. Structures of the glycosaminoglycans and their linkage regions to protein. Two disaccharide repeating units are shown to emphasize the microheterogeneity that exists in some cases. Heparan sulfate and heparin show many structural similarities. However, heparan sulfate contains more GlcNAc(a-1 — 4)GlcUA repeating units fewer glucosamine residues are N-sulfated, and few iduronic acid residues are sulfated at C2.

Several studies have shown that hyaluronidase is iidiibited by ft1, Fe Cu +, Ag+, Hg2+, Zn2+, Cd2+, and Pb2+ salts [26,51,58,77,78]. Substrate analogs like chondroitin sulfate tit desulfeted chondroitin sulfate B, dermatan sulfate, keratan sulfate, heparitin sulfate, and heparin were shown to be competitive inhibitors of hyaluronidase [14,54]. 

Most of the polysaccharides of interest in this text are termed glycosaminoglycans, polymers that contain an amino sugar in the repeat unit. Glycosaminoglycans that are abundant in mammalian tissues include hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparin-heparan sulfate (see Table 2.4). Most of these glycosaminoglycans,... 

Aldurazyme polymorphic variation of human a-L-iduronidase lysosomal hydrolase hydrolysis of terminal a-L-iduronic acid residues of dermatan sulfate and heparin sulfate No genotoxicity studies clinical trials Studies to assess mutagenic and carcinogenic potential have not been conducted No warnings or precautions regarding carcinogenic risk... 

The interaction of partially purified, commercial preparations of P. vulgaris with a large number of serum glycoproteins was studied by Morse.105 The lectin precipitated a2-macroglobulin, /3-lipoproteins, and immunoglobulin M. Preparations ofarglycoprotein, orosomucoid, and several immunoglobulin A myeloma proteins also reacted.105 Chon-droitin 4-sulfate, dermatan sulfate, and heparin also precipitated a partially purified preparation of red kidney-bean the precipitation reaction was completely inhibited by 0.5 M sodium chloride solution.3663... 

Hoppensteadt D, Racanelli A, Walenga JM, Fareed J Comparative antithrombotic and hemorrhagic effects of dermatan sulfate, hqiaran sulfate and heparin. Semin Thromb Hemost (1989) 15 378-385. 

CIONS is also found. Although heparan sulfate and heparin are structurally similar one should keep in mind that both are found on different core proteins. 

Rienits later studied the zone-electrophoretic behavior of hyaluronic acid, chondroitin hydrogen sulfate, and heparin on paper strips in nonborate buffers he found that, whereas hyaluronic acid can be separated from chondroitin hydrogen sulfate and heparin, the latter two mucopolysaccharides cannot be separated. The mucopolysaccharides could be located by the use of a method similar to that of Gardell, Gordon and Aqvist, or by staining the pherogram with Toluidine Blue. The mobility of hyalu-... 

IFNy binds with high affinity to heparin sulfate and heparin molecules through its carboxyl-terminal domain. In vivo, IFNy is eliminated from the Mood stream with a half-fife of 1.1 minutes, caused by binding to heparin sulfate. Unbound IFNy is cleaved rapidly at the carboxyl-terminal side, a process that inactivates the cytokine. When bound to heparin, the plasma clearance of IFNy is greatly decreased (half-fife =99 minutes), and the cytokine activity is increased by as much as 600%. These data demonstrate that the blood clearance of IFNy is a nonreceptor-mediated process and that in vivo the local concentration of heparin sulfate and/or heparin-like molecules regulates the activity of this cytokine. "... 

The ido configuration is present, isolated in the middle of other monosaccharide residues, in the polycondensed chains called glycosaminoglycans of natural polysaccharides dermatan sulfate, heparan sulfate, and heparin. The derivative in question belonging to the L-series is 2-0-sulfo-L-iduronic acid. It is represented (2.34, R = R = H) in a non-conformational manner with the a-L-idopyrano configuration present in these polysaccharides. The L-ido residue is isolated in the sequence, in the centre of the chains attached to 0-1 and 0-4, respectively (Section 17.3). It is found as a mixture of the l- C4 (2.35) and l- Sq (2.36) conformations. The proportion of the skew form varies from 40 to 60% according to the attached oligosaccharide sequences, R and R (Casu et al. 1986). 

There are quantitative differences in the chemical constitution of heparan sulfate and heparin polysaccharides, but qualitative differences in their biological location and core protein. " Heparin is biosynthesised only in connective tissue mast cells and attached only to a unique protein core (serglycin). The initial polysaccharide chains have a DP (dimer) of 25(T400, but can be cleaved subsequently to give an array of heparin polysaccharides. Heparan sulfate, by contrast, can be synthesised on an array of proteins in various cells, with two major subfamilies of heparan sulfate proteoglycans, the syndecans and glypi-cans, which carry fewer and shorter polysaccharide chains. 

Fig. 2. Typical oligosaccharide structures of heparan sulfate and heparin.

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