Glycosaminoglycans 2-sulfated iduronic acid

Contamination from other L-iduronic acid-containing glycosaminoglycans (dermatan sulfate and heparan sulfate species) cannot usually be lowered below the 1-2% level, unless repeated precipitations or treatments with resin are made. As will be discussed in Section VIII, extensive... 

Periodate oxidation was used in early work for obtaining information on the substitution pattern of heparin.1,100 102 In fully N-substituted (N-sulfated or N-acetylated, or both) glycosaminoglycans, the only bond susceptible to splitting by periodate is C-2-C-3 of unsubstituted uronic acid residues. As illustrated in Scheme 4 for heparin, only nonsulfated D-glucuronic acid and L-iduronic acid residues are split by periodate. 

Dermatan sulfate, also termed chondroitin sulfate B, a related glycosaminoglycan constituent of connective tissue, was known to be composed of galactosamine and a uronic acid, originally believed to be glucuronic acid but then claimed to be iduronic acid based largely on color reactions and paper chromatography. However, the d or L-enantiomer status of the latter monosaccharide was not clear. Jeanloz and Stoffyn unequivocally characterized the monosaccharide as L-iduronic acid by consecutive desulfation, reduction, and hydrolysis of the polysaccharide, followed by isolation of the crystalline 2,3,4-tri-0-acetyl-l,6-anhydro-/ -L-idopyranose, which was shown to be identical to an authentic specimen synthesized from 1,2-0-isopropylidene-/ -L-idofuranose.34... 

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. 

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.

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). 

Fig. 49.8. Repeating disaccharides of some glycosaminoglycans. These repeating disaccharides usually contain an A-acetylated sugar and a uronic acid, which usually is glucuronic acid or iduronic acid. Sulfate groups are often present but are not included in the sugar names in this figure.

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