Iduronic acid

Monosaccharides can be oxidized enzymatically at C-6, yielding uronic acids, such as D-glucuronic and L-iduronic acids (Figure 7.10). L-Iduronic acid is similar to D-glucuronic acid, except for having an opposite configuration at C-5. Oxidation at both C-1 and C-6 produces aldaric acids, such as D-glucaric... 

In the condensed form, the configurational symbol and the letter denoting ring size are omitted. It is understood that the configuration is D (with the exception of fucose and iduronic acid which are usually L) and that the rings are in pyranose form unless otherwise specified. The anomeric descriptor is written in the parentheses with the locants. 

The core proteins of DS-PG I and DS-PG II are homologous to those of CS-PG I and CS-PG II found In bone (Table 48-9). A possible explanation Is that osteoblasts lack the epimerase required to convert glucuronic acid to Iduronic acid, the latter of which Is found In dermatan sulfate. 

Heparin HEP L-iduronic acid 2-amino-2-deoxy-D-glucose a-IdoA-2S-(l—4)-a-GlcNS-6S-(l —4)- (1—4)-0-(a-L-idopyranosyluronic acid 2-sulfate)-(l—4)-(2-deoxy-2-sulfamino-a-D-glucopyranosyl 6-sulfate)-... 

It is important to note that the foregoing, biosynthetic-polymer modification is usually incomplete. In fact, only a fraction of the heparin precursor undergoes all of the transformations shown in Scheme 1. However, as the product of each enzymic reaction constitutes the specific substrate for the succeeding enzyme, the biosynthesis of heparin is not a random process. Thus, sulfation occurs preferentially in those regions of the chain where the amino sugar residues have been N-deacetylated and N-sulfated, and where D-glucuronic has been epimerized to L-iduronic acid.20... 

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... 

The identification of L-iduronic acid as the major glycuronic acid constituent of heparin proved to be a much slower process than the identification of the amino sugar residue. Although this compound was detected in acid hydrolyzates of heparin116117 and heparin oligosaccharides,118 its yield was usually poor, because of the drastic conditions used for the acid hydrolysis (which are known to lead to extensive destruction of uronic acid).119120 Also, L-iduronic acid escaped detection as L-idose in the hydrolyzates of carboxyl-reduced heparin, probably because L-idose is readily converted into 1,6-anhydro-L-idose under the usual hydrolytic conditions. 

Examination of early -n.m.r. spectra of heparin and of chemically modified heparins121 prompted a reinvestigation of N,0-desulfated, carboxyl-reduced heparin, leading to the isolation of substantial amounts of L-iditol pentaacetate.121,122 In addition, improved conditions for the acid hydrolysis of heparin and carboxyl-reduced heparin gave increased recoveries of L-iduronic acid and 1,6-anhydro-L-idose, respectively.123 These findings confirmed the L-enantiomeric designation of the iduronic acid, and established that it is the main uronic acid in heparin. 

In contrast to L-iduronic acid residues, most of which are sulfated at C-2, D-glucuronic acid residues in heparin and heparan sulfate are largely or exclusively nonsulfated. This was especially proved by their susceptibility to periodate oxidation,123 and through characterization of D-glucuronic acid-containing di- and tetra-saccharides from deamina-tive104 109 110 138 or heparinase - heparanase cleavage137,145 of heparin. 

Although usually less prominent than D-glucuronic acid, nonsulfated L-iduronic acid (probably incorporated as in 3) is also a constituent of irregular regions of heparin,8,12,85 and accounts for up to 20% of some heparan sulfate species.8,85,146... 

The amino sugar counterparts of D-glucuronic acid and nonsulfated L-iduronic acid in heparin are either N-acetylated, or nonsulfated at C-6, or both. 2-Acetamido-2-deoxy-D-glucosyl residues account for only a minor proportion of the total hexosamine in heparin, and are especially low in beef-lung preparations (see Table II).8,138,147 -149 In contrast, they... 

Ana,6s (2 AM6S (where I = a-L-iduronic acid, ANA6S = 2-acetamido-2-deoxy-a-D-glucopyranose 6-sulfate, G = / -D-glucuronic acid, and AMes = 2,5-anhydro-D-mannitol 6-sulfate, the last arising from 2-deoxy-... 

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. 

Glycol groups of nonsulfated D-glucuronic acid or L-iduronic acid residues, or both, have been split by periodate (see Section VIII,3) to give oxyheparins,1,150,151,260,270 reduced oxyheparins,151,152,270 and the corresponding fragments, by depolymerization with base151,270 or acid,137,151,152,155,239,270 respectively. 

Fig. 9. — (a) H-N.m.r. Spectrum (270 MHz, Resolution-enhanced) of Beef-lung Heparin in D20 (40%, w/v) at 90° (b) Computer-simulated Spectrum, with Calculated, Interproton Coupling-Constants (/, at 35°) for the Amino Sugar (A) and L-Iduronic acid (I) Residues.84... 

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