Dermatan sulfate formation

Malmstrom A, Fransson LA. Biosynthesis of dermatan sulfate. I. Formation of L-iduronic acid residues. J Biol Chem 1975 250 3419-3425. 

Scott JE, Heatley F, Wood B. Comparison of secondary structures in water of chondroitin-4-sulfate and dermatan sulfate implications in the formation of tertiary structures. Biochemistry 1995 34 15467-15474. 

The glycosaminoglycans in the subretinal fluid of rhegmatogenous retinal detachment were characterized (52). The results revealed that hyaluronan alone (HA type) was present in 50% of the eyes. A combination of chondroitin sulfate (chSA) and hyaluronan (chSA type) was present in 15% of the eyes. A combination of dermatan sulfate (DS) and hyaluronan (DS type) was present in 35% of the eyes. Retinal detachment with a demarcation line resulted in subretinal strand formation in the DS-type eyes, while no such formation was seen in the chSA type. Vitreous haze was observed in one eye of the DS type. All eyes with grade C proliferative vitreoretinopathy were the DS type. The eyes with reoperated surgeries were the DS type. The presence of DS may indicate an advanced condition of retinal detachment. 

All these results clearly indicate that the BT-HAase activity towards HA can be either enhance or suppress by formation of electrostatic complexes. The BT-HAase activity can be enhance by polycations, which in vivo are mainly proteins, to the condition that (i) they are able, by forming electrostatic complexes with HA, to avoid, or at least to limit, the formation of electrostatic complexes between HA and BT-HAase and, (ii) the ratio of the polycation over HA quantities in the HA-polycation complexes allows enough HA P(l,4) bonds to remain accessible to BT-HAase. Suppression of the BT-HAase activity may result from the formation of two types of electrostatic complexes (i) HA-polycation complexes in which the accessibility of BT-HAase to the HA P(l,4) bonds is hindered because of a too high value of the ratio of the polycation over HA quantities in the complexes and, (ii) polyanion-BT-HAase complexes in which BT-HAase is catalytically inactive. In our study, the only one polyanion was HA and we showed that it is able to form electrostatic complexes with BT-HAase in which BT-HAase is catalytically inactive. Nevertheless, many polyanions, including GAG other than HA (heparin, heparan sulfate, dermatan sulfate), HA derivatives (0-sulfonated HA) and synthetic polyanions (poly(styrene-4-sulfonate)) are known to inhibit HAase (Aronson and Davidson, 1967 Girish and Kemparaju, 2005 Isoyama et al., 2006 Mathews and Dorfman, 1955 Toida et al., 1999). In the case of heparin, Maksimenko et al. (2001) demonstrated that the inhibition results from the formation of electrostatic heparin-HAase complexes. 

In contrast, similar experiments carried out with human fibroblasts in tissue culture (Matalon and Dorfman, 19fl6, 1968) showed an inhibition of hyaluronic acid foimation bj puromycin. The effect was not as pronounced as on ehondroitin sulfate or dermatan sulfate synthesis, but despite the quantitative differences, the results support the idea that mammalian hyaluronic acid is covalently linked to protein and that its synthesis is dependent on prior formation of the protein moiety. 

A number of other problems pertaining to the biosynthesis of dermatan sulfate could be mentioned, but since this entire area is still a matter of speculation rather than actual knowledge, only one additional question will be pointed out. It has been indicated by preliminary experiments that at least the immediate sequence of amino acids surrounding the carbohydrate-protein linkage in dermatan sulfate from skin is different from that found in the chondroitiii sulfate-protein of bovine nasal cartilage (Stern and Rod6n, 1969). It wall therefore be of interest to study the acceptor specificity of the xylose transfer reaction, since tw o different xylcffiyltransferases could conceivably be involved in the formation of dermatan sulfate and chondroitin sulfate. 

The biosynthesis of heparin and heparan sulfate presents a number of problems whicii are specific for these polysaccharides, including (1) the formation of a-g ycosidic linkages ratlier than 3-linkages which predominate among the other glycosaminog yeans (with the exception of the somewhat special ease of the cr-Iinked L-iduronic acid residues in dermatan sulfate) (2) the mechanism of sulfation of the amino groups and (3) the introduction of sulfate into the uronic acid residues. 

The HS C5-epimerase that catalyzes the conversion of GlcA to IdoA has been cloned from bovine lung [41]. This enzyme is distinct from the epimerase involved in dermatan sulfate biosynthesis [42]. IdoA has a more flexible conformation than GlcA [43], and the formation of IdoA in GAGs is therefore believed to generally promote binding of the polysaccharides to proteins. The GlcA C5-epimerization is the only modification reaction in heparin/HS biosynthesis that cannot be reproduced without an enzyme catalyst [44]. 

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... 

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