Heparin sulfate biosynthesis

Sasisekharan R, Venkataraman G. Heparin and heparan sulfate biosynthesis, structure and function. Cutr. Opin. Chem. Biol. 2000 4 626-631. 

Funderburgh JL. Keratan sulfate biosynthesis. lUBMB Life 2002 54 187-194. Sugahara K, Yamada S, Yoshida K, de Waard P, Vliegenthart JF. A novel sulfated structure in the carbohydrate-protein linkage region isolated from porcine intestinal heparin. J Biol Chem 1992 267 1528-1533. 

That there is a similarity between heparan sulfate (formerly known as heparin sulfate, etc.) and heparin, as may be supposed from the suggestion in the name, in that the former is a further sulfated version of the latter, is incorrect. Aldiough heparan sulfate appears to have backbone carbohydrate structures identical or similar to those of heparin, it differs from heparin in its A -sulfate and N-acetate contents, the location of its biosynthesis (see Section 4.6), and in its manifestation (see, e.g., Section 7.6, pp. 60-61). 

In view of the observations discussed above, it is thus possible that the initial stages of heparin and heparan sulfate biosynthesis are identical. Subsequent modifications of the product would then occur in the form of partial removal of the protein moiety and substitution of iV-sulfate groups for A -acetjd groups. The extent of these modifications may be a function... 

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]. 

Figure 48-9. Structure of heparin. The polymer section illustrates structural features typical of heparin however, the sequence of variously substituted repeating disaccharide units has been arbitrarily selected. In addition, non-O-sulfated or 3-0-sulfated glucosamine residues may also occur. (Modified, redrawn, and reproduced, with permission, from Lindahl U et al Structure and biosynthesis of heparin-like polysaccharides. Fed Proc 1977 36 19.)...

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... 

Some of the polysaccharides constituting intermediate stages in the biosynthesis of heparin have been physically isolated.23 Their structure is strikingly similar to those of heparan sulfates,24 thus re-opening the often-raised question as to whether heparan sulfate indeed represents products of incomplete biosynthesis of heparin. A detailed account of the structure and biological properties of heparan sulfate is beyond the scope of this article. However, in view of similarities of structural fea-... 

Enzymic transfer of D-xylose from uridine 5 -(D-xylopyranosyI-HC pyrophosphate) to L-serine residues of endogenous protein acceptors from (a) a cell tumor of the mouse188 and (b) chick-embryo cartilage189 occurs in cell-free extracts of both of these tissues, in the absence of biosynthesis of protein. The enzyme preparations employed were from the supernatant liquor, although activity was also present in the insoluble fractions. In these two types of tissue, the acceptors are heparin and chondroitin sulfate, respectively, but the presence of other D-xylose-containing glycoproteins in ascites fluid from... 

An understanding of the structures of the molecules of heparin and heparan sulfate has come, in part, from studies with degradative enzymes, but also with biosynthetic enzymes. Both polysaccharides are based on the disaccharide unit which, in the initial stage of biosynthesis, consists of... 

Kim B-T, Kitagawa H, Tamura J-i, Saito T, Kusche-Gullberg M, Lindahl U, et al. Human tumor suppressor EXT gene family members EXTLl and EXTL3 encode a-1,4-V-acetylglucos-aminyltransferases that likely are involved in heparan sulfate/ heparin biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 2001 98 7176-7681. 

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