Heparin biosynthesis

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. 

Heparan-sulphate was isolated for the first time as a byproduct of commercial heparin isolation in 1948 and described as a low sulphated heparin by Jorpes and Gardell. During its early stage some researchers thought heparan-sulphate to represent a new class of glycosaminoglycans. Others supposed it to be an intermediate of the heparin-biosynthesis. ... 

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.)...

Various aspects of this progress have been discussed in the Proceedings of specialized symposia2 3 4 5 6 and in a book.7 Reviews dealing with the structure and biosynthesis,8 pharmacology,9-10 11 12 and molecular biology11,12 of heparin are available. 

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-... 

U Lindahl, DS Feingold, L Roden. Biosynthesis of heparin. TIBS 11 221-225, 1986. 

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... 

An important question in proteoglycan biosynthesis is how different GAGs (DS, CS, HS, and heparin) are assembled starting from the common tetrasaccharide structure. The precise molecular mechanisms, namely, whether it is the... 

Fibrinogen Biosynthesis by Isolated Liver. In our isolated rat liver perfusion studies homologous heparinized oxygenated rat blood is routinely diluted with Ringer s solution, so that its final volume is in-... 

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

Figure 5 Biosynthesis and structure of glycosaminoglycans. Synthesis u GlcAT-l. The repeating disaccharides of heparin/HS, CS, and DS are shown.

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