Synthesis of Glycosaminoglycans

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Chapter: Biochemistry : Glycosaminoglycans, Proteoglycans, and Glycoproteins

The heteropolysaccharide chains are elongated by the sequential addition of alternating acidic and amino sugars donated by their uridine diphosphate (UDP)-derivatives.


The heteropolysaccharide chains are elongated by the sequential addition of alternating acidic and amino sugars donated by their uridine diphosphate (UDP)-derivatives. The reactions are catalyzed by a family of specific glycosyltransferases. The synthesis of GAGs is analogous to that of glycogen except that GAGs are produced for export from the cell. Their synthesis occurs, therefore, primarily in the Golgi, rather than in the cytosol.


A. Synthesis of amino sugars

Amino sugars are essential components of GAGs, glycoproteins, and glycolipids and are also found in some antibiotics. The synthetic pathway of amino sugars is very active in connective tissues, where as much as 20% of glucose flows through this pathway.


1. N-Acetylglucosamine and N-acetylgalactosamine: The monosaccharide fructose 6-phosphate is the precursor of N-acetyl-glucosamine (GlcNAc), N-acetylgalactosamine (GalNAc), and the sialic acids, including N-acetylneuraminic acid (NANA). In each of these sugars, a hydroxyl group of the precursor is replaced by an amino group donated by glutamine (Figure 14.8). [Note: The amino groups are then almost always acetylated.] The UDP-derivatives of GlcNAc and GalNAc are synthesized by reactions analogous to those described for UDP-glucose synthesis. These nucleotide sugars are the activated forms of the monosaccharides that can be used to elongate the carbohydrate chains.

Figure 14.8 Synthesis of the amino sugars. UTP = uridine triphosphate; UDP = uridine diphosphate; CoA = coenzyme A; PEP = phosphoenoylpyruvate; CTP = cytidine triphosphate; CMP = cytidine monophosphate; PPi = pyrophosphate.


2. N-Acetylneuraminic acid: NANA, a nine-carbon, acidic monosaccharide, is a member of the family of sialic acids, each of which is acylated at a different site. These compounds are usually found as terminal carbohydrate residues of oligosaccharide side chains of glycoproteins; glycolipids; or, less frequently, of GAGs. The carbons and nitrogens in NANA come from N-acetylmannosamine and phosphoenolpyruvate (an intermediate in the glycolytic pathway;). [Note: Before NANA can be added to a growing oligosaccharide, it must be converted into its active form by reacting with cytidine triphosphate (CTP). The enzyme CMP-NANA synthetase catalyzes the reaction. This is the only nucleotide sugar in human metabolism in which the carrier nucleotide is a monophosphate.]


B. Synthesis of acidic sugars

D-Glucuronic acid, whose structure is that of glucose with an oxidized carbon 6 (– CH2OH → –COOH) and its C-5 epimer, L-iduronic acid, are essential components of GAGs. Glucuronic acid is also required in detoxification reactions of a number of insoluble compounds, such as bilirubin, steroids, and many drugs, including the statins. In plants and mammals (other than guinea pigs and primates, including humans), glucuronic acid serves as a precursor of ascorbic acid (vitamin C). The uronic acid pathway also provides a mechanism by which dietary D-xylulose can enter the central metabolic pathways.


1. Glucuronic acid: Glucuronic acid can be obtained in small amounts from the diet. It can also be obtained from the lysosomal degradation of GAGs, or from glucose 6-phosphate via the uronic acid pathway. The end product of glucuronic acid metabolism in humans is D-xylulose 5-phosphate, which can enter the pentose phosphate pathway and produce the glycolytic intermediates glyceraldehyde 3-phosphate and fructose 6-phosphate (Figure 14.9; see also Figure 13.2). The active form of glucuronic acid that donates the sugar in GAG synthesis and other glucuronidation reactions is UDP-glucuronic acid, which is produced by oxidation of UDP-glucose (Figure 14.10).

Figure 14.9 Metabolism of glucuronic acid. NADPH = reduced nicotinamide adenine dinucleotide phosphate.

Figure 14.10 Oxidation of UDP-glucose to UDPglucuronic acid. NAD(H) = nicotinamide adenine dinucleotide.


2. L-Iduronic acid synthesis: Synthesis of L-iduronic acid residues occurs after D-glucuronic acid has been incorporated into the carbohydrate chain. Uronosyl 5-epimerase causes epimerization of the D- to the L-sugar.


C. Synthesis of the core protein

The core protein is synthesized by ribosomes on the rough endoplasmic reticulum (RER) and enters the RER lumen. The protein is then glycosylated by membrane-bound glycosyltransferases located in the Golgi.


D. Synthesis of the carbohydrate chain

Carbohydrate chain formation begins by synthesis of a short linkage region on the core protein on which carbohydrate chain synthesis will be initiated. The most common linkage region is formed by the transfer of a xylose from UDP-xylose to the hydroxyl group of a serine (or threonine) catalyzed by xylosyltransferase. Two galactose molecules are then added, completing the trihexoside. This is followed by sequential addition of alternating acidic and amino sugars (Figure 14.11) and epimerization of some D-glucuronyl to L-iduronyl residues.


E. Addition of sulfate groups

Sulfation of a GAG occurs after the particular monosaccharide to be sulfated has been incorporated into the growing carbohydrate chain. The source of the sulfate is 3’-phosphoadenosyl-5’-phosphosulfate ([PAPS], a molecule of adenosine monophosphate with a sulfate group attached to the 5’-phosphate). The sulfation reaction is catalyzed by sulfotransferases. [Note: An example of the synthesis of a sulfated GAG, chondroitin sulfate, is shown in Figure 14.11.] PAPS is also the sulfur donor in glycosphingolipid synthesis.


A defect in the sulfation of the growing glycosaminoglycan chains results in one of several autosomal recessive disorders, the chondrodystrophies, that affect the proper development and maintenance of the skeletal system.

Figure 14.11 Synthesis of chondroitin sulfate.

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