1. Glucuronic acid: Glucuronic acid can be obtained in small amounts from the diet and from the lysosomal degradation of GAG. It also can be synthesized by the uronic acid pathway, in which glucose 1-phosphate reacts with uridine triphosphate (UTP) and is converted to UDP-glucose. Oxidation of UDP-glucose produces UDP-glucuronic acid, the form that supplies glucuronic acid for GAG synthesis and glucuronidation (Fig. 14.10). The end product of glucuronic acid metabolism in humans is Dxylulose 5-phosphate, which can enter the pentose phosphate pathway and produce the glycolytic intermediates glyceraldehyde 3-phosphate and fructose 6-phosphate (see Fig. 14.9; see also Fig. 13.2, p. 146).
2. l-Iduronic acid: Synthesis of L-iduronic acid occurs after D-glucuronic acid has been incorporated into the carbohydrate chain. Uronosyl 5epimerase causes epimerization of the D-to the L-sugar.
C. Core protein synthesis
The core protein is made by ribosomes on the rough endoplasmic reticulum (RER), enters the RER lumen, and then moves to the Golgi, where it is glycosylated by membrane-bound glycosyltransferases.
D. Carbohydrate chain synthesis
Carbohydrate chain formation is initiated by synthesis of a short linker on the core protein on which carbohydrate chain synthesis will occur. The most common linker is a trihexoside 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 (Fig. 14.11) and epimerization of some D-glucuronyl to Liduronyl residues.
E. Sulfate group addition
Sulfation of a GAG occurs after the 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; see Fig. 17.16, p. 210). The sulfation reaction is catalyzed by sulfotransferases. Synthesis of the sulfated GAG chondroitin sulfate is shown in Figure 14.11. [Note: PAPS is also the sulfur donor in glycosphingolipid synthesis (see p. 210).]
A defect in the sulfation of the growing GAG chains results in one of several autosomal-recessive disorders, the chondrodystrophies, which affect the proper development and maintenance of the skeletal system.
IV. DEGRADATION
GAG are degraded in lysosomes, which contain hydrolytic enzymes that are most active at a pH of ~5. Therefore, as a group, these enzymes are called acid hydrolases. [Note: The low pH optimum is a protective mechanism that prevents the enzymes from destroying the cell should leakage occur into the cytosol where the pH is neutral.] The half-lives of GAG vary from minutes to months and are influenced by the type of GAG and its location in the body.
A. GAG phagocytosis