Biosynthesis of Complex Carbohydrates

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reaction involves epimerization of UDP­N­acetylglucosamine by a 2­epimerase to N­acetylmannosamine, concomitant with elimination of UDP. Since the monosaccharide product is no longer bound to nucleotide, this epimerization is clearly different from those previously encountered. Most likely, this 2­epimerase reaction proceeds by a trans elimination of UDP, with formation of the unsaturated intermediate, 2­acetamidoglucal. In mammalian tissues N­acetyl­mannosamine is phosphorylated by ATP to N­acetylmannosamine 6­phosphate, which then condenses with phosphoenolpyruvate to form N­acetylneuraminic acid 9­phosphate. This product is cleaved by a phosphatase and activated by CTP to form the CMP derivative, CMP­N­acetylneuraminic acid. This is an unusual nucleotide sugar, containing only one phosphate group, and is formed by an irreversible reaction. N­Acetylneuraminic acid is a precursor of other sialic acid derivatives, some of which evolve by modification of N­acetyl to N­glycolyl or O­acetyl after incorporation into glycoprotein.
8.4— Biosynthesis of Complex Carbohydrates
In complex carbohydrate­containing molecules, sugars are linked to other sugars by glycosidic bonds, formed by specific glycosyltransferases. Energy is required for synthesis of a glycosidic bond and is derived from nucleotide sugars as donor substrates. A glycosyltransferase reaction proceeds by donation of the glycosyl unit from the nucleotide derivative to the nonreducing end of an acceptor sugar. The nature of the bond formed is determined by the specificity of the glycosyltransferase, which is unique for the sugar acceptor, the sugar transferred, and the linkage formed. Thus polysaccharide synthesis is controlled by a nontemplate mechanism directed by specific glycosyltransferases. A glycosyltransferase reaction is summarized as follows:
At least 40 different glycosidic bonds have been identified in mammalian oligosaccharides and about 15 more in connective tissue polysaccharides. The number of possible linkages is even greater and arises both from the diversity of monosaccharides covalently bonded and from the formation of both a and b
CLINICAL CORRELATION 8.5 Glucuronic Acid: Physiological Significance of Glucuronide Formation
The biological significance of glucuronic acid extends to its ability to be conjugated with certain endogenous and exogenous substances, forming a group of compounds collectively termed glucuronides in a reaction catalyzed by UDP­glucuronyltransferase. Conjugation of a compound with glucuronic acid produces a strongly acidic compound that is more water soluble at physiological pH than its precursor and therefore may alter the metabolism, transport, or excretion properties. Glucuronide formation is important in drug detoxification, steroid excretion, and bilirubin metabolism. Bilirubin is the major metabolic breakdown product of heme, the prosthetic group of hemoglobin. The central step in excretion of bilirubin is conjugation with glucuronic acid by UDP­
glucuronyltransferase. Development of this conjugating mechanism occurs gradually and may take several days to 2 weeks after birth to become fully active in humans. So­called physiological jaundice of the newborn results in most cases from the inability of the neonatal liver to form bilirubin glucuronide at a rate comparable to that of bilirubin production. A defect in glucuronide synthesis has been found in a mutant strain of Wistar ("Gunn") rats, due to a deficiency of UDP­glucuronyltransferase and results in hereditary hyperbilirubinemia. In humans a similar defect is found in congenital familial nonhemolytic jaundice (Crigler–Najjar syndrome). Patients with this condition are also unable to conjugate foreign compounds efficiently with glucuronic acid.
Crigler, J. F., and Najjar, V. A. Congenital familial non­hemolytic jaundice with kernicterus. Pediatrics 10:169, 1952; Gunn, C. H. Hereditary acholuric jaundice in a new mutant strain of rats. J. Hered. 29:137, 1938; and Ostrow, J. D. (Ed.). Bile Pigments and Jaundice. New York: Marcel Dekker, 1986.
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Figure 8.8 Biosynthesis of CMP­N­acetylneuraminic acid.
linkages, with each of the available hydroxyl groups on the acceptor saccharide. The large and diverse number of molecules that can be generated suggests that oligosaccharides have the potential for great informational content. In fact, it is known that the specificity of many biological molecules is determined by the nature of the composite sugar residues. For example, the specificity of the major blood types is determined by sugars (see Clin. Corr. 8.6). N­Acetylgalactosamine is the immunodeterminant of blood type A and galactose of blood type B. Removal of N­acetylgalactosamine from type A erythrocytes, or of galactose from type B erythrocytes, converts both to type O erythrocytes. Increasingly, other examples of sugars as determinants of specificity for cell surface receptor and lectin interactions, targeting of cells to certain tissues, and survival or clearance from the circulation of certain molecules are being recognized. All glycosidic bonds identified in biological compounds are degraded by specific hydrolytic enzymes, glycosidases. In addition to being valuable tools for the