N-Acetylneuraminic acid biosynthesis

S ATP + N-acetyl-D-mannosamine (<5> highly specific for ATP and N-acetyl-D-mannosamine [3] <4> metabolic pathway between hexoses and siahc acids [2] <4> enzyme is involved in sialic acid metabolism [5] <4> involved in N-acetylneuraminic acid metabolism, key enzyme in N-acetylneuraminic acid biosynthesis [6,9-11]) (Reversibility [1-12]) [1-12]... 

Hinderlich, S. Staesche, R. Zeitler, R. Reutter, W. A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epi-merase/N-acetyhnannosamine kinase. J. Biol. Chem., 272, 24313-24318 (1997)... 

Fig. 1.4.7. Early steps in combinatorial ganglioside biosynthesis [9]. The sites of (indirect) inhibition by 11 and 12 are indicated. Abbreviations Cer, ceramide, N-acylsphingosine Clc, glucose Gal, galactose GalNAc, N-acetylgalactosamine NeuAc, N-acetylneuraminic acid SAT, sialyltransferase GalNAcT, N-acetylgalactosaminyltransferase ...

The first enzymatic step involves the covalent attachment of the first carbohydrate unit to the side chain of a specific amino acid residue. Further sugar residues are added in sequential order by specific glycosyltransferases for each of the sugar residues. It appears that specific multienzyme systems are required for the biosynthesis of each type of polymer (153). Frequently the carbohydrate chain terminates with an N-acetylneuraminic acid residue. 

Figure 16.14 Biosynthesis of N-acetylneuraminic acid (sialic acid) from UDP-N-acetylglucosamine. 

A similar example is the biosynthesis of UDP-2-acetamido-2-deoxy-D-glucose and CMP-N-acetylneuraminic acid in rat liver.Here again, both sugars are needed for syntliesis of complex saccharides, and each sugar nucleotide inhibits the first enzyme of the pathway unique to its synthesis, as shown by the dotted arrows in the following Scheme. 

The transfer of the pyruvate unit as phosphoenolpyruvate (PEP) to aldoses results in 4-hydroxy-2-oxocarboxylic acid structures and constitutes an important natural C-C bond forming reaction for the biosynthesis of ulosonic [36] and sialic acids [37,38]. Important compounds such as N-acetylneuraminic acid, 3-de-oxy-D-manno-octulosonic acid (KDO), and 3-deoxy-D-araZ mo-2-heptulosonic acid 7-phosphate (DAHP), the precursor of shikimic acid, are formed in this way. 

CMP-N-acetylneuraminic acid is formed by a series of reactions which are outgrowths of the pathways of hexosamine biosynthesis. As seen from Fig. 8A, N-acetylmannosamine can be regarded as the first specific intermediate in the biosynthesis of the nucleotide sugar and may be formed by 2-epimerization from either UDP-N-acetylglucosamine or N-acetylglucosamine. The mechanisms of these two reactions have recently been investigated and will be discussed below. 

Warren, L., and H. Felsenfeld N-acetylmannosamine-6-phosphate on N-acetylneuraminic acid-9-phosphate as intermediates in sialic acid biosynthesis. Biochem. biophys. Res. Commun. 6, 185 (1961). 

Hinderlich S, Berger M, Keppler OT et al. (2001) Biosynthesis of N-acetylneuraminic acid in cells lacking UDP-N-acetylglucosamine 2-epimerase/N-acetyl-mannosamine kinase. Biol Chem 382 291-297. 

A key intermediate in the biosynthesis of glycoconjugates is the sugar nucleotide cytidine-5 -monophospho-N-acetylneuraminic acid (CMP-NeuSAc). To check its... 

Hagemeier, C., Vischer, P., and Buddecke, E. Studies on the biosynthesis of N-acetylneuraminic acid in cultured arterial wall cells. Biochem. Soc. Trans., 1986,14, 1173-1174. 

Warren, L., and Blacklow, R. S., 1962, The biosynthesis of cytidine-5 -monophospho-N-acetylneur-aminic acid by an enzyme from Neisseria meningitidis, J. Biol. Chem. 237 3527-3534. Warren, L., and Felsenfeld, H., 1961a, The biosynthesis of N-acetylneuraminic acid, Biochem. Biophys. Res. Commun. 4 232-235. 

Buscher, H.-R, Casals-Stenzel, J., Mestres-Ventura, R, and Schauer, R., 1977, Biosynthesis of N-glycoloylneuraminic acid in porcine submandibular glands. Subcellular site of hydroxylation of N-acetylneuraminic acid in the course of glycoprotein biosynthesis, Eur. J. Biochem. 77 297-310. 

Kawano, T., Kozutsumi, Y, Takematsu, H., Kawasaki, T., and Suzuki, A., 1993a, Regulation of biosynthesis of N-glycolylneuraminic acid-containing glycoconjugates Characterization of factors required for NADH-dependent cytidine 5 -monophosphate-N-acetylneuraminic acid hy-droxylation, Glycoconj. J. 10 109-115. 

Muchmore, E. A., Milewski, M., Varki, A., and Diaz, S., 1989, Biosynthesis of N-glycolylneur-aminic acid The primary site of hydroxylation of N-acetylneuraminic acid is the cytosolic sugar nucleotide pool, J. Biol. Chem. 264 20216-20223. 

Schoop, H. J., Schauer, R., and Faillard, H., 1969, Biosynthesis of N-glycolylneuraminic acid. Oxidative conversion of N-acetylneuraminic acid to N-glycolylneuraminic acid, Z. Physiol. Chem. 350 155. 

Troy, F. A., Vijay, I., and Tesche, N., 1973, Lipid-bound N-acetylneuraminic acid (N-AN) as a precursor in the biosynthesis of sialyl polymers in E. coli. Fed. Proc. 32 481. 

Schauer, R., 1970c, Biosynthesis of N-acetylneuraminic acids I Incorporation of [ C] acetate into slices of the submaxillary salivary glands of ox and horse, Hoppe-Seyl. Z. 351 595-602. 

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