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)... 

Figure 24-9. Biosynthesis of gangliosides. (NeuAc, W-acetylneuraminic acid.)...

Example 5 Hayakawa and Noyori group in their studies on new activators for phosphoroamidite coupling reactions have applied the most effective member of the group of acid/azole complexes AT-(phenyl)imidazolium tri-flate (N-PhIMT) in the efficient synthesis of biologically important compounds [20j]. A noteworthy example is synthesis of cytidine-5 -monophos-pho-AT-acetylneuraminic acid. This compound is a source of sialic acid in the sialyltransferase-catalysed biosynthesis of sialyl oligosaccharides [25]. 

Outline of biosynthesis of some glycosphingolipids. (Glc = glucose, Gal = galactose, GalNAc = A-acetylgalactosamine, NeuAc = w-acetylneuraminic acid. 

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 ...

Fig. 15. Biosynthesis of CMP-A -glycolylneuraminic acid with the aid of CMP-At-acetylneuraminic acid monooxygenase in the cytosol, translocation of CMP-Neu5Gc into the Golgi vesicle and transfer of the NeuSGc moiety onto nascent glycoconjugates [188,654,684]. From ref [690] by permission of Oxford University Press, Oxford.

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. 

Szabo and his colleagues have prepared 3-deoxy-D-crj f/iro- and U-threo-hcx-2-ulosonic acid 5-phosphate in the ratio 2 1 as illustrated in Scheme 1. The products were isolated in 37 and 23% yield, respectively, as their magnesium salts.In parallel fashion, Russian workers have developed a synthesis of 3-deoxyaldulosonic acids as depicted in Scheme Studies by n.m.r. spectroscopy of ot- and /3-A-acetylneuraminic acid derivatives and determination of /c-i-H-3 e values allowed the conclusion that, in cytidine 5-phospho-iV-acetyl-neuraminic acid, a key intermediate in the biosynthesis of glyconoconjugates, the neuraminic acid moiety has the 3-configuration. ... 

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). 

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