Sialic acid biosynthesis

FIGURE 10. The alternative pathways for mucin biosynthesis. Sialic acid addition prevents further sugar additions. Wavy line represents polypeptide backbone of submaxillary mucin. 

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]. 

The pathway of the biosynthesis of Neu5Ac demonstrates the origin of sialic acids from the cellular hexose and hexosamine pools. These sugars are, therefore, suitable components for the study of the biosynthesis of sialic acid. However, only ManNAc has been shown to be a relatively specific precursor of sialic acids, as may be seen from the distribution of radioactivity between the individual monosaccharides of glycoconjugates after incubation. Injections of radioactive ManNAc into animals, or incubation of surviving tissue slices or individual cells with this compound, give incorporation of label mainly into the sialic acids.226 227... 

Nonphysiological compounds have also been described as influencing the overall metabolism of sialic acid. Administration of ethanol (2 g/kg) to rats significantly decreases the sialic acid content of brain tissue.246 Convulsions induced by pentylenetetrazole (6,7,8,9-tetrahy-dro-5/f-tetrazoloazepine) are accompanied by a diminution in the rate of biosynthesis of polysialogangliosicles GT, and GQn, in rat brain.227 Such ManNAc analogs as 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D-mannopyranose or the 2-(trifluoroacetamido) derivative lead to a marked lowering of the incorporation of radioactivity from labelled ManNAc into glycoconjugate sialic acids of murine, erythroleukemia (Friend) cells.247... 

In contrast to the biosynthesis of Neu5Ae, the pathways leading to the many other sialic acids known have not yet been completely elucidated. Insight has, however, been obtained into the biosynthesis of Neu5Gc and the 4-0- and 9-O-acetylated sialic acids. 

Nothing is yet known concerning the formation of lactvl groups found at 0-9 of sialic acids from different sources, reported in Section II. This is also true of the biosynthesis of methyl ether and sulfuric ester groups occurring in some natural sialic ac ids. 

Three different rare genetic metabolic defects in sialic acid metabolism are known, as indicated in Fig. 4.3.2 [3, 21] (1) free sialic acid storage disease (SASD Online Mendelian Inheritance in Man, OMIM 604369, 269920), a lysosomal membrane transporter defect (2) sialuria (OMIM 269921), a feedback inhibition defect in sialic acid biosynthesis (3) sialidosis (OMIM 256550), a breakdown defect of sialyloli-gosaccharides caused by a defect of lysosomal sialidase. In all these genetic defects, an increased amount of sialic acid can be found in tissues and or body fluids, either bound to OGSs as in (3), or in its free state as in (1) and (2). 

Exposure of HeLa cells to butyrate had no effect on the activity of GM3-sialidase when GM3 specifically labeled in the sialic acid residue was used as substrate (Fig. 3a). We were unable to detect any "ecto"-sialidase activity in either control or butyrate-treated cells (14) although others have postulated that such an enzyme is important in regulating plasma membrane gangliosides (15,16). In contrast, the activity of the specific sialyl transferase involved in GM3 biosynthesis increased over 20-fold following butyrate treatment (Fig. 3b). The effect was specific as activities of the other glycosphingolipid transferases that could be measured in HeLa cells were not altered in butyrate-treated cells (4,8,17). 

In contradistinction to sialic acids,1 2 little is known about biosynthesis of 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Some data are available on biosynthesis of derivatives of pseudaminic acid16 and legionaminic acid47 in human pathogens C. jejuni and L. pneumophila. 

Based on these findings, it is likely that ORFs 23, 24, and 25 encode enzymes that play a role in biosynthesis and polymerization of legionaminic acid and that the biosynthetic pathway is similar to that of bacterial sialic acid-containing polysaccharides.1 ORFs that encode putative legionaminic acid transferase or polymerase were not found in the 32.6-kb locus. 

The data presented here demonstrate that lectins may be used to explore structural aspects of the carbohydrate moieties of specific cell surface bound antigens. Furthermore, it is suggested that the H-2D antigen possesses differences in the structure of the carbohydrate moieties which may reflect microheterogeneity due to the biosynthesis of only partial structures, differences in the number of sialic acid residues, the relationship of the carbohydrate chains to the specific antigenic determinants and/or major structural differences of the carbohydrate chains on different H—2D antigens. 

N-acetylglucosamine (see Chapter 9) is a component of glycoproteins, connective tissue proteoglycans, and complex lipids. It may be synthesized in the human organism from fructose-6-phosphate, as indicated in Figure 18.17. N-acetylglucosamine is also a precursor of N-acetylmannosamine, which along with pyruvic acid participates in the biosynthesis of sialic acid. 

---