Cytidine 5 -monophosphate sialic acid

Cytidine monophosphate-sialic acid synthetase (EC 2.7.7.43) catalyzes the activation of /V-acetylneuraminic acid (NANA) by CTP to form CMP-NANA. 

Wolf et al. reported the synthesis of cytidine-5 -monophosphate-sialic acid derivatives (70). The synthesis involves the reaction of cyclo-Sal-nucleotides with different phosphate nucleophiles. Cyc/o-Sal-nucleotides were also used to prepare monophosphate-linked sugar nucleotides in high yields. These compounds were used for enzymatic studies (bacterial polysialyltransferase) and the enzyme showed marked differences in utilising these compounds. 

A-Acetyl-9-deoxy-9-fluoroneuraminic acid (591) was prepared by treatment of a protected 6-hydroxyl precursor with A, A-diethylaminosulfur trifluoride (DAST) or through condensation of 2-acetamido-2,6-dideoxy-6-fluoro-D-mannopyranose with potassium di(/ >r/-butyl) oxaloacetate. Compound 591 is a substrate for cytidine monophosphate (CMP)-sialic acid synthetase, giving rise to CMP-5-A-acetyl-9-deoxy-9-fluoroneuraminic acid, which is cytotoxic against tumor cells. 5-A-Acetyl-3-fluoroneuraminic acids 592-594 were prepared through fluorine (or acetyl hypofluorite) addition (in AcOH) to methyl 5-acetamido-4,7,8,9-tetra-0-acetyI-2,6-anhy-dro-2,3,5-trideoxy-D- /ycm>D- a/arto-non-2-enopyranosate. Compound 592 was found to be a potent neuraminidase inhibitor. 

Fig. 4.3.2 Human sialic acid metabolism and genetic defects. -6P -6-Phosphate, -9P -9-phos-phate, CMP cytidine 5 -monophosphate, CTP cytidine 5 -triphosphate, UDP-GlcNAc uridine diphosphate-N-acetyl-D-glucosamine, ManNAc N-acetylmannosamine, NeuAc N-acetylneur-aminic acid, OGS oligosaccharides, SASD sialic acid storage disease...

Scheme L Synthesis of a2,64inked sialyl-N-acetyllactosamine using a one-pot multi-enzyme system with in situ regeneration of CMP-Neu5Ac. Abbreviations for enzymes CSS, CMP-sialic acid synthetase NMK, nucleoside monophosphate kinase PK, pyruvate kinase PPase, pyrophosphatase. Abbreviations for compounds PEP, phosphoenolpyruvate ADP, adenosine 5 -diphosphate ATP, adenosine 5 -triphosphate CMP, cytidine 5-monophosphate CDP, cytidine 5 -diphosphate CTP, cytidine 5-triphosphate LacNAc, N-acetyllactosamine NeuSAc, N-acetylneuraminic acid PPi, inorganic pyrophosphate.

Figure 11.22 Possible pathways for the synthesis of gangliosides. Cer, ceramide Glc, glucose Gal, galactose GalNAc, N-acetylgalactos-amine CMP, cytidine monophosphate NANA, A/-acetylneuraminic add (sialic acid) UDP, uridine diphosphate. Reproduced from Gurr and James (1980) with permission.

A similar approach has been used to prepare oligosaccharides that contain sialic acid (N-acetylneuraminic acid) (8). We saw earlier that sialic acid itself can be prepared using an aldolase reaction, and this forms the starting point for another cascade of enzyme-catalysed reactions. In this instance, sialic acid is firstly activated as its cytidine monophosphate (CMP) derivative via coupling with cytidine triphosphate (CTP) in the... 

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