Unique self-anhydride formation in the degradation of cytidine-5'-monophosphosialic acid (CMP-Neu5Ac) and cytidine-5'-diphosphosialic acid (CDP-Neu5Ac) and its application in CMP-sialic acid analogue synthesis.

Yasuhiro Kajihara, Sachiko Nishigaki, Daisuke Hanzawa, Go Nakanishi, Ryo Okamoto, Naoki Yamamoto

Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka 560-0043, Japan. kajihara@chem.sci.osaka-u.ac.jp

Chemistry (Weinheim an der Bergstrasse, Germany) 2011 Jun 27

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Sialyloligosaccharides are synthesised by various glycosyltransferases and sugar nucleotides. All of these nucleotides are diphosphate compounds except for cytidine-5'-monophosphosialic acid (CMP-Neu5Ac). To obtain an insight into why cytidine-5'-diphosphosialic acid (CDP-Neu5Ac) has not been used for the sialyltransferase reaction and why it is not found in biological organisms, the compound was synthesised. This synthesis provided the interesting finding that the carboxylic acid moiety of the sialic acid attacks the attached phosphate group. This interaction yields an activated anhydride between carboxylic acid and the phosphate group and leads to hydrolysis of the pyrophosphate linkage. The mechanism was demonstrated by stable isotope-labelling experiments. This finding suggested that CMP-Neu5Ac might also form the corresponding anhydride structure between carboxylic acid and phosphate, and this seems to be the reason why CMP-Neu5Ac is acid labile in relation to other sugar nucleotides. To confirm the role of the carboxylic acid, CMP-Neu5Ac derivatives in which the carboxylic acid moiety in the sialic acid was substituted with amide or ester groups were synthesised. These analogues clearly exhibited resistance to acid hydrolysis. This result indicated that the carboxylic acid of Neu5Ac is associated with its stability in solution. This finding also enabled the development of a novel chemical synthetic method for CMP-Neu5Ac and CMP-sialic acid derivatives. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Yasuhiro Kajihara, Sachiko Nishigaki, Daisuke Hanzawa, Go Nakanishi, Ryo Okamoto, Naoki Yamamoto. Unique self-anhydride formation in the degradation of cytidine-5'-monophosphosialic acid (CMP-Neu5Ac) and cytidine-5'-diphosphosialic acid (CDP-Neu5Ac) and its application in CMP-sialic acid analogue synthesis. Chemistry (Weinheim an der Bergstrasse, Germany). 2011 Jun 27;17(27):7645-55