Sialyltransferases inhibition

CMP, CDP, CTP, and synthetic derivatives of these nueleotides have been found to inhibit sialyltransferase activity.301" 02 Interest in such inhibitors is increasing, as they may be expected to serve as anticancer agents.269 901,303 Therefore, regulation of Golgi sialyltransferase activity appears possible by nucleotides as products of sialyl- and other glycosyl-transferase activities.1" 2 Interestingly, Epstein-Barr virus infection of human B, lymphoblastoid cell-lines leads to a diminution of sialyltransferase activity.304... 

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 cascade begins with stoichiometric amounts of phosphoenolpyruvate (PEP), 8-allyl-A-acetyl lactosamine 120, NeuAc 1, and catalytic quantities of ATP and CMP. Initially, CMP is converted to CDP by nucleoside monophosphate kinase (NMK) in the presence of ATP. The CDP produced reacts with PEP under pyruvate kinase (PK) catalysis to form CTP. Next, CMP-NeuAc synthetase catalyzes the in situ formation of the sialyl donor from NeuAc and CTP. The pyrophosphate byproduct is decomposed to inorganic phosphate by inorganic pyrophosphatase (PPase). Subsequently, the a-2,6-sialyltransferase accomplishes the sialyation of the lactosamine acceptor 120 and produces the ttansferase inhibitor CMP as a by-product. The CMP concentrations are kept low by conversion to CDP, and in so doing the problem of product inhibition is minimized. The cycle afforded 21% of the sialylated ttisac-charide 121, which is remarkable considering the complexity of the system and number of synthetic steps that can be avoided. 

This compound inhibits 3-galactoside 0-2,6-sialyltransferase from bovine colostrum with a K of 0.025 mM [647]. 

Among the most relevant and well-studied parasite glycotopes ate the sialic acid group of sugars and their derivatives. Expression of surface terminal sialic acid and its derivative is due to the interplay between several enzymes namely sialidases, sialyltransferases, O-acetyl transferase and O-acetyl esterase. Therefore, synthetic analogues design to inhibit their expression appears to be an attractive treatment protocol. 

The incorporation of A-acetylneuraminic acid from the CMP-nucleotide derivative into neuraminidase-treated human lipoproteins of very low density was catalysed by preparations from porcine liver microsomes. The activity of the CMP-A -acetylneuraminic acidiglycoprotein sialyltransferase present in rat-liver microsomes has been shown to be stimulated by UDP, but to be inhibited by CMP. The functions of glycosyltransferases in the processes of recognition and binding of asialoglycoproteins in liver have been investigated. ... 

Inhibition of enzyme activity may be due to substrate, product or other effector molecules, and the concentrations of these components in the cell may lead to regulation of the pathway. Competitive product inhibition has been ascribed a significant role in sialyltransferase reactions (Bernacki 1975, Klohs et al. 1979, Eppler et al. 1980 b) with CMP yielding apparent Kj values of 50 (xM (Klohs et al. 1979). This inhibition may be a self-regulatory effect in situ in view of the high nucleotide phosphatase activity of Golgi apparatus. A non-competitive inhibition of sialyltransferase activity was also observed with other nucleotides (Bernacki et al. 1978, Klohs et al. 1979). 

Sun, H., Yang, J., Amaral, K.E. and Horenstein, B.A. (2001) Synthesis of a new transition-state analogue of the sialyl donor. Inhibition of sialyltransferases. Tetrahedron Letters, 42, 2451-2553. 

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