Sialic acid metabolism

Asymmetric C-C bond formation is the most important and most challenging problem in synthetic organic chemistry. In Nature, such reactions are facilitated by lyases, which catalyze the addition of carbonucleophiles to C=0 double bonds in a manner that is classified mechanistically as an aldol addition [1]. Most enzymes that have been investigated lately for synthetic applications include aldolases from carbohydrate, amino acid, or sialic acid metabolism [1, 2]. Because enzymes are active on unprotected substrates under very mild conditions and with high chemo-, regio-, and stereoselectivity, aldolases and related enzymes hold particularly high potential for the synthesis of polyfunctionalized products that are otherwise difficult to prepare and to handle by conventional chemical methods. 

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). 

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...

Table 4.3.1 Disorders of sialic acid metabolism with storage of sialic acid, clinical, and biochemical discrimination. ISSD Infantile sialic acid storage disease, OGS oligosaccharide, SASD free sialic acid storage disease...

The neuraminidases together with gangliosides have been localized in the nerve ending structures (6, 7 ). Theoretically the sialylation and desialylation cycle may mediate a cyclic reaction at a very important locale in a nerve synaptic structure. This hypothetical involvement of sialic acid metabolism in synaptic transmission has gained support from several studies which have suggested a synaptic localization of the glycosyltransferases (8, 9,10,11) and from proposed theoretical models in which the sialo-glycolipids are considered an important constituent in the functional units of neuronal membranes (12,13,14). 

The extensive manipulations which have been carried out on sialic acids themselves have been reviewed b) Tupp) and Gottschalk [63], Holmquist [101], Vliegenthart and Kammerling [102], in detail by Zbiral [4], and recently by von Itzstein and Kiefel [103]. This account will therefore give an overview of the transformations which have been carried out, resulting in modification at every carbon of NeuSAc. The derivatives prepared have been used to probe the requirements of sialic acid-recognising proteins, in particular the enzymes involved in sialic acid metabolism such as CMP-sialate synthase, sialidases, and NeuSAc aldolase. 

Free sialic acids are used by the enzymes of sialic acid metabolism, CMP-sialate synthase and Neu5Ac aldolase. However the majority of sialic acid-metabolising and -recognising proteins interact with glycosidically bound sialic acid. There-... 

Cardenas A, Bernard AM, Lauwerys R. Disturbance of sialic acid metabolism by chronic cadmium exposure and Its relation to proteinuria.Toxicol AppI Pharmacol 1991 108 547-558. 

Sialidases are enzymes that catalyze the removal of terminal sialic acids from sialosides (56, 57). Human sialidases play pivotal roles in sialic acid metabolism (58). They relate to a number of disease states such as sialidosis (59-62) and cancer (63-65). Bacterial and viral play significant roles in the pathogenesis and pathology of bacterial and viral infections (66, 67). Viral sialidases such as neuraminidases of influenza virus catalyze the removal of sialic acid from the surface of infected host cells to release the newly formed progeny virus (68). 

MOE was pioneered with the sialic acid biosynthetic pathway [15], which has proved to be especially amenable at accommodating the flux of nonnatural metabolic intermediates. This path converts (V-acetyl-D-mannosamine (ManNAc) into the nine-carbon sugar sialic acid through condensation with phospho-enolpyruvate and then installs the cytidine monophosophate (CMP)-derivatized form of this sugar onto the termini of newly synthesized glycans by the action of one of 20 sialyltransferases (see refs. 16 to 18 for more information on sialic acid metabolism). Almost two decades of experiments have established... 

Kontou, M., Bauer, C., Reutter, W., Horstkorte, R. (2008). Sialic acid metabolism is involved in the regulation of gene expression during neuronal differentiation of PC12 cells. Glycoconjug. J., 25, 237-244. 

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]... 

Corfield, A.P. Rainey, J.B. Clamp, J.R. Wagner, S.A. Changes in the activity of the enzymes involved in sialic acid metabolism in isolated rat colonic mucosal cells on administration of azoxymethane. Biochem. Soc. Trans., 11, 766-767 (1983)... 

Luchansky SJ, Yarema KJ, Takahashi S, Bertozzi CR. (2003) GlcNAc 2-epimerase can serve a catabolic role in sialic acid metabolism. J Biol Chem 278, 8035-8042. 

It is noteworthy that some low organisms like a few bacterial and protozoan species possess sialic acids. This may help these parasites to survive in the host. For a similar reason it may be advantageous for some microorganisms to have at their disposal catabolic enzymes of sialic acid metabolism like sialidase and N-acetylneuraminate lyase. Strikingly, many of these organisms are pathogenic for mammals. It could well be that sialidase is required for a faster spreading of... 

Fig. 2. Mammalian sialic acid metabolism. The formation and interconversions of the sialic acids continuing Fig. 1 from UDP-GlcNAc and GlcNAc. Acylneuraminic acids (NeuAcyl) include Neu5Ac, Neu5Gc and O-acyl derivatives. CMP-NeuAcyl and the corresponding acylmannosamines (ManAcyl) are indicated in the same way.----------- Anabolic reactions ------- catabolic reactions X-, acceptor complex carbohydrate for sialyltransfer.

An area of great interest in the field of sialic acid metabolism has been and remains that of sialyltransfer. The literature on this single aspect of sialic, acid... 

The importance of CMP-Neu5Ac hydrolase in sialic acid metabolism has not yet been assessed. The occurrence in the plasma membranes, separated from the site of CMP-Neu5Ac synthesis (nucleus) or consumption (Golgi membranes), and the observation that the enzyme is feedback-inhibited by UDP-GlcNAc, are indications that a close integration of this enzyme in sialic acid metabolism exists. 

The discovery of a number of metabolic diseases involving defective sialic acid metabolism, partially due to sialidase activity deletion or reduction, has been invaluable in pinpointing areas of importance for future study. These disorders called sialidoses are discussed in chapter K. 

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