Metabolic Conversion of ManNAc Analogs to Cell Surface Sialosides

The notion that unnatural analogs of ManNAc might be metabolized to sialic acids in living cells was first explored in the 1970s. Initial studies of the sialic acid bio-synthetic pathway focused on the inhibitory properties of metabolic precursors [62,149,150]. It was discovered that some ManNAc analogs, while exhibiting a degree of toxicity to the cells, competed with native ManNAc and were incorporated into the sialic acid biosynthetic pathway. This finding, along with the earlier knowledge that cells can take up exogenous ManNAc and convert it into sialic acid [117,151], opened up many possibilities for cell surface modification. Figure 11 shows the different ManNAc analogs that have been successfully metabolized by cells and converted into cell surface sialosides. For example, peracetylated N-trifluo-roacetyl ManN, although toxic to cells at high micromolar concentrations, competed with ManNAc in glycoconjugate biosynthesis [62].

The expression of metabolically modified sialic acids on the cell surface has been used to modulate several biological processes. Schmidt et al. showed that N-propanoylmannosamine (ManProp), which is metabolized to SiaProp, stimulates proliferation in specific cells found in the rat central nervous system (CNS) [152]. Incubation of cells from neonatal rat brain with ManProp successfully stimulated proliferation of astrocytes and microglia, but not of oligodendrocyte progenitor cells in culture. The basis for this proliferation is unclear, since all cells examined converted ManProp into cell surface SiaProp. Similarly, human diploid fibroblast cells grown with ManProp, N-butanoylmannosamine (ManBut), or N-pentanoylmannosa-mine (ManPent) lost their sensitivity to contact inhibition of growth [153].

Virus-receptor interactions have also been shown to be affected by these ManN derivatives [154,155]. Treatment of human B-lymphoma BJA-B cells or African green monkey kidney epithelium cells with either ManProp, ManBut, or ManPent resulted in structural modification of about 50% of total cell surface sialic acids. Polyoma viruses, which use sialic acids as ligands for binding prior to infection, show either reduced or enhanced ability to infect cells carrying these modified sialic

Figure 11 ManNAc derivatives that are metabolically converted to the corresponding cell surface sialic acid analogs in mammalian cells.

Figure 11 ManNAc derivatives that are metabolically converted to the corresponding cell surface sialic acid analogs in mammalian cells.

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