Figure 1

Systems and molecular complexity in glycobiology. (a) The glycosylation machinery consists of an intricate network of metabolic pathways that interconvert monosaccharides and produce high-energy sugar nucleotides (full details of the pathways are available in [9]). The hexosamine pathway [46] that converts glucosamine (1) to UDP-N-acetylglucosamine (UDP-GlcNAc) (2) is highlighted in blue. The versatility of the glycosylation machinery is epitomized by the conversion of UDP-GlcNAc into N-acetylmannosamine (ManNAc) (3), a sugar that is metabolically converted to CMP-sialic acid (CMP-Sia; 4) by the pathway highlighted in red. UDP-GlcNAc and CMP-Sia, together with seven other sugar nucleotides, are transported into the endoplasmic reticulum (ER) and Golgi apparatus (5), where they are used for the production of complex oligosaccharides (6) that comprise the glycosylation profile of the cell surface. This profile is made up of proteins (such as the prion protein and CD34, shown here) and glycolipids such as ganglioside GM3, a glycosphingolipid. Sialic acid (Sia) is a ubiquitous terminal modification. (b) The chemical structures of glucosamine, UDP-GlcNAc, UDP-ManNAc, and CMP-Sia. (c) As well as being used to build complex oligosaccharides, UDP-GlcNAc is a high-energy building block that provides the GlcNAc residue required for O-GlcNAc protein modification in the cytosol [13]. (d) Slight modifications to the chemical structure of CMP-Sia elicit profound changes in biological activity. The membrane glycosphingolipid ganglioside GM3 (center) is converted to pro-apoptotic gangliosides GD3 by addition of Sia (top), whereas deacetylation of GM3 yields de-N-acetyl GM3, which has a growth stimulatory effect.