Fig. 1.

Sialic acid biosynthesis pathway. The biosynthesis of sialic acid (Neu5Ac) is an intracellular process depicted above with enzymes shown in yellow and substrates in white. The initial steps of this pathway occur in the cytoplasm, with the substrate, UDP-GlcNAc, which is derived from glucose. In the rate-limiting step of the pathway, UDP-GlcNAc is converted into ManNAc by UDP-GlcNAc 2-epimerase, encoded by the epimerase domain of GNE. ManNAc is phosphorylated by ManNAc kinase encoded by the kinase domain of GNE. Sialic acid becomes “activated” by CMP-sialic acid synthetase in the cell nucleus. CMP-sialic acid acts as a sialic acid donor to sialylate glycans on nascent glycoproteins (sia) and glycolipids in the Golgi; it also acts as a cytoplasmic feedback inhibitor of the UDP-GlcNAc 2-epimerase enzyme by binding to its allosteric site. Sialylation-increasing therapies (ManNAc and sialic acid), and sialylated glycoproteins (siallylactose and IVIG) are boxed in white. Adapted with permission from Xu et al. [1]