Sialic acid is an essential biomolecule and critical for mammalian life �  homozygous inactivation of the enzyme that catalyzes the first committed step of sialic acid biosynthesis results in early embryonic lethality in mice.  By serving as the terminal sugar on many glycan chains, sialic acid regulates diverse cellular processes and disruptions in sialic acid metabolism lead to a variety of human diseases ranging from muscle conditions to neurologic disease to autoimmune disorders. Additionally, cancer cells are known to display unusual sialylated epitopes that are thought to aid in immune system evasion and cancer cell survival. Given the sensitivity of human health to sialic acid content, I hypothesize that sialic acid levels are tightly regulated and alterations in sialic acid metabolism lead to changes in signaling and metabolism.I designed experiments to reveal how changes in sialic acid production affect cellular homeostasis. Microarray analysis and metabolomics studies suggest a defect with sialic acid biosynthesis causes only minimal changes in global gene expression and metabolism.  However, a deficiency in sialic acid production does perturb the hexosamine biosynthetic pathway. Sialic acid is produced from UDP-GlcNAc, and cells that make sialic acid appear to have reduced levels of UDP-GlcNAc.  UDP-GlcNAc serves as the precursor to both the critical O-GlcNAc modification and to N-linked glycan branching. Immunoblot analysis suggests that global levels of O-GlcNAc are unaffected by sialic acid production,  but lectin binding experiments demonstrate that reduced sialic acid production alters N-linked glycan branching.  Furthermore, the change in N-glycan branching leads to altered galectin-1 binding. Thus, sialic acid synthesis alters the N-linked glycome of membrane proteins and consequently affects interactions that occur with N-linked glycans.

Effects of sialic acid biosynthesis on the hexosamine biosynthetic pathway and N-linked glycans

247th National Meeting (2014)

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