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Unusual chemical and enzymatic stability of polysialic acid containing N‐glycolylneuraminic acid

The sialic acid N‐glycolylneuraminic acid (Neu5Gc) is present only at trace levels in the brains of all vertebrates tested to date, suggesting a detrimental effect of Neu5Gc. As a candidate mechanism for this potential toxicity, we hypothesized a reduced enzymatic breakdown of polysialic acid (PSA), a polymer of α2–8 linked N‐acetylneuraminic acid (Neu5Ac) found on the neural cell adhesion molecule (NCAM) and critical in many neurodevelopmental processes. We demonstrate that cultured neuroblastoma cells are able to incorporate Neu5Gc into PSA. Chemically synthesized polymers containing Neu5Gc exhibit resistance to the mammalian sialidase NEU1, an effect abolished by replacing the N‐glycolyl group with N‐propyl. Additional enzymatic and acidic conditions are being evaluated. Molecular modeling predicts similar tertiary structures of α2–8 linked Neu5Ac and Neu5Gc, but the presence of a glycolyl group creates a potentially stabilizing hydrogen bond with the adjacent carboxylate. This intrinsic stability of α2–8 linked Neu5Gc in PSA provides a potential explanation for the evolutionarily conserved absence of Neu5Gc from the vertebrate brain.