Intramolecular self-cleavage of polysialic acid.

Polysialic acid (PSA) is an unusual homopolymer of sialic acid (Sia) found on a limited number of animal glycoproteins and in the capsules of certain pathogenic bacteria. The biological properties of PSA are known to vary markedly with the length of the polymer. We confirm here that while the primary linkage unit of PSA (Sia alpha 2-8Sia) is more stable than commoner Sia linkages, PSA with > 3 Sia units is substantially more labile. A "limit digest" of PSA yields fragments of degree of polymerization (DP) = 2 and 3 and little monomeric Sia. In keeping with this, the fragmentation of PSA of DP 4 is non-random, with the internal glycosidic bond being more labile than those at the two ends. The accelerated breakdown of PSA involves an intramolecular mechanism that is not explained by lactone formation, cation effects, or specific secondary structural features. However, it is dependent upon the intactness of internal carboxyl groups, which have an anomalously high pKa. Thus, the instability of PSA appears to result from intramolecular self-cleavage of the glycosidic bonds of internal Sia units, in which the adjacent carboxyl group with a high pKa acts as a proton donor for general acid catalysis. This lability of PSA is seen under mildly acidic conditions that can be encountered in various physiological and pathological situations and thus has potential implications for neuronal adhesion, embryogenesis, and bacterial pathogenicity.