The structural basis for the susceptibility of gangliosides to enzymatic degradation

The conformational properties of GM2, GalNac beta-4(Neu5Ac alpha-3) Gal bet a-4Glc beta-1Cer have been compared to those of 6'-GM2, in which the linkag e between the GalNAc and Gal was altered from GalNAc beta-4Gal beta- to Gal Nac beta-6Gal beta-, and to those of GD1a, Neu5Ac alpha-3Gal beta-3GalNAc b eta-4(Neu5Ac alpha-3)Gal beta-4Glc beta-1Cer, and GalNAc-GD1a. Our results revealed that unlike the compact and rigid oligosaccharide head group found in GM2, where the Neu5Ac and the GalNAc residues interact, the sugar chain of 6'-GM2 is in an open spatial arrangement, with the Neu5Ac n o longer interacting with GalNAc, freely accessible to external interaction s. The structure of GD1a can be regarded as that of GM2 with an extension of t he terminal Neu5Ac alpha-3Gal beta-disaccharide. The inner portion of GD1a is that of GM2 comprising the very rigid GalNAc-[Neu5Ac-]Gal trisaccharide. The terminal Neu5Ac-Gal linkage is flexible and fluctuates between two lim iting conformations. In GalNAc-GDla the outer sialic acid gains conformatio nal rigidity due to the presence of the outer GalNAc in position 4 of galac tose. This ganglioside has two 'core' GalNAc-[Neu5Ac-]Gal trisaccharide lin ked in tandem.