Gangliosides Potentially Inhibit Extracellular Nucleotide Metabolism

Gangliosides are glycolipids that contain sialic acid and they are mainly located on the outer leaflet of the cellular plasma membrane of most vertebrate and some invertebrate cells. Because they have structurally diverse, bulky and negatively charged oligosaccharide moieties, gangliosides endow cell membranes with unique molecular characteristics. Although they are abundant in the central nervous system (CNS), the complete loss of gangliosides in mice does not result in gross morphological abnormalities of the CNS. However, mutant mice develop neurodegenerative diseases and die soon after birth, suggesting that gangliosides are required for the maintenance and development of a stable CNS and are crucial to sustain life. At the cellular level, gangliosides influence cell growth and death, probably because they are involved in the lipid-mediated assembly of signaling molecules such as growth factor receptors or integrins on the membranes. This article addresses the structural similarity between the tandem sialic acid residues of gangliosides and nicotinamide adenine dinucleotide (NAD+) determined from biochemical data showing that gangliosides inhibit NAD+ glycohydrolase activity and theoretical considerations. An essential feature of the structural similarity resides in a negative charge cluster formed by the two carboxyl groups in the tandem sialic acid residues and the diphosphate moiety of NAD+. The potential physiological role(s) of gangliosides on the regulation of extracellular nucleotide metabolism are discussed.