GANGLIOSIDES: STRUCTURE, FUNCTIONS, SYNTHESIS AND APPLICATIONS - BIOLOGY - 2025

The gangliosides are membrane sphingolipids belonging to the class of acidic glycosphingolipids. They are among the most abundant glycolipids and are involved in the regulation of many membrane properties, as well as proteins associated with them. They are especially abundant in nervous tissues.

They are characterized by the presence of sugar residues with carboxyl groups (sialic acids) and, together with sulfatides, that contain an O-sulfate group linked to a glucose or galactose residue. They represent one of the two families of acidic glycosphingolipids in eukaryotes.

Example of the structure of a ganglioside (Source: Caitlin Sedwick, via Wikimedia Commons)

The term ganglioside was coined in 1939 by the German biochemist Ernst Klenk, when he referred to a mixture of compounds extracted from the brain of a patient with Niemann-Pick disease. However, the first structure of a ganglioside was elucidated in 1963.

They share the hydrophobic ceramide skeleton with the other sphingolipids, which is composed of a sphingosine molecule linked by an amide bond to a fatty acid of between 16 and 20 carbon atoms, with a trans double bond between the carbons in the 4 positions and 5.

Structure

Gangliosides are characterized by presenting oligosaccharide chains in their polar head group, in whose composition there are sialic acid molecules linked by β-glucosidic bonds to the hydrophobic skeleton of the ceramide.

They are extremely diverse molecules in view of the multiple possible combinations between the oligosaccharide chains, the different types of sialic acid and the apolar tails attached to the ceramide skeleton, both of sphingosine and of the fatty acids linked by amide bonds to said skeleton.

In nervous tissue the most common fatty acid chains among gangliosides are represented by palmitic and stearic acid.

Characteristics of the polar group

The polar head region of these sphingolipids provides them with a strong hydrophilic character. This polar group is very bulky compared to that of phospholipids like phosphatidylcholine, for example.

The reason for this bulk has to do with the size of the oligosaccharide chains, as well as the amount of water molecules associated with these carbohydrates.

General structure of gangliosides (Source: Ryan_1991, via Wikimedia Commons)

Sialic acids are derivatives of 5-amino-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosoic acid, or neuraminic acid. There are three known types of sialic acids in gangliosides: 5-N -acetyl, 5-N -acetyl-9-O -acetyl and 5-N -glycolyl derivative, which is the most common in healthy humans.

In general, mammals (including primates) are capable of synthesizing 5-N-glycolyl-neuraminic acid, but humans must obtain it from food sources.

The classification of these lipids can be based both on the number of sialic acid residues (from 1-5), as well as on their position in the glycosphingolipid molecule.

The most common oligosaccharide sequence is the tetrasaccharide Galβ1-3GalNAcβ1-4Galβ1-4Glcβ, but fewer residues can also be found.

Features

The exact biological implications of gangliosides have not been fully elucidated, however, they appear to be involved in cell differentiation and morphogenesis, in the binding of some viruses and bacteria, and in type-specific cell adhesion processes as ligands for proteins. selectins.

In the nervous system

Glycosphingolipids with sialic acid are of special relevance in the nervous system, especially in the gray matter cells of the brain. This has to do with the fact that glycoconjugates, in general, are recognized as efficient information and storage vehicles for cells.

They are predominantly located in the outer monolayer of the plasma membrane, therefore they have an important participation in the glycocalyx, together with glycoproteins and proteoglycans.

This glycocalyx or extracellular matrix is ​​essential for cell movement and activation of signaling pathways involved in growth, proliferation and gene expression.

In cell signaling

As with other sphingolipids, the by-products of ganglioside degradation also have important functions, especially in signaling processes and in the recycling of elements for the formation of new lipid molecules.

Within the bilayer, gangliosides occur largely in sphingolipid-rich lipid rafts, where "glyco-signaling domains" are established that also mediate intercellular interactions and transmembrane signaling by stabilization and association with integral proteins. These lipid rafts perform important functions in the immune system.

In the structure

They promote the conformation and correct folding of important membrane proteins, such as the GM1 ganglioside, in maintaining the helical structure of the α-synuclein protein, whose aberrant form is associated with Parkinson's disease. They have also been associated with the pathologies of Huntington, Tay-Sachs and Alzheimer's disease.

Synthesis

Glycosphingolipid biosynthesis is highly dependent on intracellular transport through vesicle flow from the endoplasmic reticulum (ER), through the Golgi apparatus, and ending at the plasma membrane.

The biosynthetic process begins with the formation of the ceramide skeleton on the cytoplasmic face of the ER. The formation of glycosphingolipids occurs later in the Golgi apparatus.

The glycosidase enzymes responsible for this process (glucosyltransferase and galactosyltransferase) are found on the cytosolic side of the Golgi complex.

The addition of sialic acid residues to the growing oligosaccharide chain is catalyzed by a few glycosyltransferases bound to the membrane, but which are restricted to the luminal side of the Golgi membrane.

Different lines of evidence suggest that the synthesis of the simplest gangliosides occurs in the early region of the Golgi membrane system, while the most complex occur in the more “late” regions.

Regulation

Synthesis is regulated in the first instance by the expression of glycosyltransferases, but epigenetic events such as phosphorylation of the enzymes involved and others may also be involved.

Applications

Some researchers have focused their attention on the usefulness of a particular ganglioside, GM1. The toxin synthesized by V. cholera in cholera patients has a subunit responsible for the specific recognition of this ganglioside, which is presented on the surface of the mucous cells of the intestine.

Thus, GM1 has been used for the recognition of markers of this pathology as it is included in the synthesis of liposomes used for the diagnosis of cholera.

Other applications include the synthesis of specific gangliosides and their binding to stable supports for diagnostic purposes or for the purification and isolation of compounds for which they have an affinity. It has also been found that they can serve as markers for some types of cancer.

References

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