SIALIC ACID: STRUCTURE, FUNCTIONS AND DISEASES - BIOLOGY - 2024

The sialic acids are monosaccharides nine carbon atoms. They belong to the family of neuraminic acid derivatives (5-amino-3,5-dideoxy-D-glycero-D-galacto-nonulosonic acid) and are widely distributed in nature, particularly in the animal kingdom.

They do not normally occur as free molecules, but are linked by α-glucosidic bonds to carbohydrate molecules or to other sialic acid molecules, and can then occupy terminal or internal positions within a linear carbohydrate chain.

Schematic of a sialic acid molecule (Source: User: glycoform via Wikimedia Commons)

The term "sialic acid" was first coined by Gunnar Blix in 1957, although previous reports by other researchers indicate that their discovery dates back a decade or two earlier, when they were described as part of sialo mucin glycoproteins and sialo sialo sphingolipids (gangliosides)..

Sialic acids are present in much of the kingdoms of nature. They have been detected in some viruses, pathogenic bacteria, protozoa, crustaceans, flatworms, insects and vertebrates such as fish, amphibians, birds and mammals. On the contrary, they have not been found in fungi, algae or plants.

Structure

Sialic acids occur mainly in the terminal portion of surface glycoproteins and glycolipids, providing great diversity to these glycoconjugates. Differential "sialylation" patterns are products of the expression of tissue-specific glycosyltransferases (sialyltransferases).

Structurally, sialic acids belong to a family of about 40 natural derivatives of neuraminic acid that are N-acylated, giving rise to two “parent” structures: N-acetylneuraminic acid (Neu5Ac) or N-glycolyl neuraminic acid (Neu5Gc).

Its structural characteristics include the presence of an amino group (which can be modified) at position 5, and a carboxylic group at position 1, which can be ionized at physiological pH. A deoxygenated C-3 carbon and a glycerol molecule at the C-6 position.

Schematic of a molecule of sialic acid with the enumeration of the carbons (Source: User: glycoform via Wikimedia Commons)

Many derivatives arise from the substitution of the hydroxyl groups at the C-4, C-7, C-8 and C-9 positions by acetyl, glycol, lactyl, methyl, sulfate and phosphate portions; as well as the introduction of double bonds between C-2 and C-3.

In the linear terminal position, the attachment of a sialic acid portion to an oligosaccharide chain involves an α-glucosidic bond between the hydroxyl group of the C-2 anomeric carbon of sialic acid and the hydroxyl groups of the C-3, C- carbons. 4 or C-6 of the monosaccharide portion.

These linkages can be between galactose residues, N-acetylglucosamine, N-acetylgalactosamine and in some unique gangliosides, glucose. They can occur through N-glycosidic or O-glycosidic bonds.

Features

Sialic acids are thought to help parasitic organisms survive within the host organism; examples of this are mammalian pathogens that produce sialic acid metabolism enzymes (sialidases or N-acetylneuraminic lyases).

There is no mammalian species for which the presence of sialic acids has not been reported as part of glycoproteins in general, glycoproteins of the serum, of the mucosa, as part of cell surface structures or as part of complex carbohydrates.

They have been found in acidic oligosaccharides in the milk and colostrum of humans, cattle, sheep, dogs and pigs, and also as part of the urine of rats and humans.

Role in cell adhesion processes

Glycoconjugates with sialic acid moieties play an important role in information exchange processes between neighboring cells and between cells and their environment.

The presence of sialic acid in cell membranes contributes to the establishment of a negative charge on the surface, which has positive consequences in some electrostatic repulsion events between cells and some molecules.

In addition, the negative charge gives the sialic acids in the membrane a role in the transport of positively charged ions.

It has been reported that the binding of the endothelium and epithelium to the glomerular basement membrane is facilitated by sialic acid, and this also influences the contact between these cells.

Role in the lifespan of blood cell components

Sialic acid has important functions as part of glycophorin A in the plasma membrane of erythrocytes. Some studies have shown that the content of sialic acid is inversely proportional to the age of these cells.

Erythrocytes treated with neuraminidase enzymes, responsible for the degradation of sialic acid, drastically decrease their half-life in the bloodstream from 120 days to a few hours. The same case has been observed with platelets.

Platelets lose their adhesion and aggregation capacity in the absence of sialic acid in their surface proteins. In lymphocytes, sialic acid also plays an important role in cell adhesion and recognition processes, as well as in the interaction with surface receptors.

Functions in the immune system

The immune system is able to distinguish between its own or invading structures based on the recognition of the sialic acid patterns present in the membranes.

Sialic acid, as well as the enzymes neuraminidase and sialyltransferase, possess important regulatory properties. The terminal portions of sialic acid in plasma membrane glycoconjugates have masking functions or as membrane receptors.

Additionally, various authors have raised the possibility that sialic acid has antigenic functions, but it is not yet known with certainty. However, the masking functions of sialic acid residues are very important in cell regulation.

Masking can have a direct or indirect protective role, depending on whether the sialic acid portion directly covers the antigenic carbohydrate residue, or whether it is a sialic acid in an adjacent glycoconjugate that masks the antigenic portion.

Some antibodies possess Neu5Ac residues that exhibit virus-neutralizing properties, since these immunoglobulins are capable of preventing adhesion of viruses to only conjugates (glycoconjugates with portions of sialic acid) on the cell membrane.

Other functions

In the intestinal tract, sialic acids play an equally important role, since they are part of the mucins, which have lubricating and protective properties, essential for the whole organism.

In addition, sialic acids are also present in the membranes of bronchial, gastric and intestinal epithelium cells, where they are involved in transport, secretion and other metabolic processes.

Diseases

Numerous diseases are known to involve abnormalities in sialic acid metabolism and these are known as sialidosis. Among the most prominent are sialuria and Salla's disease, which are characterized by urinary excretion with large amounts of free sialic acids.

Other diseases of an immunological nature have to do with alterations in anabolic and catabolic enzymes related to the metabolism of sialic acid, which cause an aberrant accumulation of glycoconjugates with portions of sialic acid.

Some diseases related to blood factors are also known, such as thrombocytopenia, which consists of a decrease in the level of thrombocytes in the blood probably caused by a lack of sialic acid in the membrane.

Von Willebrand's disease corresponds to a defect in the adhesion capacity of thrombocytes to the subendothelial membrane glycoconjugates of the blood vessel wall, caused by deficiencies or deficiencies in glycosylation or sialylation.

Glanzmann's thrombasthenia is another congenital disorder of thrombocyte aggregation whose root is the presence of defective glycoproteins in the membrane of the thrombocytes. Defects in these glycoproteins have been shown to be associated with reduced Neu5Ac content.

References

1. Clayden, J., Greeves, N., Warren, S., & Wothers, P. (2001). Organic Chemistry (1st ed.). New York: Oxford University Press.
2. Demchenko, AV (2008). Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance. Wiley-VCH.
3. Rosenberg, A. (1995). Biology of the Sialic Acids. New York: Springer Science + Business Media, LLC.
4. Schauer, R. (1982). Sialic Acids: Chemistry, Metabolism and Function. Springer-Verlag Wien New York.
5. Traving, C., & Schauer, R. (1998). Structure, function and metabolism of sialic acids. CMLS Cellular and Molecular Life Sciences, 54, 1330–1349.