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Sialic acid

Sialic acid

Overview
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid
Neuraminic acid
Neuraminic acid is a 9-carbon monosaccharide, a derivative of a ketononose. Neuraminic acid may be visualized as the product of an aldol-condensation product of pyruvic acid and D-mannosamine...

, a monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...

 with a nine-carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid
N-Acetylneuraminic acid
N-Acetylneuraminic acid is the predominant sialic acid found in mammalian cells.This negatively charged residue is found in complex glycans on mucins and glycoproteins found at the cell membrane...

 (Neu5Ac or NANA). Sialic acids are found widely distributed in animal tissues and to a lesser extent in other species ranging from plants and fungi to yeasts and bacteria, mostly in glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s and ganglioside
Ganglioside
Ganglioside is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. The 60+ known gangliosides differ mainly in the position and number of NANA residues.It is a component of the cell plasma membrane that modulates cell signal transduction events...

s. The amino group generally bears either an acetyl or glycolyl group but other modifications have been described. The hydroxyl substituents may vary considerably: acetyl, lactyl, methyl, sulfate, and phosphate groups have been found. The term "sialic acid" (from the Greek for saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...

, σίαλον/sialon) was first introduced by Swedish
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....

 biochemist Gunnar Blix in 1952.
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Encyclopedia
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid
Neuraminic acid
Neuraminic acid is a 9-carbon monosaccharide, a derivative of a ketononose. Neuraminic acid may be visualized as the product of an aldol-condensation product of pyruvic acid and D-mannosamine...

, a monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...

 with a nine-carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

 backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid
N-Acetylneuraminic acid
N-Acetylneuraminic acid is the predominant sialic acid found in mammalian cells.This negatively charged residue is found in complex glycans on mucins and glycoproteins found at the cell membrane...

 (Neu5Ac or NANA). Sialic acids are found widely distributed in animal tissues and to a lesser extent in other species ranging from plants and fungi to yeasts and bacteria, mostly in glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s and ganglioside
Ganglioside
Ganglioside is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. The 60+ known gangliosides differ mainly in the position and number of NANA residues.It is a component of the cell plasma membrane that modulates cell signal transduction events...

s. The amino group generally bears either an acetyl or glycolyl group but other modifications have been described. The hydroxyl substituents may vary considerably: acetyl, lactyl, methyl, sulfate, and phosphate groups have been found. The term "sialic acid" (from the Greek for saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...

, σίαλον/sialon) was first introduced by Swedish
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....

 biochemist Gunnar Blix in 1952.

Structure


The numbering of the sialic acid structure begins at the carboxylate carbon and continues around the chain. The configuration which places the carboxylate in the axial position is the alpha-anomer.


Biosynthesis


In bacterial systems, sialic acids are biosynthesized by an aldolase
Aldolase
Aldolase A is an enzyme that catalyses a reverse aldol reaction: The substrate, fructose 1,6-bisphosphate is broken down into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate . This reaction is a part of glycolysis. Three aldolase isozymes , encoded by three different genes, are...

 enzyme. The enzyme uses a mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....

 derivative as a substrate, inserting three carbons from pyruvate into the resulting sialic acid structure. These enzymes can be used for chemoenzymatic synthesis of sialic acid derivatives.


Function


Sialic acid-rich glycoproteins (sialoglycoprotein
Sialoglycoprotein
A sialoglycoprotein is a combination of sialic acid and glycoprotein, which is, itself, a combination of sugar and protein.Glycophorin C is one common sialoglycoprotein....

s) bind selectin
Selectin
Selectins are a family of cell adhesion molecules . All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding...

 in humans and other organisms. Metastatic cancer cells often express a high density of sialic acid-rich glycoproteins. This helps these late-stage cancer cells enter the blood stream.

Sialic acid also plays an important role in human influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

 infections. The influenza viruses (orthomyxoviridae
Orthomyxoviridae
The Orthomyxoviridae are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. A sixth has recently been described...

) have hemagglutinin
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...

 activity (HA) glycoproteins on their surface that bind to sialic acids found on the surface of human erythrocytes and on the cell membranes of the upper respiratory tract. This is the basis of hemagglutination when viruses are mixed with blood cells, and entry of the virus into cells of the upper respiratory tract.

Sialic acid-rich oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...

s on the glycoconjugates (glycolipids, glycoproteins, proteoglycans) found on surface membranes help keep water at the surface of cells. The sialic acid-rich regions contribute to creating a negative charge on the cells' surface. Since water is a polar molecule with partial positive charges on both hydrogen atoms, it is attracted to cell surfaces and membranes. This also contributes to cellular fluid uptake.

Sialic acid can "hide" mannose antigens on the surface of host cells or bacteria from mannose-binding lectin. This prevents activation of complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...

.

Sialic acid in the form of polysialic acid is an unusual posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....

 that occurs on the neural cell adhesion molecules, NCAM
Neural Cell Adhesion Molecule
Neural Cell Adhesion Molecule is a homophilic binding glycoprotein expressed on the surface of neurons, glia, skeletal muscle and natural killer cells...

. In the synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

, the strong negative charge of the polysialic acid prevents NCAM cross-linking of cells.

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