Sialic acids are a class of alpha-keto acid
sugars
Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...
with a nine-
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...
backbone.
[
] The term "sialic acid" (from the Greek for
saliva, - ''síalon'') was first introduced by
Swedish
Swedish or ' may refer to:
Anything from or related to Sweden, a country in Northern Europe. Or, specifically:
* Swedish language, a North Germanic language spoken primarily in Sweden and Finland
** Swedish alphabet, the official alphabet used by ...
biochemist
Gunnar Blix
Fritiof Gunnar Blix (7 September 1894 in Lund – 10 June 1981 in Uppsala) was a Swedish chemist and Professor of Medical and Physiological chemistry at the University of Uppsala. He was the son of professor Magnus Blix, father of politician Hans ...
in 1952. The most common member of this group is
''N''-acetylneuraminic acid (Neu5Ac or NANA) found in animals and some prokaryotes.
Sialic acids are found widely distributed in animal tissues and related forms are found to a lesser extent in other organisms like in some micro-algae, bacteria and archaea. Sialic acids are commonly part of
glycoproteins, glycolipids or
ganglioside
A ganglioside is a molecule composed of a glycosphingolipid (ceramide and oligosaccharide) with one or more sialic acids (e.g. ''N''-acetylneuraminic acid, NANA) linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate si ...
s, where they decorate the end of sugar chains at the surface of cells or soluble proteins.
However, sialic acids have been also observed in ''Drosophila'' embryos and other insects.
Generally, plants seem not to contain or display sialic acids.
In humans the brain has the highest sialic acid content, where these acids play an important role in neural transmission and ganglioside structure in
synaptogenesis
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...
.
More than 50 kinds of sialic acid are known, all of which can be obtained from a molecule of neuraminic acid by substituting its amino group of one of its hydroxyl groups.
In general, the amino group bears either an acetyl or a glycolyl group, but other modifications have been described. These modifications along with linkages have shown to be tissue specific and developmentally
regulated expressions, so some of them are only found on certain types of
glycoconjugates
Glycoconjugates are the classification family for carbohydrates – referred to as glycans – which are covalently linked with chemical species such as proteins, peptides, lipids, and other compounds. Glycoconjugates are formed in processes term ...
in specific cells.
The hydroxyl substituents may vary considerably; acetyl, lactyl, methyl, sulfate, and phosphate groups have been found.
Structure
The sialic acid family includes many derivatives of the nine-carbon sugar
neuraminic acid
Neuraminic acid (5-amino-3,5-dideoxy-D-''glycero''-D-''galacto''-non-2-ulosonic acid) is an acidic (in particular ulosonic) amino sugar with a backbone formed by nine carbon atoms. Although 9-carbon sugars do not occur naturally, neuramini ...
, but these acids rarely appear free in nature. Normally they can be found as components of oligosaccharide chains of mucins,
glycoproteins
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosy ...
and
glycolipids
Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the conne ...
occupying terminal, nonreducing positions of complex carbohydrates on both external and internal membrane areas where they are very exposed and develop important functions.
The numbering of the carbon atoms starts at the carboxylate carbon and continues along the chain. The configuration that places the carboxylate in the axial position is the alpha-anomer.
The alpha-anomer is the form that is found when sialic acid is bound to glycans. However, in solution, it is mainly (over 90%) in the beta-anomeric form. A bacterial enzyme with
sialic acid mutarotase
N-acetylneuraminate epimerase (, ''sialic acid epimerase'', ''N-acetylneuraminate mutarotase'', sialic acid mutarotase, ''YjhT'', NanM) is an enzyme with systematic name ''N-acetyl-alpha-neuraminate 2-epimerase''. This enzyme catalyses the followi ...
activity, NanM, that is able to rapidly equilibrate solutions of sialic acid to the resting equilibrium position of around 90% beta/10% alpha has been discovered.
In contrast to other animals, humans are genetically unable to produce the sialic acid variant
N-glycolylneuraminic acid (Neu5Gc). Small amounts of Neu5Gc detected in human tissue however may be incorporated from exogenous (nutrient) sources.
Biosynthesis
Sialic acid is synthesized by glucosamine 6 phosphate and
acetyl-CoA through a
transferase
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of ...
, resulting in ''N''-acetylglucosamine-6-P. This becomes ''N''-acetylmannosamine-6-P through
epimerization
In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...
, which reacts with
phosphoenolpyruvate
Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/m ...
producing ''N''-acetylneuraminic-9-P (sialic acid). For it to become active to enter in the oligosaccharide biosynthesis process of the cell, a monophosphate nucleoside is added, which comes from a
cytidine triphosphate
Cytidine triphosphate (CTP) is a pyrimidine nucleoside triphosphate. CTP, much like ATP, consists of a ribose sugar, and three phosphate groups. The major difference between the two molecules is the base used, which in CTP is cytosine.
CTP is ...
, turning sialic acid into cytidine monophosphate-sialic acid (CMP-sialic acid). This compound is synthesized in the nucleus of the animal cell.
In bacterial systems, sialic acids can be also biosynthesized by an
aldolase
Fructose-bisphosphate aldolase (), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phospha ...
. This enzyme uses for example a
mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ...
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 containing glycoproteins (
sialoglycoprotein
A sialoglycoprotein is a combination of sialic acid and glycoprotein, which is, itself, a combination of sugar and protein. These proteins often contain one or more sialyl oligosaccharides that are covalently bound to the rest of the molecule.
Gl ...
s) bind
selectin
The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminu ...
in humans and other organisms.
Metastatic cancer
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, the ...
cells often express a high density of sialic acid-rich glycoproteins. This overexpression of sialic acid on surfaces creates a negative charge on cell membranes. This creates repulsion between cells (cell opposition) and helps these late-stage cancer cells enter the blood stream. Recent experiments have demonstrated the presence of sialic acid in the cancer-secreted
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
.
Sialic acid-rich
oligosaccharide
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...
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' surfaces. 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
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-clas ...
.
Sialic acid in the form of polysialic acid is an unusual
posttranslational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribo ...
that occurs on the
neural cell adhesion molecules (NCAMs). In the
synapse, the strong negative charge of the polysialic acid prevents NCAM cross-linking of cells.
Administration of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
to castrated mice leads to a dose-dependent reduction of the sialic acid content of the vagina. Conversely, the sialic acid content of mouse vagina is a measure of the potency of the estrogen. Reference substances are
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
for subcutaneous application and
ethinylestradiol
Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...
for oral administration.
Immunity
Sialic acids are found at all cell surfaces of vertebrates and some invertebrates, and also at certain bacteria that interact with vertebrates.
Many viruses such as the Ad26 serotype of
adenoviruses
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...
(''
Adenoviridae
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from th ...
''),
rotavirus
''Rotavirus'' is a genus of double-stranded RNA viruses in the family ''Reoviridae''. Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus ...
es (''
Reoviridae
''Reoviridae'' is a family of double-stranded RNA viruses. Member viruses have a wide host range, including vertebrates, invertebrates, plants, protists and fungi. They lack lipid envelopes and package their segmented genome within multi-layere ...
'') and influenza viruses (''
Orthomyxoviridae'') can use host-sialylated structures for binding to their target host cell. Sialic acids provide a good target for these viruses since they are highly conserved and are abundant in large numbers in virtually all cells. Unsurprisingly, sialic acids also play an important role in several human viral infections. The influenza viruses have
hemagglutinin
In molecular biology, hemagglutinins (or ''haemagglutinin'' in British English) (from the Greek , 'blood' + Latin , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the '' Paramyxoviridae'' family. Hemagglutinins a ...
activity (HA) glycoproteins on their surfaces that bind to sialic acids found on the surface of human
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
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. Widely used anti-influenza drugs (
oseltamivir
Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high ...
and
zanamivir
Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and ap ...
) are sialic acid analogs that interfere with release of newly generated viruses from infected cells by inhibiting the viral enzyme
neuraminidase
Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:
: Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glyc ...
.
Some bacteria also use host-sialylated structures for binding and recognition. For example, evidence indicates that free sialic acids can behave as a signal to some specific bacteria, like ''
Pneumococcus
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
''. Free sialic acid possibly can help the bacterium to recognize that it has reached a vertebrate environment suitable for its colonization. Modifications of Sias, such as the ''N''-glycolyl group at the 5 position or ''O''-acetyl groups on the side chain, may reduce the action of bacterial sialidases.
Metabolism
The synthesis and degradation of sialic acid are distributed in different compartments of the cell. The synthesis starts in the cytosol, where
''N''-acetylmannosamine 6 phosphate and
phosphoenolpyruvate
Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/m ...
give rise to sialic acid. Later on, Neu5Ac 9 phosphate is activated in the nucleus by a cytidine monophosphate (CMP) residue through CMP-Neu5Ac synthase. Although the linkage between sialic acid and other compounds tends to be a α binding, this specific one is the only one that is a β linkage. CMP-Neu5Ac is then transported to the endoplasmic reticulum or the Golgi apparatus, where it can be transferred to an oligosaccharide chain, becoming a new glycoconjugate. This bond can be modified by O-
acetylation or O-
methylation. When the glycoconjugate is mature it is transported to the cell surface.
The
sialidase
Exo-α-sialidase (EC 3.2.1.18, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:
: Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycos ...
is one of the most important enzymes of the sialic acid catabolism. It can cause the removal of sialic acid residues from the cell surface or serum sialoglycoconjugates. Usually, in higher animals, the glycoconjugates that are prone to be degraded are captured by endocytosis. After the fusion of the late endosome with the lysosome, lysosomal sialidases remove sialic acid residues. The activity of these sialidases is based on the removal of ''O''-acetyl groups. Free sialic acid molecules are transported to the cytosol through the membrane of the lysosome. There, they can be recycled and activated again to form another nascent glycoconjugate molecule in the Golgi apparatus. Sialic acids can also be degraded to acylmannosamine and pyruvate with the cytosolic enzyme acylneuraminate lyase.
Some severe diseases can depend on the presence or absence of some enzymes related to the sialic acid metabolism.
Sialidosis
Mucolipidosis type I (ML I) is an inherited lysosomal storage disease that results from a deficiency of the enzyme alpha-N -acetyl neuraminidase (sialidase). The lack of this enzyme results in an abnormal accumulation of complex carbohydrates know ...
and Sialic acid deficiency with mutations in the ''NANS'' gene (see below) would be examples of this type of disorder.
Brain development
Rat pups supplemented with sialic acid showed improved learning and memory as adults.
A relationship between dietary sialic acid supplementation and cognitive function was seen in piglets that had been fed high doses of sialic acid.
Diseases
Sialic acids are related to several different diseases observed in humans.
Sialic acid deficiency with mutations in the ''NANS'' gene
Biallelic recessive mutations in the sialic acid synthesis gene, N-acetyl-neuraminic acid synthase (''NANS'') in humans may result in a severe disease featuring intellectual disability and short stature, highlighting the importance of sialic acid in brain development. A therapeutic trial with a short-term supplementation of sialic acid given orally has failed to show a significant beneficial effect on biochemical parameters
Salla disease
Salla disease is an extremely rare illness which is considered the mildest form of the free sialic acid accumulation disorders
though its childhood form is considered an aggressive variant and people who suffer from it have mental retardation. It is an
autosomic recessive disorder caused by a mutation of the
chromosome 6. It mainly affects the nervous system
and it is caused by a lysosomal storage irregularity which comes from a deficit of a specific sialic acid carrier located on the lysosomal membrane Currently, there is no cure for this disease and the treatment is supportive, focusing on the control of symptoms.
Atherosclerosis
Subfractions of LDL cholesterol that are implicated in causing
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
have reduced levels of sialic acid.
These include
small high density LDL particles and electronegative LDL.
Reduced levels of sialic acid in small high density LDL particles increases the affinity of those particles for the
proteoglycans in
arterial
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
walls.
Influenza
All
influenza A virus strains need sialic acid to connect with cells. There are different forms of sialic acids which have different affinity with influenza A virus variety. This diversity is an important fact that determines which species can be infected. When a certain influenza A virus is recognized by a sialic acid receptor the cell tends to endocytose the virus so the cell becomes infected.
Sialic acids and other nonulosonic acids (NulOs) in prokaryotes
Sialic acids are highly abundant in vertebrate tissues where they are involved in many different biological processes. Originally discovered within the Deuterostome lineage of animals, sialic acids can be actually considered as a subset of a more ancient family of 9-carbon backbone monosaccharides called nonulosonic acids (NulOs), which more recently have been also found in Eubacteria and Archaea.
Many pathogenic bacteria incorporate sialic acid into cell surface features like their
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
or capsule polysaccharides, which helps them to evade the innate immune response of the host.
A recent genome level study examined a large set of sequenced microbial genomes, which indicated that biosynthetic pathways to produce nonulosonic acids (NulOs) are far more widely distributed across the phylogenetic tree of life, than previously realized. This finding is moreover supported by recent lectin staining studies and a molecular level survey on prokaryotic nonulosonic acids, showing that also many non-pathogenic and purely environmental strains produce bacterial sialic acids (NulOs). Some (
anammox
Anammox, an abbreviation for anaerobic ammonium oxidation, is a globally important microbial process of the nitrogen cycle that takes place in many natural environments. The bacteria mediating this process were identified in 1999, and were a gre ...
) bacteria produce NulOs that in addition to the very acidic alpha-keto acid group also display (neutralizing) basic groups (free amines). Comparable cell surface sialic acids have been produced by chemical remodelling to manipulate the cell surface charge by producing a free amine at C5, which neutralizes the negatively charged carboxyl group at C1.
See also
*
Sialidosis
Mucolipidosis type I (ML I) is an inherited lysosomal storage disease that results from a deficiency of the enzyme alpha-N -acetyl neuraminidase (sialidase). The lack of this enzyme results in an abnormal accumulation of complex carbohydrates know ...
*
Sialoglycoprotein
A sialoglycoprotein is a combination of sialic acid and glycoprotein, which is, itself, a combination of sugar and protein. These proteins often contain one or more sialyl oligosaccharides that are covalently bound to the rest of the molecule.
Gl ...
*
Sialyltransferase
Sialyltransferases are enzymes that transfer sialic acid to nascent oligosaccharide. Each sialyltransferase is specific for a particular sugar substrate. Sialyltransferases add sialic acid to the terminal portions of the sialylated glycolipids ...
*
Orthomyxoviridae
References
External links
Sialic acid in evolution
{{Authority control
Carbohydrate chemistry
Sugar acids
Monosaccharides