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Glycosylation is the reaction in which a
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
(or ' glycan'), i.e. a
glycosyl donor A glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new ...
, is attached to a hydroxyl or other functional group of another molecule (a
glycosyl acceptor A glycosyl acceptor is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of t ...
) in order to form a
glycoconjugate 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 ...
. In biology (but not always in chemistry), glycosylation usually refers to an enzyme-catalysed reaction, whereas
glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proce ...
(also 'non-enzymatic glycation' and 'non-enzymatic glycosylation') may refer to a non-enzymatic reaction (though in practice, 'glycation' often refers more specifically to Maillard-type reactions). Glycosylation is a form of co-translational and
post-translational 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 ...
. Glycans serve a variety of structural and functional roles in membrane and secreted proteins. The majority of proteins synthesized in the rough endoplasmic reticulum undergo glycosylation. Glycosylation is also present in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
and nucleus as the ''O''-GlcNAc modification. Aglycosylation is a feature of engineered antibodies to bypass glycosylation. Five classes of glycans are produced: * ''N''-linked glycans attached to a
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
of
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
or
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
side-chains. ''N''-linked glycosylation requires participation of a special lipid called dolichol phosphate. * ''O''-linked glycans attached to the
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
of serine, threonine,
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
,
hydroxylysine Hydroxylysine (Hyl) is an amino acid with the molecular formula C6H14N2O3. It was first discovered in 1921 by Donald Van Slyke as the 5-hydroxylysine form. It arises from a post-translational hydroxy modification of lysine. It is most widely kno ...
, or
hydroxyproline (2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank. Structure and discovery In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin ...
side-chains, or to oxygens on lipids such as ceramide * phosphoglycans linked through the phosphate of a phosphoserine; *''C''-linked glycans, a rare form of glycosylation where a sugar is added to a carbon on a tryptophan side-chain. Aloin is one of the few naturally occurring substances. * glypiation, which is the addition of a GPI anchor that links proteins to lipids through glycan linkages.


Purpose

Glycosylation is the process by which a
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
is
covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
ly attached to a target macromolecule, typically
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s and
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s. This modification serves various functions. For instance, some proteins do not fold correctly unless they are glycosylated. In other cases, proteins are not stable unless they contain
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 linked at the
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
of certain
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
residues. The influence of glycosylation on the folding and stability of
glycoprotein 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 glyco ...
is twofold. Firstly, the highly soluble glycans may have a direct physicochemical stabilisation effect. Secondly, ''N''-linked glycans mediate a critical quality control check point in glycoprotein folding in the endoplasmic reticulum. Glycosylation also plays a role in cell-to-cell adhesion (a mechanism employed by cells of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
) via sugar-binding proteins called lectins, which recognize specific carbohydrate moieties. Glycosylation is an important parameter in the optimization of many glycoprotein-based drugs such as monoclonal antibodies. Glycosylation also underpins the
ABO blood group The ABO blood group system is used to denote the presence of one, both, or neither of the A and B antigens on erythrocytes. For human blood transfusions, it is the most important of the 43 different blood type (or group) classification system ...
system. It is the presence or absence of glycosyltransferases which dictates which blood group
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
s are presented and hence what antibody specificities are exhibited. This immunological role may well have driven the diversification of glycan heterogeneity and creates a barrier to zoonotic transmission of viruses. In addition, glycosylation is often used by viruses to shield the underlying viral protein from immune recognition. A significant example is the dense glycan shield of the envelope spike of the human immunodeficiency virus. Overall, glycosylation needs to be understood by the likely evolutionary selection pressures that have shaped it. In one model, diversification can be considered purely as a result of endogenous functionality (such as
cell trafficking Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
). However, it is more likely that diversification is driven by evasion of pathogen infection mechanism (e.g. '' Helicobacter'' attachment to terminal saccharide residues) and that diversity within the multicellular organism is then exploited endogenously. Glycosylation can also module the thermodynamic and kinetic stability of the proteins.


Glycoprotein diversity

Glycosylation increases diversity in the proteome, because almost every aspect of glycosylation can be modified, including: * Glycosidic bond—the site of glycan linkage * Glycan composition—the types of sugars that are linked to a given protein * Glycan structure—can be unbranched or branched chains of sugars *
Glycan length The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...
—can be short- or long-chain oligosaccharides


Mechanisms

There are various mechanisms for glycosylation, although most share several common features: *Glycosylation, unlike
glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proce ...
, is an enzymatic process. Indeed, glycosylation is thought to be the most complex
post-translational 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 ...
, because of the large number of enzymatic steps involved. *The donor molecule is often an activated nucleotide sugar. *The process is non-templated (unlike DNA transcription or protein
translation Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
); instead, the cell relies on segregating enzymes into different cellular compartments (e.g.,
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
, cisternae in
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
). Therefore, glycosylation is a site-specific modification.


Types


''N''-linked glycosylation

''N''-linked glycosylation is a very prevalent form of glycosylation and is important for the folding of many eukaryotic glycoproteins and for cell–cell and cell–
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 ...
attachment. The ''N''-linked glycosylation process occurs in eukaryotes in the lumen of the endoplasmic reticulum and widely in archaea, but very rarely in
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
. In addition to their function in protein folding and cellular attachment, the ''N''-linked glycans of a protein can modulate a protein's function, in some cases acting as an on/off switch.


''O''-linked glycosylation

''O''-linked glycosylation is a form of glycosylation that occurs in eukaryotes in the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
, but also occurs in archaea and
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
.


Phosphoserine glycosylation

Xylose Xylose ( grc, ξύλον, , "wood") is a sugar first isolated from wood, and named for it. Xylose is classified as a monosaccharide of the aldopentose type, which means that it contains five carbon atoms and includes an aldehyde functional g ...
, fucose,
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 glycosylat ...
, and GlcNAc phosphoserine glycans have been reported in the literature. Fucose and GlcNAc have been found only in ''Dictyostelium discoideum'', mannose in '' Leishmania mexicana'', and xylose in ''
Trypanosoma cruzi ''Trypanosoma cruzi'' is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood o ...
''. Mannose has recently been reported in a vertebrate, the mouse, ''Mus musculus'', on the cell-surface laminin receptor alpha dystroglycan4. It has been suggested this rare finding may be linked to the fact that alpha dystroglycan is highly conserved from lower vertebrates to mammals.


''C''-mannosylation

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 glycosylat ...
sugar is added to the first tryptophan residue in the sequence W–X–X–W (W indicates tryptophan; X is any amino acid). A
C-C bond CC, cc, or C-C may refer to: Arts, entertainment, and media Fictional characters * C.C. (''Code Geass''), a character in the ''Code Geass'' anime series, pronounced "C-two" * C.C. Babcock, a character in the American sitcom ''The Nanny'' * Com ...
is formed between the first carbon of the alpha-mannose and the second carbon of the tryptophan. However, not all the sequences that have this pattern are mannosylated. It has been established that, in fact, only two thirds are and that there is a clear preference for the second
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
to be one of the polar ones (Ser, Ala, Gly and Thr) in order for mannosylation to occur. Recently there has been a breakthrough in the technique of predicting whether or not the sequence will have a mannosylation site that provides an accuracy of 93% opposed to the 67% accuracy if we just consider the WXXW motif.
Thrombospondins Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. The first member of the family, thrombospondin 1 (T ...
are one of the proteins most commonly modified in this way. However, there is another group of proteins that undergo ''C''-mannosylation, type I
cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...
s. ''C''-mannosylation is unusual because the sugar is linked to a
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 ma ...
rather than a reactive atom such as
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
or
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
. In 2011, the first crystal structure of a protein containing this type of glycosylation was determined—that of human complement component 8. Currently it is established that 18% of human
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s, secreted and transmembrane undergo the process of C-mannosylation. Numerous studies have shown that this process plays an important role in the secretion of Trombospondin type 1 containing proteins which are retained in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
if they do not undergo C-mannosylation This explains why a type of
cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...
s, erythropoietin receptor remained in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
if it lacked C-mannosylation sites.


Formation of GPI anchors (glypiation)

Glypiation is a special form of glycosylation that features the formation of a GPI anchor. In this kind of glycosylation a protein is attached to a lipid anchor, via a glycan chain. (See also
prenylation Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar ...
.)


Chemical glycosylation

Glycosylation can also be effected using the tools of synthetic organic chemistry. Unlike the biochemical processes, synthetic glycochemistry relies heavily on protecting groups (e.g. the 4,6-''O''-benzylidene) in order to achieve desired regioselectivity. The other challenge of chemical glycosylation is the stereoselectivity that each glycosidic linkage has two stereo-outcomes, α/β or ''cis''/''trans''. Generally, the α- or ''cis''-glycoside is more challenging to synthesis. New methods have been developed based on solvent participation or the formation of bicyclic sulfonium ions as chiral-auxiliary groups.


Non-enzymatic glycosylation

The non-enzymatic glycosylation is also known as
glycation Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic proce ...
or non-enzymatic glycation. It is a spontaneous reaction and a type of
post-translational 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 ...
of proteins meaning it alters their structure and biological activity. It is the
covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
attachment between the carbonil group of a reducing sugar (mainly glucose and fructose) and the amino acid side chain of the protein. In this process the intervention of an enzyme is not needed. It takes place across and close to the water channels and the protruding tubules. At first, the reaction forms temporary molecules which later undergo different reactions ( Amadori rearrangements, Schiff base reactions,
Maillard reaction The Maillard reaction ( ; ) is a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive flavor. Seared steaks, fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and m ...
s, crosslinkings...) and form permanent residues known as Advanced Glycation end-products (AGEs). AGEs accumulate in long-lived extracellular proteins such as collagen which is the most glycated and structurally abundant protein, especially in humans. Also, some studies have shown lysine may trigger spontaneous non-enzymatic glycosylation.


Role of AGEs

AGEs are responsible for many things. These molecules play an important role especially in nutrition, they are responsible for the brownish color and the aromas and flavors of some foods. It is demonstrated that cooking at high temperature results in various food products having high levels of AGEs. Having elevated levels of AGEs in the body has a direct impact on the development of many diseases. It has a direct implication in
diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinati ...
that can lead to many complications such as: cataracts,
renal failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
, heart damage... And, if they are present at a decreased level, skin elasticity is reduced which is an important symptom of aging. They are also the precursors of many
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s and regulate and modify their receptor mechanisms at the DNA level.


Deglycosylation

There are different enzymes to remove the glycans from the
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
or remove some part of the
sugar 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 do ...
chain. * α2-3,6,8,9-Neuraminidase (from Arthrobacter ureafaciens): cleaves all non-reducing terminal branched and unbranched sialic acids. * β1,4-Galactosidase (from Streptococcus pneumoniae): releases only β1,4-linked, nonreducing terminal galactose from complex carbohydrates and glycoproteins. * β-''N''-Acetylglucosaminidase (from Streptococcus pneumoniae): cleaves all non-reducing terminal β-linked N-acetylglucosamine residues from complex carbohydrates and glycoproteins. * ''endo''-α-''N''-Acetylgalactosaminidase (''O''-glycosidase from '' Streptococcus pneumoniae''): removes ''O''-glycosylation. This enzyme cleaves serine- or threonine-linked unsubstituted Galβ1,3GalNAc * PNGase F: cleaves
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
-linked oligosaccharides unless α1,3-core fucosylated.


Regulation of Notch signalling

Notch signalling is a cell signalling pathway whose role is, among many others, to control the
cell differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
process in equivalent precursor cells. This means it is crucial in embryonic development, to the point that it has been tested on mice that the removal of glycans in Notch proteins can result in embryonic death or malformations of vital organs like the heart. Some of the specific modulators that control this process are glycosyltransferases located in the
Endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
and the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
. The Notch proteins go through these organelles in their maturation process and can be subject to different types of glycosylation: N-linked glycosylation and O-linked glycosylation (more specifically: O-linked glucose and O-linked fucose). All of the Notch proteins are modified by an O-fucose, because they share a common trait: O-fucosylation consensus sequences. One of the modulators that intervene in this process is the Fringe, a glycosyltransferase that modifies the O-fucose to activate or deactivate parts of the signalling, acting as a positive or negative regulator, respectively.


Clinical

There are three types of glycosylation disorders sorted by the type of alterations that are made to the glycosylation process: congenital alterations, acquired alterations and non-enzymatic acquired alterations. * Congenital alterations: Over 40 congenital disorders of glycosylation (CGDs) have been reported in humans. These can be divided into four groups: disorders of protein ''N''-glycosylation, disorders of protein ''O''-glycosylation, disorders of lipid glycosylation and disorders of other glycosylation pathways and of multiple glycosylation pathways. No effective treatment is known for any of these disorders. 80% of these affect the nervous system. * Acquired alterations: In this second group the main disorders are infectious diseases, autoimmune illnesses or
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. In these cases, the changes in glycosylation are the cause of certain biological events. For example, in Rheumatoid Arthritis (RA), the body of the patient produces antibodies against the enzyme lymphocytes galactosyltransferase which inhibits the glycosylation of IgG. Therefore, the changes in the N-glycosylation produce the immunodeficiency involved in this illness. In this second group we can also find disorders caused by mutations on the enzymes that control the glycosylation of Notch proteins, such as
Alagille syndrome Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and ...
. * Non-enzymatic acquired alterations: Non-enzymatic disorders, are also acquired, but they are due to the lack of enzymes that attach oligosaccharides to the protein. In this group the illnesses that stand out are Alzheimer's disease and
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
. All these diseases are difficult to diagnose because they do not only affect one organ, they affect many of them and in different ways. As a consequence, they are also hard to treat. However, thanks to the many advances that have been made in
next-generation sequencing Massive parallel sequencing or massively parallel sequencing is any of several high-throughput approaches to DNA sequencing using the concept of massively parallel processing; it is also called next-generation sequencing (NGS) or second-generation ...
, scientists can now understand better these disorders and have discovered new CDGs.


Effects on therapeutic efficacy

It has been reported that mammalian glycosylation can improve the therapeutic efficacy of biotherapeutics. For example, therapeutic efficacy of recombinant human interferon gamma, expressed in HEK 293 platform, was improved against drug-resistant
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
cell lines.


See also

* * * * *


References


External links


GlycoEP
*
GlyProt: In-silico ''N''-glycosylation of proteins on the web

NetNGlyc: The NetNglyc server predicts ''N''-glycosylation sites in human proteins using artificial neural networks that examine the sequence context of Asn-Xaa-Ser/Thr sequons.

Supplementary Material of the Book "The Sugar Code"

Additional information on glycosylation and figures
* {{Metabolism Post-translational modification Organic reactions Carbohydrates Carbohydrate chemistry Biochemistry Congenital disorders of glycosylation