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 dystroglycan
4. 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 webNetNGlyc: 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