O-linked glycosylation
Encyclopedia
O-N-acetylgalactosamine (O-GalNAc)
O-linked glycosylation occurs at a later stage during protein processing, probably in the Golgi apparatusGolgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
. This is the addition of N-acetyl-galactosamine to serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
or threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
residues by the enzyme UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase , followed by other carbohydrates (such as galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
and sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
). This process is important for certain types of proteins such as proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
s, which involves the addition of glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
chains to an initially unglycosylated "proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
core protein." These additions are usually serine O-linked glycoproteins, which seem to have one of two main functions. One function involves secretion to form components of the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, adhering one cell to another by interactions between the large sugar complexes of proteoglycans. The other main function is to act as a component of mucosal secretions, and it is the high concentration of carbohydrates that tends to give mucus its "slimy" feel. Proteins that circulate in the blood are not normally O-glycosylated, with the exception of IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
1 and IgD
IGD
IGD can refer to:*Internet Gateway Device as defined in UPnP.*İGD, İlerici Gençler Derneği, Progressive Young Association of Turkey*Immunoglobulin D, an antibody protein involved in the maturation of B cells....
(two types of antibody) and C1-inhibitor
C1-inhibitor
C1-inhibitor is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during...
.
O-fucose
O-fucose is added between the second and third conserved cysteines of EGF-like repeats in the NotchNotch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
protein, and other substrates by GDP-fucose protein O-fucosyltransferase 1
GDP-fucose Protein O-fucosyltransferase 1
GDP-fucose protein O-fucosyltransferase 1 is an enzyme responsible for adding fucose sugars in O linkage to serine or threonine residues between the second and third conserved cysteines in EGF-like repeats on the Notch protein...
, and to Thrombospondin repeats by GDP-fucose protein O-fucosyltransferase 2
GDP-fucose protein O-fucosyltransferase 2
GDP-fucose protein O-fucosyltransferase 2 is an enzyme responsible for adding fucose sugars in O linkage to serine or threonine residues in Thrombospondin repeats...
. In the case of EGF-like repeats, the O-fucose
Fucose
Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on N-linked glycans on the mammalian, insect and plant cell surface, and is the fundamental sub-unit of the fucoidan polysaccharide...
may be further elongated to a tetrasaccharide by sequential addition of N-acetylglucosamine
N-Acetylglucosamine
N-Acetylglucosamine is a monosaccharide derivative of glucose. It is an amide between glucosamine and acetic acid...
(GlcNAc), galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
, and sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
, and for Thrombospondin repeats, may be elongated to a disaccharide by the addition of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
. Both of these fucosyltransferases have been localized to the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, which is unusual for glycosyltransferases, most of which function in the Golgi
Golgi
Golgi may refer to:*Camillo Golgi , Italian physician and scientist after which the following terms are named:**Golgi apparatus , an organelle in the eukaryotic cell...
apparatus.
O-glucose
O-glucose is added between the first and second conserved cysteines of EGF-like repeats in the NotchNotch
Notch may refer to:* The nock of an arrow* Notch , a Hip hop, R&B, reggae, dancehall and reggaeton artist* Notch signaling pathway, a cell signaling system present in most multicellular organisms...
protein, and possibly other substrates by protein:O-glucosyltransferase (Poglut). This enzyme is known as Rumi in Drosophila, and is also localized to the ER like the O-fucosyltransferases. The O-glucose modification appears to be necessary for proper folding of the EGF-like repeats of the Notch protein, and increases secretion of this receptor.
O-N-acetylglucosamine (O-GlcNAc)
O-GlcNAc is added to serines or threonines by O-GlcNAc transferase. O-GlcNAc appears to occur on most serines and threonines that would otherwise be phosphorylated by serine/threonine kinases. Thus, if phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
occurs, O-GlcNAc does not, and vice versa. This is an incredibly important finding because phosphorylation/dephosphorylation has become a scientific paradigm for the regulation of signaling within cells. A massive amount of cancer research is focused on phosphorylation. Ignoring the involvement of this form of glycosylation, which clearly appears to act in concert with phosphorylation, means that a lot of current research is missing at least half of the picture. O-GlcNAc addition and removal also appears to be a key regulator of the pathways that are disrupted in diabetes mellitus. The gene encoding the O-GlcNAcase enzyme has been linked to non-insulin dependent diabetes mellitus. It is the terminal step in a nutrient-sensing hexosamine signaling pathway.
O-N-acetylglucosamine In Other Contexts
Recently, O-GlcNAc was reported to occur between the fifth and sixth conserved cysteines in some EGF-like repeats from the Notch protein. It would seem unlikely that this modification would be due to the same enzyme involved with addition of O-GlcNAc to cytoplasmic and nuclear localized proteins. Considering that O-fucose and O-glucose addition to EGF-like repeats is due to ER localized enzymes, presumably an ER localized protein O-GlcNAc transferase exists.O-mannose
During O-mannosylation, a mannose residue is transferred from mannose-p-dolichol to a serine/threonine residue in secretory pathway proteins. O-mannosylation is common to both prokaryotes and eukaryotes.Collagen Glycosylation
Many lysineLysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
s in collagen are hydroxylated to form hydroxylysine
Hydroxylysine
5-Hydroxylysine is an amino acid with the molecular formula C6H14N2O3. It was first discovered in 1921 by Donald Van Slyke. It is a hydroxy derivative of lysine. It is most widely known as a component of collagen....
, and many of these hydroxylysines are then glycosylated by the addition of galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
. This galactose monosaccharide can then be further elongated by the addition of a glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
. This glycosylation is required for the proper functioning of collagen. Glycosylation of hydroxlysine occurs in the ER.
Hydroxyproline Glycosylation
Proline is also hydroxylated in collagen, however, no glycosylation occurs here as the hydroxyprolines are necessary for hydrogen bonding in the collagen triple helix. There is one protein named Skp1 in Dictyostelium discoideumDictyostelium discoideum
Dictyostelium discoideum is a species of soil-living amoeba belonging to the phylum Mycetozoa. D. discoideum, commonly referred to as slime mold, is a eukaryote that transitions from a collection of unicellular amoebae into a multicellular slug and then into a fruiting body within its lifetime. D...
that carries a GlcNAc on hydroxyproline, but this would appear to be an extremely rare form of glycosylation. Otherwise, only plants appear to carry glycans on hydroxyproline, with both galactose
Galactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
and arabinose
Arabinose
Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde functional group.For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, or structurally analogous to D-glyceraldehyde.For sugars, the D/L...
glycans being reported in the literature.
Glycosylation of Glycogenin
Liver and muscle glycogenin carries a glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
on a tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
side chain. This is the only known example of glycosylated tyrosine in nature.
Glycosylation of Ceramide
Either a galactoseGalactose
Galactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
or a glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
can be added to a hydroxyl on the lipid ceramide. The glucose can be further elongated to a disaccharide by the addition of a galactose.