The term glycan refers to a
polysaccharideor oligosaccharide. Glycan may also be used to refer to the carbohydrateportion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan (or more specifically a glucan) composed of beta-1,4-linked D-glucose, and chitin is a glycan composed of beta-1,4-linked N-acetyl-D-glucosamine. Glycans can be homo or heteropolymers of monosaccharide residues, and can be linear or branched.
Glycans and Proteins
Glycans can be found attached to proteins as in glycoproteins and proteoglycans. They are generally found on the exterior surface of cells. O- and N-linked glycans are very common in
eukaryotesbut may also be found, although less commonly, in prokaryotes.
N-Linked glycans are found attached to the R-group nitrogen (N) of
asparaginein the sequon. The sequon is a Asn-X-Ser or Asn-X-Thr sequence, where X is any amino acid except prolineand may be composed of N-acetyl galactosamine, galactose, neuraminic acid, N-acetylglucosamine, fructose, mannose, fucoseand other monosaccharides.
In eukaryotes, N-linked glycans are derived from a core 14-
sugarunit assembled in the cytoplasmand endoplasmic reticulum. First, two N-acetyl glucosamine residues are attached to dolichol phosphate, a lipid, on the external side of the endoplasmic reticulum membrane. Five mannose residues are then added to this structure. At this point, the partially finished core glycan is flipped across the endoplasmic reticulum membrane, so that it is now located within the reticular lumen. Assembly then continues within the endoplasmic reticulum, with the addition of four more mannose residues. Finally, three glucose residues are added to this structure. Following full assembly, the glycan is transferred en bloc by the glycosyltransferase oligosaccharyltransferaseto a nascent peptide chain, within the reticular lumen. This core structure of N-linked glycans thus consists of 14 residues (3 glucose, 9 mannose, and 2 N-acetylglucosamine).
Dark squares are N-acetyl-glucosamine; light circles are mannose; dark triangles are glucose.
Processing, modification, and diversity
Once transferred to the nascent peptide chain, N-linked glycans generally undergo extensive processing reactions, whereby the three glucose residues are removed, as well as several mannose residues, depending on the N-linked glycan in question. The removal of the glucose residues is dependent on proper protein folding. These processing reactions occur in the
golgiapparatus. Modification reactions may involve the addition of a phosphate or acetyl group onto the sugars, or the addition of new sugars, such as neuraminic acid. Processing and modification of N-linked glycans within the golgi does not follow a linear pathway. As a result, many different variations of N-linked glycan structure are possible, depending on enzyme activity in the golgi.
Functions and importance
N-linked glycans are extremely important in proper protein folding in eukaryotic cells. Chaperone proteins in the endoplasmic reticulum, such as
calnexinand calreticulinbind to the three glucose residues present on the core N-linked glycan. These chaperone proteins then serve to aid in the folding of the protein that the glycan is attached to. Following proper folding, the three glucose residues are removed, and the glycan moves on to further processing reactions. If the protein fails to fold properly, the three glucose residues are reattached, allowing the protein to re-associate with the chaperones. This cycle may repeat several times until a protein reaches its proper conformation. If a protein repeatedly fails to properly fold, it is excreted from the endoplasmic reticulum and degraded by cytoplasmic proteases.
N-linked glycans also contribute to protein folding by steric effects. For example,
cysteineresidues in the peptide may be temporarily blocked from forming disulfide bonds with other cysteine residues, due to the size of a nearby glycan. The presence of a N-linked glycan therefore allows the cell to control which cysteine residues will form disulfide bonds.
N-linked glycans also play an important role in cell-cell interactions. For example, tumour cells make N-linked glycans that are abnormal. These are recognized by the CD337 receptor on
Natural Killer cells as a sign that the cell in question is cancerous.
The targeting of degradative
lysosomalenzymes is also accomplished by N-linked glycans. The modification of an N-linked glycan with a mannose-6-phosphateresidue serves as a signal that the protein which this glycan is attached to should be moved to the lysosome. This recognition and trafficking of lysosomal enzymes by the presence of mannose-6-phosphate is accomplished by two proteins: CI-MPR (cation independent mannose-6-phosphate receptor) and CD-MPR (cation dependent mannose-6-phosphate receptor).
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.figgrp.1703 : CD-MPR and CI-MPR, with CI-MPR shown binding a lysosomal enzyme.http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.figgrp.1704 : CD-MPR with bound mannose-6-phosphate (yellow-green).
In eukaryotes, O-linked glycans, are assembled one sugar at a time on a
serineor threonineresidue of a peptide chain in the Golgi apparatus. Unlike with N-linked glycans, there is as of yet no known consensus sequence. However, the placement of a prolineresidue at either -1 or +3 relative to the serine or threonine is favourable for O-linked glycosylation.
The first monosaccharide attached in the synthesis of O-linked glycans is N-acetyl-galactosamine. After this, several different pathways are possible. A Core 1 structure is generated by the addition of galactose. A Core 2 structure is generated by the addition of N-acetyl-glucosamine to the N-acetyl-galactosamine of the Core 1 structure. Core 3 structures are generated by the addition of a single N-acetyl-glucosamine to the original N-acetyl-galactosamine. Core 4 structures are generated by the addition of a second N-acetly-glucosamine to the Core 3 structure. Other core structures are possible, though are less common.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.figgrp.561 : Core 1 and Core 2 generation. White square = N-acetyl-galactosamine; black circle = galactose; Black square = N-acetly-glucosamine; note, there is a mistake in this diagram. The bottom square should always be white in each image, not black.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.figgrp.562 : Core 3 and Core 4 generation.
A common structural theme in O-linked glycans is the addition of
polylactosamineunits to the various core structures. These are formed by the repetitive addition of galactose and N-acetyl-glucosamine units. Polylactosamine chains on O-linked glycans are often capped by the addition of a sialic acidresidue (similar to neuraminic acid). If a fucose residue is also added, to the next to penultimate residue, a sialyl-lewis-X(SLex)) structure is formed.
Functions and importance
Sialyl lewis xis important in ABOblood antigen determination.
SLex is also important to proper immune response. E-
selectinrelease from Weibel-Paladebodies, on blood vessel epithelial cells can be induced by a number of factors. One such factor is the response of the epithelial cell to certain bacterial molecules, such as peptidoglycan. E-selectin binds to the Slex structure that is present on neutrophils in the blood stream, and helps to mediate the extravasationof these cells into the surrounding tissue during and infection.
O-linked glycans, particularly mucin, have been found to be important in developing normal intestinal microflora. Certain strains of intestinal bacteria specifically bind to mucin, allowing them to colonize the intestine.
Examples of O-linked
Glycophorin, a protein in erythrocyte cell membranes
Mucin, a protein in salivainvolved in formation of dental plaque
*Notch, a transmembrane receptor involved in development and cell fate decisions
Urinary type Plasminogen Activator
Another type of cellular glycan are the glycosaminoglycans. These comprise 2-aminosugars linked in an alternating fashion with uronic acids and include polymers such as heparin, heparan sulfate, chondroitin, keratin and dermatan. Some glycoaminoglycans are found attached to the cell surface where they are linked through a single xylosyl residue to a protein.
Glycans and lipids
*Varki, Ajit; Cummings, Richard; Esko, Jeffrey; Freeze, Hudson; Hart, Gerald; Marth, Jamey, editors.Plainview (NY): Cold Spring Harbor Laboratory Press; c1999.(available online at http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=glyco.TOC&depth=2 )
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