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O-linked glycosylation

In the field of biochemistry, O-linked glycosylation is the attachment of a sugar molecule to an oxygen atom in an amino acid residue in a protein.[1] O-linked glycosylation is a form of glycosylation that occurs in the Golgi apparatus in eukaryotes.[2] It also occurs in archaea and bacteria.


O-N-acetylgalactosamine (O-GalNAc)

O-linked glycosylation occurs at a later stage during protein processing, probably in the Golgi apparatus. This is the addition of N-acetyl-galactosamine to serine or threonine residues by the enzyme UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (EC number, followed by other carbohydrates (such as galactose and sialic acid). This process is important for certain types of proteins such as proteoglycans, which involves the addition of glycosaminoglycan chains to an initially unglycosylated "proteoglycan 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, 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. GlcNAc-β-Ser/Thr, which are found in nuclear and cytoskeletal proteins, were the first reported example of glycosylated proteins found in a location other than secretory channels.[3]


O-fucose is added between the second and third conserved cysteines of EGF-like repeats in the Notch protein, and other substrates by GDP-fucose protein O-fucosyltransferase 1, and to Thrombospondin repeats by GDP-fucose protein O-fucosyltransferase 2. In the case of EGF-like repeats, the O-fucose may be further elongated to a tetrasaccharide by sequential addition of N-acetylglucosamine (GlcNAc), galactose, and sialic acid, and for Thrombospondin repeats, may be elongated to a disaccharide by the addition of glucose. Both of these fucosyltransferases have been localized to the endoplasmic reticulum, which is unusual for glycosyltransferases, most of which function in the Golgi apparatus.


O-glucose is added between the first and second conserved cysteines of EGF-like repeats in the Notch 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 (OGT). O-GlcNAc appears to occur on most serines and threonines that would otherwise be phosphorylated by serine/threonine kinases. Thus, if phosphorylation occurs, O-GlcNAc does not, and vice versa. This apparently competitive modification of certain sites may have significant consequences for some research directions. Much cancer research is focused on phosphorylation, because of its important role in cell signalling pathways. As competitive or variable glycosylation occurs at the same sites, there is a risk that phosphorylation research has overlooked important roles that these modification sites play when glycosylated. 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 (OGA) enzyme has been linked to non-insulin dependent diabetes mellitus. It is the terminal step in a nutrient-sensing hexosamine signaling pathway.

Recently, O-GlcNAc was reported to occur between the fifth and sixth conserved cysteines in some EGF-like repeats from the Notch protein. This modification is performed by a second O-N-acetyglucosaminyl-transferase named eOGT.


During O-mannosylation, a mannose residue is transferred from mannose-p-dolichol to a serine/threonine residue in secretory pathway proteins.[4] O-mannosylation is common to both prokaryotes and eukaryotes.



Many lysines in collagen are hydroxylated to form hydroxylysine, and many of these hydroxylysines are then glycosylated by the addition of galactose. This galactose monosaccharide can then be further elongated by the addition of a glucose. This glycosylation is required for the proper functioning of collagen. Glycosylation of hydroxylysine starts in the ER, but occurs predominantly in the Golgi apparatus.[5]

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 discoideum 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 and arabinose glycans being reported in the literature.


Liver and muscle glycogenin carries a glucose on a tyrosine side chain. This was one of the first known examples of glycosylated tyrosine in nature and is due to auto-modification by the enzyme.


The large and complex glycans that modify proteoglycans are initiated by addition of xylose to serine. There are only two other forms of glycosylation known to begin with xylose addition directly to protein. One is xylose seen on phospho-serine in Dictyostelium discoideum, and the other is a rare modification on Notch EGF-like repeats where O-xylose is transferred by the Rumi enzyme in place of O-glucose in certain contexts.


Either a galactose or a glucose 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.

See also


  1. ^ Van den Steen P, Rudd PM, Dwek RA, Opdenakker G (1998). "Concepts and principles of O-linked glycosylation". Crit. Rev. Biochem. Mol. Biol. 33 (3): 151–208. doi:10.1080/10409239891204198. PMID 9673446.
  2. ^ William G. Flynne (2008). Biotechnology and Bioengineering. Nova Publishers. pp. 45–. ISBN 978-1-60456-067-1. Retrieved 13 November 2010.
  3. ^ Spiro RG (2002). "Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds". Glycobiology. 12 (4): 43R–65R. doi:10.1093/glycob/12.4.43r. PMID 12042244.
  4. ^ Lommel M, Strahl S (August 2009). "Protein O-mannosylation: conserved from bacteria to humans". Glycobiology. 19 (8): 816–28. doi:10.1093/glycob/cwp066. PMID 19429925.
  5. ^ Harwood R, Grant ME, Jackson DS (1975). "Studies on the glycosylation of hydroxylysine residues during collagen biosynthesis and the subcellular localization of collagen galactosyltransferase and collagen glucosyltransferase in tendon and cartilage cells". The Biochemical Journal. 152 (2): 291–302. doi:10.1042/bj1520291. PMC 1172471. PMID 1220686.

External links

  • GlycoEP : In silico Platform for Prediction of N-, O- and C-Glycosites in Eukaryotic Protein Sequences