Chemistry Reference
In-Depth Information
chains.
15
Conversely, the expression of b6GlcNAc T1 is low or absent in
50% of breast cancers, leading to the expression of shorter sialylated
structures such as sTn or core 1 based sialylated O-glycans.
16
The synthesis of core 3 is achieved by a unique b1,3-N-Acetyl-
glucosaminyltransferase (b3GlcNAc T6) expressed in mucous epithelia
from the gastrointestinal and respiratory tracts.
17
Core 3 synthase en-
zyme is down-regulated in colon cancers and its expression suppresses
the metastatic capacity of cancer cells.
18
In addition, mice lacking core
3-derived O-glycans show an increased susceptibility to colitis and
colorectal tumours.
19
As mentioned earlier, b6GlcNAc T2, also named C2/
4GnT, is involved in both core 2 and core 4 biosynthesis.
3.1.3 Elongation of O-glycan chains. O-glycan chains can be elong-
ated by repeating b-Galp-(1
3) units (i-antigen, poly-N-
Acetyl-lactosamine type 2 chains) that are synthesized by the alternating
actions of b1,4-galactosyltransferases and ib1,3-N-Acetyl-glucosaminyl-
transferases (Table 2). Three different ib1,3-N-Acetyl-glucosaminyl-
transferases (iGlcNAcT), b3GlcNAc T2, T3, and T4, are able to catalyze the
initiation and elongation of poly-N-Acetyl-lactosamine sugar chains.
However, they exhibit different expression patterns and substrate speci-
ficity suggesting specific functions.
20
Several b1,4-galactosyltransferases
are also required for poly-N-Acetyl-lactosamine chains biosynthesis. For
example, extension of core 4 branches was found to be synthesized most
eciently by iGlcNAcT and b4Gal T1, whereas b4Gal T4 is the most
ecient enzyme for poly-N-Acetyl-lactosamine extension of core 2 bran-
ched oligosaccharides.
21,22
b4Gal T5 may also function in the synthesis
of LacNAc units on O-linked chains, particularly in tissues which do not
express b4Gal T1.
23
Linear i-antigen can be converted during develop-
ment to I-antigen by the action of branching b1,6-N-Acetyl-glucosami-
nyltransferases (IGnT). Three IGnTs differentially expressed are
generated by alternative splicing of a single gene CGNT2, sharing exons 2
and 3, but their precise role in branched structures biosynthesis remains
unclear.
24
b6GlcNAc T2, the core 2/4 synthase, is also involved in I-anti-
gens biosynthesis.
In certain tissues, especially in the gastrointestinal or reproductive
tracts, b1,3-galactosyltransferase(s) can add b1,3-linked Galp residues on
terminal GlcpNAc of mucin O-glycans. This reaction yields the b-Galp-
(1
-
4)-b-GlcpNAc-(1
-
3)-b-GlcpNAc disaccharide that defines type-1 chains. Among the
different b1,3-galactosyltransferases characterized, b3Gal T5 is respon-
sible for the synthesis of type 1 Lewis antigens in colonic mucosa and
pancreatic tissue, and also displays activity towards the core 3 b-GlcpNAc-
(1
-
3)-a-GalpNAc structure.
25,26
Type 1 and type 2 chains can subsequently be modified by several
glycosyltransferases (fucosyltransferases, sialyltransferases, N-Acetyl-
galactosaminyltransferases) and sulfotransferases, leading to the syn-
thesis of a variety of terminal structures, such as blood-group-active
structures, and other types of sialylated, fucosylated, and sulphated
structures.
-
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