N-Glycosylation - The Sugar Code - page 104

6.3 and 6.5c). The next obligate step in this process is the addition of a GlcNAc
residue to the 6 - N - acetylglu-

cosaminyltransferase II; Q10469). The resulting biantennary N - glycans may be
acceptor substrates for medial Golgi-located MGAT5A (Q09328) or MGAT5B
(Q3V5L5), which produce triantennary

′ - antenna by MGAT2 ( α 1,6 - mannosyl - glycoprotein 2 - β

1,6 - branched N - glycans. Alternatively,
bisecting MGAT3 (Q09327) may modify biantennary N - glycans at the core
mannose, which precludes further branching by MGAT5, but not by MGAT4
enzymes. Therefore, spatial and temporal positioning of both MGAT3 and MGAT5
activity regulates biosynthesis of glycans, and infl uences function at a central
point. Effects of

β

1,6 branches in glycoproteins on cell growth, motility, cell adhe-
sion and differentiation are well documented. They range from regulating metabo-
lism, growth and immune reactions [16], to participation in tissue regeneration
[17], as well as a strong correlation between detectable

β

1,6 branches in primary
tumor and survival of colon carcinoma patients [18]. Further branching by three
MGAT4 isoenzymes may modify the

β

1,3-mannosyl branch to form either tri- or
tetraantennary N -glycans. These isoenzymes are broadly expressed with tissue-
specifi c variations and exhibit distinctive protein- substrate specifi cities (for pheno-
types of KO mice, please see Table 23.1).

α

6.8.2
N - Acetylglucosaminyl - - Galactosyltransferases β

The GlcNAc added by MGAT3 is the only terminal, nonreducing GlcNAc residue
found in mature N -linked oligosaccharides in human. All others are elongated by
galactose through various 1,4 - galactosyltransferases (B3GT and B4GT)

to form either type I or II glycans [Gal

β 1,3 - or β

1,(3)4GlcNAc: LacNAc] that are susceptible
to further condensation reactions. Whether N -glycans of type I or type II are syn-
thesized is not encoded in the glycoprotein itself, but depends on the availability
of the respective galactosyltransferases. NCAM1 obtained from human brain
carries type II N -glycans, whereas NCAM1 synthesized in calf brain exhibits both
types. The fi ve different human N - glycan - processing B4GT isoenzymes act rather
nonspecifi cally. They add galactose to any terminal GlcNAc residue, independent
of its linkage and irrespective of its presence on N - and O -glycans or a lipid. B4GTs
are widely expressed with tissue- specifi c variations and located in trans cisternae
of the Golgi apparatus in a COG-dependent manner. The ubiquitous B4GT1
(P15291) acts as a cell-surface lectin on germ cells and exists as a soluble enzyme
in various body fl uids (milk, semen, etc.). In addition to its major role in N - glycan
processing, B4GT1 is the lactose-synthesizing enzyme in mammary glands. Defi -
ciency of B4GT1 activity cannot be complemented by its homologs in every tissue
and therefore causes CDG type IId in humans (see Table 22.1 ).

β

6.8.3
Capping Sugars Provide Functions

Terminal reactions on N -glycans through which sialic acid, fucose, glucuronic acid
and sulfate are added, represent modifi cations functionally involved in many bio-