Chemistry Reference
In-Depth Information
Info Box 2
The transfer of GalNAc to the serine/threonine residues to initiate the
O
-
GalNAc, mucin-type glycans was fi rst identifi ed by Saul Roseman in 1967.
Examination of substrate specifi city showed that there were sequence require-
ments for the serine or threonine acceptors and this led ultimately to the iden-
tifi cation of a family ppGaNTases (EC 2.4.1.41) largely through the work of the
Henrik Clausen (Copenhagen, Denmark) and Lawrence Tabac (Bethesda, USA)
groups. The ppGaNTases are type II membrane proteins comprising a short
N
-terminal cytoplasmic tail linked to a small transmembrane anchor, which is
in turn associated via a stem domain to a large component located in the lumen
of the Golgi. The family has more than 19 members, and refl ects the need for
generation of clustered
O
-glycan substitution in mucin tandem repeat sequences
and the stem domains of membrane glycoproteins. The detection of a number
of pseudogenes during cloning work on these transferases emphasized the
need to demonstrate enzymatic activity for each protein identifi ed. The large
number of family members refl ects the importance of the initial transfer of
GalNAc to initiate mucin-type
O
-glycans and the need to ensure maximum
occupancy of tandem repeat domains in molecules such as the mucins where
the carbohydrate content plays roles in physical properties such as viscoelastic-
ity in addition to information conferred by the glycan sequence. Although the
ppGaNTases are present in the majority of tissues examined there is a selective
expression of members of the family and this matches the main glycoprotein
substrates found in these tissues. The substrate specifi city shows that different
isoenzymes show specifi city for peptides or glycopeptides and prior glycosyl-
ation of serine or threonine with GalNAc at certain positions in the peptide.
Further evidence for selective subcellular expression of ppGaNTase isoenzymes
between the rough endoplasmic reticulum (ER) and Golgi apparatus further
underlines the sophisticated utilization of the family of transferases to ensure
optimal
O
-glycosylation. The data available for mucin substrates suggests that
the initial transfer of GalNAc takes place in a hierarchical manner. Thus the
complete glycosylation of such substrates relies on the coordinated action of
multiple ppGaNTase family members.
enzyme is similar but distinct from other
N
- acetylglucosaminyl transferases
leading to the formation of the same linkage in
N
- glycans. Considerable interest
has followed the identifi cation of these two glycosyltransferases as their deletion
has been associated with a number of congenital abnormalities which are detailed
in Chapter 22.2.2.
The completion of the
O
-Man glycans depends on the action of galactosyl and
sialyltransferases and the binding of fukutin, itself a glycosyltransferase. Fukutin
is found to colocalize with POMGnT1 in the Golgi most likely through the
formation of a complex and may play a role in modulating the glycosyltransferase
activity. Recent developments have shown that GnT-Vb also plays a role in the
