Chemistry Reference
In-Depth Information
same-site occupancy has been shown for c-Myc (c-Myc is a member of the family
of
myc
protooncogenes derived from a chicken retrovirus and codes for a transcrip-
tion factor oncoprotein) and estrogen receptor-
, while adjacent occupancy has
been reported in the tumor suppressor p53. The cycling of GlcNAc and phosphate
on the same protein, both posttranslational modifi cations, each with independent
regulation, represents a rapid response mechanism with a considerable molecular
range for control of protein interaction and function [5] .
β
7.3.3
O
- M an
Regulation of
O
-Man glycan synthesis is largely due to the enzyme specifi city of
the POMT transferases with regard to the few known protein substrates. Most data
are available for
-dystroglycan. Extension through the action of POMGnT1 also
shows tight substrate specifi city and offers an additional site of regulation. Further
extension of the GlcNAc
α
-
O
-Ser/Thr disaccharide through fukutin and a
variety of other glycosyltransferases is probably regulated at species-, tissue- and
cell - specifi c levels, and depends on the complement, enzyme concentration, speci-
fi city and activity, leading to competition for substrates.
The subcellular separation of initial
O
-mannosylation by the POMTs in the ER
and the extension of the glycans by POMGnT1 and other glycosyltransferases
located in the Golgi apparatus is a further and more sophisticated point of regula-
tion depending on complex formation with other transport proteins.
β
1,2Man
α
7.3.4
O
- F uc and
O
- G lc
The regulation of
O
- Fuc and
O
-Glc expression is complex and only a brief overview
is given here. Both of these protein-linked sugars yield glycan chains that have
signifi cant biological activities and much of the data available suggesting regula-
tory activity for their formation has been tested in biological systems where glycans
of different structure have been assessed. Initially the transfer of the sugar to the
protein acceptor depends on the existence of consensus sequences in limited
protein domains, as detailed earlier. The occurrence of the correct acceptor
sequence is evidence of regulation and this is apparent for both the
O
- fucosylation
and
O
-glucosylation of EGF and TSR domains of characterized substrates [7, 8].
The extension of the glycans beyond the initial monosaccharide may be regu-
lated through substrate availability at the relevant subcellular location. This will
include (glyco)protein acceptor and nucleotide donor, the combination of relevant
glycosyltransferases and chaperones or other regulatory proteins or cofactors. For
example, the alteration in
O
-Fuc saccharide structure caused by Fringe modulates
the response of Notch to its ligands [8]. Thus, glycosylation serves an important
role in regulating Notch activity. Finally the regulation of transport of products
from their subcellular sites of synthesis is important, as has been demonstrated
with POFUT1.
