Chemistry Reference
In-Depth Information
brain, GM2/GD2 synthase null mice have apparently normal brain morphology.
With age, the KO mice show marked degeneration and demyelination of nerves,
and poor regeneration of resected nerves, indicating that gangliosides are essential
for the maintenance and repair of nerve tissues.
The biosynthesis of the HS chain is divided into three phases: chain initiation,
polymerization and modifi cation (please see Chapter 11.1 for biosynthetic pathway
of HS chain). In the chain-initiation phase, linkage tetrasaccharides (GlcA
β
1 -
3Gal
1-O-Ser) are assembled on selected serine residues in the
core protein. Following addition of GlcNAc to the linkage tetrasaccharides, polym-
erization of the chain is carried out through alternating transfer of GlcA and
GlcNAc units to the nonreducing end of the growing polysaccharide. As the chain
grows, modifying enzymes introduce sulfate groups at various positions and some
of the
D
-glucuronic acid residues are converted into
L
- iduronic acid (please see
Chapter 1.3 for special features of
L
-iduronic acid). The obligatory initiation step
of this modifi cation is catalyzed by GlcNAc
N
- deacetylase/
N
- sulfotransferase
(NDST). Depending on the targeted enzyme, HS proteoglycans are remodeled in
a different way (Figure 23.9) [5]. If polymerases (EXT1 and EXT2, called after
hereditary multiple exostoses, please see Chapter 22.3) are knocked out, only short
stubs containing the linkage tetrasaccharides are attached. If NDST is inactivated,
nonsulfated polysaccharide chains are formed. If other specifi c
O
- sulfotransfer-
ases are knocked out, a more subtle change is induced.
A number of important signaling molecules, such as fi broblast growth factors
(FGFs), Wingless (Wg/Wnt), TGF-
β
1 - 3Gal
β
1 - 4Xyl
β
and Hedgehog, need HS proteoglycans to
display their proper function during development. Therefore, mice lacking the HS
chain would be expected to present developmental disorders. Indeed, mouse
embryos lacking EXT1 or EXT2 die around the time of gastrulation [3]. NDST1
KO mice die early after birth due to lung failure, and with skull and brain defects,
while NDST2 KO mice survive until adulthood and are fertile. The NDST2 null
β
Figure 23.9
HS proteoglycans in HS chain - synthesizing enzymes KO mice.
