Chemistry Reference
In-Depth Information
mice, however, display only a phenotype with abnormal mast cells containing no
heparin (see Section 23.2.5). Mice lacking both NDST1 and NDST2 die during
early embryonic development. Phenotypes of mice with KO of 2-
O
- sulfotransfer-
ase and C5-epimerase are similar to each other. They die during neonatal period
and lack kidneys. C5-epimerase KO mice also display a lung abnormality that is
not present in the 2-OST-defi cient mice but similar to the phenotype of NDST1-
null mice.
23.2.5
Unexpected Findings Provide New Insights into Glycan Functions
A number of unexpected phenotypes have been revealed by generation of glyco-
gene KO mice. These fi ndings have provided a series of new insights into the
functions of glycans.
β
1,4 - Gal transferase (
β
4GalT - I), which was the fi rst cloned glycogene, forms
the Gal
1-4GlcNAc structure that is quite common in complex-type
N
- glycans,
O
-glycans and glycolipids (please see Chapters 6
-
8 , 10 and 30 for oligosaccharide
structures in
N
- glycans,
O
-glycans and glycolipids, respectively). Therefore, inac-
tivation of
β
4GalT-I had been expected to show severe systemic phenotypes. On
the contrary,
β
4GalT-I KO mice were born healthy and fertile, but they exhibited
growth retardation and semilethality during the neonatal period [2]. This fi nding
suggested that other isozymes compensate for the loss of
β
β
4GalT - I function. In
fact, a number of
β
1,4 - Gal transferases (
β
4GalT - II
∼
VII) have subsequently been
found (please see also Table 22.1 on CDG - IId).
- Mannosidase - II ( MII ) trims two Man residues to yield Man
3
after GlcNAc
transfer by GnT-I, which serves as the precursor for GnT-II in the biosynthesis of
complex - type
N
- glycans (Figure 23.5) (please see also Chapter 6.6 for the biosyn-
thetic pathway of
N
-glycans). It is therefore expected that MII KO mice should
display a more severe phenotype than GnT-II KO mice. However, it was found
that complex- type
N
-glycans were retained in most tissues other than erythrocytes
in MII KO mice [2]. Associated with the loss of complex-type
N
- glycans in eryth-
rocytes, null mice exhibit dyserythropoiesis that correlates with human congenital
dyserythropoietic anemia type II (HEMPAS).
α
- Mannosidase IIx (MX) was cloned
as an MII-related gene. MX KO mice were born and grew normally, but male mice
were found to be infertile. To elucidate the relationship between MII and MX
function
in vivo,
MII/MX double -KO mice were produced. The double-KO mice
completely lack complex-type
N
-glycans and display perinatal death. Thus, MII
and MX compensate for each other in most tissues except for erythrocytes and
testes.
Heparin and HS proteoglycan are well-known anticoagulants (please see Chapter
28.5 for a pharmaceutical role of heparin). 3-
O
- Sulfotransferase - 1 has been thought
to be a key enzyme in producing the pentasaccharide domain interacting with
antithrombin (Figure 1.7d). However, 3-
O
- sulfotransferase - 1 KO mice did not
show a procoagulant phenotype [3]. The NDST-2 KO mice completely lack sulfated
heparin in the secretory granules of mast cells. As NDST-2 null mice show no
α
