Chemistry Reference
In-Depth Information
signs of thrombosis, endogenous heparin is not involved in the regulation of
coagulation. It instead plays a role in regulating the mast cell mediators, such as
histamine and the mast cell- specifi c proteases (chymases and tryptases).
23.2.6
Insights into Human Diseases
The phenotype of KO mice may provide a symptomatic clue in a search for human
defi ciencies that are poorly understood at present (please see Chapter 22 for more
details on human disorders of glycosylation). KO mice also may serve as a test
animal model for the newly developed treatment.
Fucosylation is a common modifi cation of glycoproteins and is catalyzed by
fucosyltransferases, all of which require GDP-Fuc as the donor substrate (please
see Chapters 6 and 7 for biosynthesis of glycoproteins). Fucosylations in mammals
are classifi ed into four groups based on the specifi c linkages formed and the
substrates to which Fuc is added:
1,6 -
fucosylation and
O
- fucosylation. The biological signifi cance of fucosylation in
humans has been proved by studies on an autosomal recessive disease called
leukocyte adhesion defi ciency ( LAD ) - II/ congenital disorder of glycosylation
(CDG)-IIc, which is characterized by leukocyte adhesion defi ciency as well as severe
neurological and developmental abnormalities (please see Chapter 22.6 for LAD
and CDG and Table 27.4). Patients with LAD-II/CDG-IIc have a mutation in the
Golgi GDP-Fuc transporter, resulting in decreased GDP-Fuc levels in the Golgi
lumen and, hence, reduction of fucosylation in many types of glycoproteins. The
LAD may be ascribed to the loss of sialyl- Le
x
determinant containing
α
1,2 - fucosylation,
α
1,3/4 - fucosylation,
α
1,3 - fucosyl-
ation. It had been assumed that the neurological and developmental symptoms of
LAD-II/CDG-IIc patients might be linked to impaired Notch signaling mediated
by
O
- fucosylation. However,
O -
fucosylation does not occur in the Golgi, but in the
ER and, hence, is generally unaffected in LAD- II/CDG - IIc patients. Alternatively,
the neurological and developmental symptoms might be related to the loss of
α
1,6 -
fucosylation. This possibility should be assessed by studies on FucT- VIII KO mice
in the future (for emerging functions of
O -
fucosylation, please see Table 7.9 ).
The analysis of glycogene KO mice sometimes provides an insight into common
diseases such as diabetes mellitus and cancer. Glucose transporter 2 ( Glut - 2 ) on
the pancreatic
α
cell plasma membranes plays a critical role in glucose-stimulated
insulin secretion, thereby controlling blood glucose homeostasis in response to
dietary intake. The GnT-IVa (Mgat-4a) KO mice (please see Chapter 6.8 for this
part of the biosynthetic pathway of
N
-glycans) exhibit attenuation of
β
cell Glut - 2
glycosylation [2]. The attenuated glycosylation leads to endocytosis of Glut-2 and
thereby the cell-surface expression of Glut-2 is reduced. Thus, GnT- IVa KO mice
develop type 2 diabetes. The induction of diabetes by chronic ingestion of a high-
fat diet is associated with reduced GnT-IV expression and attenuated Glut-2 gly-
cosylation coincident with Glut-2 endocytosis. The lesson from the GnT- IVa KO
mice is that the fl uctuation of
β
cell Glut-2 glycosylation can be the pathogenesis
of type 2 diabetes (see also Table 25.2). On the other hand, insulin sensitivity is
β
