Carbohydrate Metabolism III: Glycoproteins, Glycolipids, GPI Anchors, Proteoglycans, and Peptidoglycans
to elevate the shorter oligosaccharide chains out of the
membrane to provide access to exoglycosidase digestion.
The accumulation of undegraded GSLs in cells, especially
brain cells, can cause characteristic neurological symp-
T ay-Sachs, G a u c h e r’s
H u r le r ’s d isea ses
all human lysosomal storage diseases. Studies using the
drug N-butyldeoxynojirimycin to block GSL biosynthe-
sis have demonstrated that the lysosomal storage disease,
Tay-Sachs, can be prevented in a mouse model of the
GSLs, because they are shed into the CSF, may be poten-
tial markers for brain pathology. In addition, shed GSLs or
bacterial GSL structural mimics may also act as antigens
in peripheral neuropathies like
G u illa in -B a rre syn d ro m e
m u ltifo ca l m o to r n eu ropath y.
Biosynthesis of Glycosaminoglycans
Glycosaminoglycans (GAGs; mucopolysaccharides) are
long, highly negatively charged, unbranched polymers of
repeating disaccharide units. They are classified according
to the hexosamine units that alternate with uronic acid in
the polymer; heparin, heparin sulfate (HS), and hyaluronic
acid (HA) are glucosaminoglycans, whereas chondroitin
sulfate (CS) and dermatan sulfate (DS) are galactosamino-
glycans (Figure 16-16). The N-sulfation of glucosamine
and O-sulfation at various positions on each sugar unit cou-
pled with the hexuronic acid gives these polymers some
of the highest negative charge density of any biological
molecules. GAGs are present in most cells and tissues
but are most often associated with connective tissue and
M ammalian Glycosam inoglycans
H N SO ;
C O O '
C O O '
H COSO '
Structures of mammalian glycosaminoglycans: the anti-thrombin-binding
pentasaccharide in heparin/HS, a CS polysaccharide, and a mammalian
HA. [Reproduced with permission from K. Lidholt, Biosynthesis of
glycosaminoglycans in mammalian cells and in bacteria.
B iochem . Soc.
Structure of a proteoglycan. [Reproduced with permission from J. E. Silbert
and G. Sugumaran, Intracellular membranes in the synthesis, transport,
and metabolism of proteoglycans.
B io ch im . B iophys. A cta
extracellular matrix. Most GAGS are a part of a larger
molecule called a proteoglycan. GAGs are attached to
the core protein of proteoglycans through an oligosaccha-
ride link region of gal-gal-xyl-ser (Figure 16-17). Many of
these proteoglycans and glycosaminoglycans are found in
the extracellular matrix including hyaluronic acid, proteo-
chondroitin/dermatan sulfate (aggrecan, versican, decorin,
biglycan), and proteoheparan sulfate. The proteoheparan
sulfate perlecan is a major constituent of basement mem-
branes. Proteoglycans attached to the cell surface may
have heparan sulfate GAGs (glypican, cerebroglycan) or
both chondroitin sulfate or dermatan sulfate and hep-
aran sulfate GAGs on the same core protein (syndecan,
-glycan). Cell surface proteoglycans can either be inte-
gral membrane proteins or attached via a GPI anchor to
the plasma membrane.
In addition to the role of proteoglycan and GAGs as
highly solvated, structural molecules, they have now been
identified as important mediators of receptor function and
may also have a role in normal morphology and malig-
nancies. In particular, a family of transmembrane cell sur-
face heparan sulfate proteoglycans, the syndecans, have
been noted for their role in cell surface interactions. The
four mammalian syndecans have different tissue distribu-
tion and their core protein expression is developmentally
Syndecans can interact with a number of extracellular
molecules (fibronectin, collagens I, III and V, tenascin,
thrombospondin; and antithrombin III) and can act as
coreceptors for high-affinity receptors of fibroblast growth
factor type 2 (FGF2). All four syndecans have a cleav-
age site within their peptide sequence near the exoplas-
mic site of their insertion into the plasma membrane.
This provides another means to rapidly down-regulate
surface expression of GAGs. Mutant cells that lack pro-
teoheparan sulfate do not respond to FGF2. Studies also
show that bacterial gonococcal attachment to human mu-
cosal cells is directed at cell surface heparan sulfate