Bhagavan Medical Biochemistry 2001, page 355 read online

322

chapter 16

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-

toms.

T ay-Sachs, G a u c h e r’s

and

H u r le r ’s d isea ses

are

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

disease.

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

and

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

HNAc

H N SO ;

OSO^

HN SO"

C O O '

H COSO '

HNAc

FIGURE 16-16

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.

Trans.

25:866 (1997).]

FIGURE 16-17

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

1241:372

(1995).]

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

regulated.

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