Chemistry Reference
In-Depth Information
replacement by
N
-sulfate. The biosynthesis of HS (Figure 11.2 ) exemplifi es the
principle of GAG synthesis (for information on animal models with defi ciency,
please see Table 23.1 D).
Figure 11.2
HS biosynthesis. The linker region
consists of a xylose, two galactose and a gluc-
uronic acid residue. Enzymes of the EXT poly-
merase family (glycosyltransferases) add al-
ternating UDP-activated
N
- acetylglucosaminyl
and glucuronyl residues (UDP-GlcNAc and
UDP-GlcA) followed by the action of specifi c
enzymes (epimerase and sulfotransferases) to
form selected highly sulfated domains of the
fi nal HS chain.
11.1.3
Catabolism
PG degradation is usually initiated in the extracellular environment where prote-
ases [matrix metalloproteinases (MMP s), membrane - type MMPs, ADAMS (metal-
loproteinases with a disintegrin domain) and cathepsins] cleave the protein core.
The MMPs are the major mediators of extracellular PG degradation. In addition,
particularly under infl ammatory conditions, reactive oxygen species released by
mononuclear leukocytes and macrophages can cause protein and polysaccharide
cleavage within the extracellular matrix. For further degradation the PG fragments
are internalized by tissue cells, and within the lysosomes a complete repertoire of
proteases, sulfatases and glycosidases converts both the protein and polysaccha-
ride component into their constituent units. Disassembling of GAG chains starts
from the nonreducing end by stepwise cleavage of glycosidic linkages of monosac-
charides. Sulfate ester and
N
-sulfate groups have to be removed prior to this
process (Figure 11.3). The lysosomal glycosidases and sulfatases have been the
subject of extensive studies since mutation in them results in a block of degrada-
tion, accumulation of oligosaccharides and lysosomal storage diseases (please see
Info Box ).
