chapter 16
Carbohydrate Metabolism III: Glycoproteins, Glycolipids, GPI Anchors, Proteoglycans, and Peptidoglycans
Keratan sulfate occurs in proteoglycans as N- and O-
linked polysaccharides. In the peptidoglycan of corneal
stroma, one to three chains are attached to the core protein
by N-glycosidic bonds between N-acetylglucosaminyl
and asparaginyl residues. The carbohydrate links be-
tween the keratan sulfate and the protein may resem-
ble the complex type of oligosaccharide in N-linked
glycoproteins synthetically and structurally. In carti-
lage, keratan sulfate chains are attached to the core
by O-glycosidic bonds between N-acetylgalactosaminyl
and seryl or threonyl residues. Biosynthesis of the car-
bohydrate linkages in these molecules and assembly
of the disaccharide polymers of keratan sulfate are
probably similar to synthesis of other glycosamino-
The turnover of glycosaminoglycans in the lysosomes
follows the same pathways as other glycoconjugates, how-
ever, N-sulfate must be removed and the deacetylated gly-
cosamine must be reacetylated for digestion by lysosomal
^-hexosaminidase. Patients with the lysosomal storage
S an fillipo C m u co p o lysa cch a rid o sis,
are unable
to reacetylate glucosamine and a buildup of undigested
glycosaminoglycan occurs.
16.2 Biosynthesis of Peptidoglycans
An understanding of the biochemistry of peptidoglycan
(PG; murein) that comprises bacterial cell walls is very
important medically since blockage of its synthesis was
the first, and continues to be a primary, point of attack in the
control of bacterial infection. In addition to inhibition of
cell wall synthesis, antimicrobial drug’s main mechanisms
are interference with nucleic acid synthesis, inhibition of
folate metabolism, and binding to ribosomes to disrupt
protein synthesis (Table 16-2).
PGs are considered to be primarily responsible for the
protective and shape-maintaining properties of walls. They
are a biologically unique class of macromolecules be-
cause they consist of netlike polymers that are linked
together by three different chemical bonds (glycosidic,
amide, and peptide). The exact chemical structure of
a PG may vary depending on environmental factors.
PG, along with endotoxin, is also a primary target
for the CD 14 molecule, which is expressed on dif-
ferent types of immune cells, especially on mono-
cytes/macrophages. The interaction between these PGs
and CD 14 leads to production and release of cytokines and
other factors that cause local and generalized inflammatory
PG biosynthesis involves about 30 enzymes and occurs
in three stages:
TABLE 16-2
M ech a n ism s o f A ctio n o f A n tib a c te ria l A g en ts
Antibacterial Agents
Inhibition of cell-wall synthesis
Ribosomal binding
Interference with nucleic acid
Inhibition of folic acid
1. N-Acetylmuramic acid (MurNAc) peptide chain
2. Synthesis of the GlcNAc-MurNAc repeating units; and
3. Cross-linking of the polymer side chains.
These stages occur in the cytoplasm, at the bacterial
cell membrane (probably on the cytoplasmic surface), and
outside the membrane in the cell wall, respectively. The
wall grows by an inside-to-outside mechanism, and new
material compensates for loss of outer wall and provides
for expansion for cell growth.
The first stage (Figure 16-18) starts with modification
of UDP-GlcNAc to UDP-MurNAc. Phosphoenolpyruvate
is enzymatically transferred to UDP-GlcNAc, yielding
UDP-GlcNAc-3-enolpyruvate ether. An NADPH-linked
reductase then reduces the pyruvyl group to lactyl, form-
ing UDP-MurNAc. The pentapeptide side chain is built
up by the sequential transfer of amino acids by specific
enzymes in ATP-dependent reactions. The last two amino
acids are added as a dipeptide (D-Ala-D-Ala). Both racem-
ization of
Ala to D-Ala and synthesis of this dipeptide are
competitively inhibited by the antibiotic D-cycloserine, a
structural analogue of D-alanine. The final product of this
stage is UDP-MurNAc-pentapeptide (“Park nucleotide”).
undecaprenyl phosphate, accompanied by the release of
UMP. Undecaprenyl phosphate (“bactoprenol phosphate”)
is a 55-carbon isoprenol similar to dolichol phosphate. It is
also a carrier in the synthesis of the O-specific antigens of
gram-negative, and of the teichoic acids of gram-positive,
bacterial cell walls. The undecaprenylpyrophosphate-
MurNAc-peptide then undergoes modification of the sugar
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