chapter 11
Heteropolysaccharides II: Proteoglycans and Peptidoglycans
infection, may be partly attributable to altered proteogly-
can metabolism.
Turnover o f Proteoglycans and Role o f Lysosomes
Proteoglycans undergo continuous turnover at rates de-
pendent upon the nature of the proteoglycan and tissue
location. Their half-life is between one and several days.
Degradation of proteoglycans is initiated by proteolytic
enzymes that release glycosaminoglycans; the latter are
subsequently degraded by
lysosomal enzymes.
Some of
the products of hydrolysis (e.g., dermatan sulfate and hep-
aran sulfate) are excreted in the urine.
Lysosomes are subcellular organelles in which a wide
range of catabolic enzymes are stored in a closed, pro-
tective membrane system. They are major sites of in-
tracellular digestion of complex macromolecules derived
from both intracellular (autophagic) and extracellular (het-
erophagic) sources. Lysosomal enzymes show optimal ac-
tivity at acidic pH. The pattern of enzymes in lysosomes
may depend upon the tissue of origin, as well as upon the
physiological or developmental state of the cells.
Lysosomal enzymes are synthesized on the ribosomes
of the rough endoplasmic reticulum, passed through the
Golgi apparatus, and packaged into vesicles. The hy-
drolyases are glycoproteins, some of which contain man-
-phosphate markers necessary for the normal uptake
of glycoproteins into lysosomes. Thus, carbohydrates may
also serve as determinants of recognition in the
localization of the glycoproteins following their syn-
thesis. In two biochemically related disorders of lysosomal
function, I-cell disease (mucolipidosis II) and pseudo-
Hurler’s polydystrophy (mucolipidosis III), the lesion is in
the posttranslational modification step for acid hydrolases
destined to be packaged into lysosomes. In normal cells,
these acid hydrolyases are glycoproteins carrying man-
-phosphate markers that direct them to lysosomes
through a receptor-mediated process. In other words,
the presence of phosphomannose residues on the newly
synthesized acid hydrolases and of phosphomannose re-
ceptors on selected membranes leads to the segregation
of these enzymes in the Golgi apparatus, with subsequent
translocation into lysosomes. In mucolipidosis II, the acid
hydrolases are not phosphorylated; in mucolipidosis III,
the enzymes either are not phosphorylated or have signif-
icantly diminished phosphate content. The lack of man-
-phosphate leads to defective localization of acid
hydrolases that, instead of being packaged in lysosomes,
are exported outside the cell; thus, the enzyme activity
in plasma reaches high levels. These enzymes could cause
indiscriminate damage. At least eight acid hydrolases (gly-
cosidases, sulfatases, and cathepsins) appear to be affected
in this manner. However, not all lysosomal enzymes and
tissue cells are affected. For example, lysosomal acid phos-
phatase and /3-glucosidase, and hepatocytes and neurons,
appear to be spared from this defect. In mucolipidosis II
and III, large inclusions of undigested glycosaminogly-
cans and glycolipids occupy almost all of the cytoplasmic
space in cultured skin fibroblasts. In addition to the phos-
phorylation defect, the acid hydrolases are much larger
than their normal counterparts, presumably owing to lack
of the limited proteolysis of the hydrolases that occurs in
normal lysosomes. Both disorders are inherited as auto-
somal recessive traits, affect primarily connective tissue,
and are characterized by psychomotor retardation, skeletal
deformities, and early death.
The segregation of lysosomal enzymes into lysosomes
requires carbohydrate recognition markers (phosphoman-
nose in some) and also the formation of coated vesicles
into which the enzymes are sequestered. Coated vesicles
shuttle macromolecules between organelles and may be re-
sponsible for selectivity in intercompartmental transport
(e.g., from endoplasmic reticulum to Golgi, from Golgi
to lysosomes). The major component of coated vesicles
a nonglycosylated protein (M.W. 180,000).
It is located on the outer surface (cytoplasmic side)
of the coated vesicles. Clathrin and its tightly bound
light chains (M.W. 33,000 and 36,000) form flexible lat-
tices that function as structural scaffolds surrounding the
In addition to their role in intracellular transport, coated
vesicles are involved in
receptor-mediated endocyto-
This process accomplishes internalization of macro-
molecules (ligands) by binding them to receptors on the
cell membranes located in specialized regions of clathrin-
containing coated pits, which invaginate into the cell to
form coated vesicles. Inside the cell, the vesicles lose their
clathrin coat (which may be reutilized) and fuse with one
another to form endosomes, whose contents are acidified
by proton pumps driven by free energy of hydrolysis de-
rived from ATP. In the endosome, the ligand and receptor
undergo dissociation. The endosome fuses with the pri-
mary lysosome to form a secondary lysosome. Receptors
may also be recycled or degraded. Thus, there are several
pathways of receptor-mediated endocytosis. In some cells,
the receptors migrate continuously to coated pits and un-
dergo internalization whether or not ligands are bound to
them (e.g., receptors for low-density lipoproteins, transfer-
rin, and asialoglycoproteins). In other cells, the receptors
are diffusely distributed and do not migrate to coated pits
unless they are bound with ligands (e.g., epidermal growth
Following internalization, the receptor-ligand complex
may be disposed of by one of four routes:
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