section 11.1
Protein Fibers and Proteoglycans
187
1. Ligand degradation and receptor reutilization (e.g.,
low-density lipoproteins, Chapter 20;
asialoglycoproteins, Chapter 10; transcobalamin II,
Chapter 38; some peptide hormones;
2. Both ligand and receptor reutilization (e.g.,
transferrin, Chapter 29; class I major
histocompatibility complex molecules on T cells
and class II molecules on macrophages,
Chapter 35);
3. Both receptor and ligand degradation (e.g., epidermal
growth factor, immune complexes);
4. Both ligand and receptor transportation out of the cell
(e.g., maternal IgG, secretory IgA Chapter 35).
Receptors for different ligands have been characterized
and show multiple functional domains (see low-density
lipoproteins, Chapter 20; insulin, Chapter 22).
Phagocytosis
is a transport system that does not involve
receptor-mediated endocytosis coupled to the formation
of coated vesicles. This type of internalization consists of
forming phagosomes, which are membrane-bound vesi-
cles containing ingested substances (e.g., bacteria or their
products, extracellular material). Secondary lysosomes
are formed when primary lysosomes fuse with phago-
somes; they can also be formed when primary lysosomes
fuse with autophagosomes, which contain internally
derived defective organelles (e.g., mitochondria or rough
endoplasmic reticulum). Within the secondary lysosomes,
the ingested macromolecules are broken down by a wide
variety of hydrolases into their respective monomeric
units (e.g., sugars, amino acids, purines, pyrimidines, fatty
acids, and cholesterol). Eventually these molecules appear
in the cytoplasm and are usable for metabolic purposes.
Undigested material is retained within the lysosomes and
forms a residual body. A schematic representation of the
formation and some functions of lysosomes is shown in
Figure 11-10.
In some circumstances, lysosomal enzymes are ex-
truded into the extracellular milieu and cause destruction
of the surrounding matrix. This extracellular catabolic pro-
cess releases materials that are taken up in phagosomes
for further breakdown by the cells. This process occurs
in the remodeling of bone and cartilage. In the thyroid
gland, lysosomes participate in the regulation of hormone
release from the cells to the blood circulation. The thyroid
hormones, thyroxine and triiodothyronine, are synthesized
on a polypeptide, thyroglobulin, and stored within the thy-
roid follicles. Under appropriate stimuli, the thyroglobulin
is internalized (endocytosed) and hydrolyzed by lysoso-
mal hydrolases to release the free hormones, which are
then transferred to the blood (Chapter 33).
In vitro,
estra-
diol, testosterone, and vitamins A and D have disruptive
effects on the lysosomal membrane, causing the release of
lysosomal enzymes. The anti-inflammatory steroid hor-
mone
cortisol
has an opposite effect. The destructive po-
tential of leukocytic lysosomal proteinases is checked by
a i-proteinase inhibitor and a
2
-macroglobulin in plasma
and synovial fluids. Enhanced catabolism of proteogly-
cans of articular cartilage occurs in rheumatoid arthritis as
a result of the action of lysosomal enzymes on articular
cartilage.
Many pathological conditions occur as a result of a
deficiency of lysosomal enzymes (e.g., storage disor-
ders of glycoproteins and glycosphingolipids). At least
41 distinct
lysosomal storage diseases
are known. Most
of these diseases are due to deficiency of a particular
enzyme and a few are due to defects in the nonlyso-
somal proteins that are necessary for lysosomal bio-
genesis. Lysosomal storage disorders are predominantly
autosomal recessive, with the exception of
Fabry’s dis-
ease
and
mucopolysaccharidosis type II,
which are X-
linked recessive disorders. Overall, lysosomal storage
disorders are relatively common with a prevalence of
1 per 7700 live births, although some disorders are
very rare.
Mucopolysaccharidoses
Mucopolysaccharidosis (MPS) encompasses disorders
in which undegraded or partly degraded glycosamino-
glycans accumulate in the lysosomes of many tissues
owing to a deficiency of specific lysosomal enzymes.
Table 11-3 lists the missing enzymes and gives rele-
vant clinical and laboratory findings. These disorders,
with the exception of Hunter’s syndrome, which is
an X-linked trait, are inherited in the autosomal re-
cessive
manner.
All
of the
deficient
enzymes
are
acid hydrolases except for acetyltransferase in Sanfil-
ippo’s syndrome type C. In mucopolysaccharidoses the
catabolism of heparan sulfate, dermatan sulfate, and
keratan sulfate is affected. Their degradation proceeds
from the nonreducing end of the carbohydrate chain
by the sequential actions of lysosomal exoglycosidases,
exosulfatases, and an acetyltransferase (Figures 11-11
through 11-13).
These disorders are rare; collectively, they may oc-
cur in 1 in 20,000 live births. Since proteoglycans are
widely distributed in human tissues, the syndromes can
affect a wide variety of tissues; thus, the clinical features
vary considerably. All types are characterized by reduced
life expectancy, with the exception of Scheie’s syndrome.
All types are characterized by skeletal abnormalities,
which are particularly severe in types IV and VI. Types
IH, IS, IV, VI, and VII usually exhibit clouding of the
