CLINICAL CASES
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is synthesized at the plasma membrane by hyaluronan synthases. Hyaluronan
synthases are integral membrane proteins that catalyze the alternate addition
of UDP-glucuronate and UDP-N- acetylglucosamine to the reducing end of
the growing hyaluronan polymer at the inner surface of the plasma membrane
as it extrudes the nonreducing end of the GAG into the extracellular space.
Hyaluronan can then assemble into large macromolecular complexes with
other proteoglycans, which are noncovalently attached to hyaluronan by link
proteins.
Degradation of proteoglycans during normal turnover of the extracellular
matrix begins with proteolytic cleavage of the core protein by proteases in the
extracellular matrix, which then enters the cell via endocytosis. The endo-
somes deliver their content to the lysosomes, where the proteolytic enzymes
complete the degradation of the core proteins and an array of glycosidases and
sulfatases hydrolyze the GAGs to monosaccharides. The lysosomes contain
both endoglycosidases, which hydrolyze the long polymers into shorter
oligosaccharides, and exoglycosidases that cleave individual acidic- or
aminosugars from the GAG fragments.
Lysosomal catabolism of GAGs proceeds in a stepwise manner from the
non-reducing end, as is shown with the degradation of heparan sulfate in
Figure 29-1. If the terminal sugar is sulfated, the sulfate bond must be
hydrolyzed by a specific sulfatase before the sugar can be removed. When the
sulfate has been removed, a specific exoglycosidase then hydrolyzes the ter-
minal sugar from the non-reducing end of the oligosaccharide leaving it one
sugar shorter. Degradation continues in this stepwise fashion, alternating
between removal of sulfates by sulfatases and cleavage of the terminal sugars
by exoglycosidases. If removal of a sulfate leaves a terminal glucosamine
residue, it must first be acetylated to N-acetylglucosamine because the lyso-
some lacks the enzyme required to remove glucosamine. This is accomplished
by an acetyltransferase that uses acetyl-CoA as the acetyl group donor. When
the glucosamine residue has been N-acetylated it can be hydrolyzed by a-N-
acetylglucosaminidase, allowing the continuation of the stepwise degradation
of the GAG.
Disease states known as mucopolysaccharidoses occur when there is a
genetic deficiency of the enzymes involved in the lysosomal breakdown of the
GAGs. A deficiency of any of these enzymes can lead to the accumulation of
partially degraded GAGs in lysosomes and increased urinary excretion of
GAG fragments. Histologic examination of affected cells shows large vacuoles,
which are lysosomes engorged with partially degraded GAGs. Because GAGs
are present throughout the body, deficiencies of enzymes that degrade them
affect bone, connective tissues, and other organs.
The mucopolysaccharidoses are classified into seven clinical types and all
are transmitted by autosomal recessive inheritance except for Hunter syn-
drome (MPS II, iduronate sulfatase deficiency), which is an X-linked disorder.
Diagnosis of the specific disorder is made by measuring the specific enzyme
activities in leukocytes or cultured skin fibroblasts. Because it takes some time
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