Human Biochemistry Volume 2 - Murray R. 1993

Special Topics
Glycoproteins and Proteoglycans
Proteoglycans and Glycosaminoglycans - Degradation of the Polysaccharide Components of Glycoproteins and Proteoglycans

The discovery of specific enzyme deficiencies in inherited human Metabolic Disorders has greatly contributed to elucidating the degradation (breakdown) pathways of Glycoproteins, Proteoglycans, and glycosaminoglycans. A significant milestone in understanding this issue was The Study of two groups of diseases: Mucopolysaccharidoses and mucolipidoses (compounds that we now refer to as proteoglycans were known for many years as "mucopolysaccharides"). Table 54.9 lists the biochemical abnormalities seen in mucopolysaccharidoses, mucolipidoses, and related disorders.

Class="center">Table 54.9. Biochemical defects and diagnostic tests in mucopolysaccharidoses, mucolipidoses, and related disorders

MPS — mucopolysaccharidosis; ML — mucolipidosis; DS — dermatan sulfate; KS — keratan sulfate; HS — heparan sulfate; GP — glycoprotein fragments.

The degradation of polysaccharide chains is carried out by Endoglycosidases, exoglycosidases, and sulfatases. Each of these enzyme groups exhibits substrate Specificity, which makes it possible to predict which polysaccharide chain will be targeted by a given glycosidase or sulfatase.

Hyaluronidase is a widely distributed endoglycosidase that cleaves hexosaminide bonds. It breaks down hyaluronic acid into a tetrasaccharide with the structure (GlcUA-β 1,3-GlcNAc-β 1,4). Hyaluronidase acts on both hyaluronic acid and chondroitin sulfate. The tetrasaccharide mentioned above can undergo further degradation through the action of β-glucuronidase and β-N-acetylhexosaminidase.

β-Glucuronidase is an exoglycosidases that removes GlcUA and IdUA from the non-reducing ends of tetrasaccharides or larger Polysaccharides. Disaccharides are generally poor substrates for β-glucuronidase. β-Glucuronidase itself is a glycoprotein localized in the Lysosomes and microsomes of many mammalian cells. Its substrates include dermatan sulfate, heparan sulfate, chondroitin sulfate, and hyaluronic acid. In hereditary β-glucuronidase deficiency, patients excrete dermatan sulfate, heparan sulfate, and chondroitin sulfate in their urine, but not hyaluronic acid. Apparently, alternative pathways exist for The breakdown of the tetrasaccharide generated from hyaluronic acid by hyaluronidase action.

β-D-acetylhexosaminidase is an exoglycosidases present in many mammalian tissues. It cleaves β-linked GlcNAc and GalNAc residues from the non-reducing ends of polysaccharides. The substrate range of β-D-acetylhexosaminidase includes gangliosides, chondroitin sulfates, hyaluronic acid, dermatan sulfates, and keratan sulfates I and II. There are two Isoenzymes of β-D-acetylhexosaminidase. Isoenzyme A consists of two different subunits, α and β ((αβ)_n), whereas isoenzyme B contains only β-subunits ((ββ)_n). Tay-Sachs disease involves a defect in the α-subunit, leaving only isoenzyme A inactive. Sandhoff disease is characterized by a defect in the β-subunit, resulting in a deficiency of both isoenzymes.

β-Galactosidases exist in animal tissues in several forms. Both chondroitin sulfate and keratan sulfate contain β-galactosides and thus serve as substrates for acid galactosidases. In acid β-galactosidase deficiency, keratan sulfate and glycoprotein fragments accumulate alongside G_M1-gangliosides (see Chapter 25).

α-L-Iduronidase is a lysosomal hydrolase that removes IdUA residues from the non-reducing end of polysaccharide chains. A deficiency of this enzyme occurs in Hurler syndrome.

Mammalian tissues contain endoglycosidases specific for heparin and heparan sulfate, most notably endoglucuronidase, which is found in the Liver, intestinal mucosa, platelets, and lysosomes.

There is a wide array of specific sulfatases that catalyze the removal of sulfate groups, including three arylsulfatases: A, B, and C. Arylsulfatase A cleaves Gal-3-sulfate from sulfatides. Arylsulfatase B removes the 4-sulfate group from chondroitin sulfate and dermatan sulfate. However, patients with inherited 4-sulfatase deficiency (Maroteaux-Lamy syndrome) excrete only dermatan sulfate in their urine. There is also an enzyme distinct from arylsulfatases A and B that cleaves the 6-sulfate group from GalNAc-6-sulfate. A deficiency of this sulfatase is found in patients with Morquio syndrome. Normally, it removes sulfate groups from Gal-6-sulfate and GalNAc-6-sulfate, which is why keratan-6-sulfate and chondroitin-6-sulfate can be detected in the urine of patients with Morquio syndrome.

A deficiency of N-acetylglucosamine-6-sulfatase is observed in MPS VIII. This enzyme can use GlcNAc-sulfate and Glc-6-sulfate as substrates.

Iduronate sulfatase is a specific exoenzyme that cleaves the C-2 sulfate group from IdUA residues at the non-reducing ends of heparin, heparan sulfate, and dermatan sulfate. The enzyme is normally present in serum, lymphocytes, fibroblasts, and amniotic fluid. An inherited deficiency of iduronate sulfatase causes Hunter syndrome.

A specific α-N-acetylglucosaminidase can remove α-linked GlcNAc residues present in heparin and heparan sulfate. The enzyme is normally detectable in fibroblasts but is absent in Sanfilippo B syndrome.

Heparin sulfamidase (heparan N-sulfatase) is found in the Spleen, Lungs, and ileum. The enzyme cleaves sulfate from GlcN sulfates at the non-reducing end of heparin and heparan sulfate. This enzyme is deficient in Sanfilippo A syndrome. Following sulfate removal, an α-glucosamine (GlcN) with a free amino group remains, which is not a substrate for the aforementioned α-N-acetylglucosaminidase. The enzyme α-glucosamine:N-acetyltransferase re-acetylates the free amino group of GlcN at the non-reducing end, using acetyl-CoA as the acetyl donor. This yields a product susceptible to the action of α-N-acetylglucosaminidase. In Sanfilippo C syndrome, acetyltransferase activity is lacking.