Biochemistry: The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Intracellular Degradation of Polysaccharides and Glycolipids

The discovery of A number of specific inherited Metabolic Disorders has drawn the attention of biochemists to the degradation pathways of complex Polysaccharides. There are at least 7 types of Mucopolysaccharidoses, characterized by the excessive tissue accumulation and increased urinary excretion of mucopolysaccharides, particularly hyaluronic acid. These disorders feature pronounced skeletal deformities, varying degrees of mental retardation, and ultimately, premature death due to hepatic, renal, or cardiovascular dysfunction. Mucopolysaccharidoses are classified as lysosomal storage diseases caused by a deficiency of lysosomal Enzymes [22], specifically the absence of one of more than 40 lysosomal Hydrolases. In mucopolysaccharidoses, as in other lysosomal storage disorders, uncleaved products accumulate as intracellular inclusions bounded by a single membrane. Different Tissues are affected to varying degrees, but the disease is progressive over time.

First described by Hurler in 1919, mucopolysaccharidosis I (Hurler syndrome) is accompanied by the accumulation of partially degraded dermatan sulfate [22]. As we recall (Fig. 2-16), this protein-bound polysaccharide consists of alternating residues of iduronic acid and ß-D-N-acetylgalactosaminuronic acid, sulfated at the C-4 position.

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Diseases of this type are typically studied using fibroblast cultures obtained from Skin biopsies. Fibroblasts cultured from patients with Hurler syndrome accumulate this polysaccharide. However, this defect can be "corrected" by co-culturing these Cells with fibroblasts from a healthy individual in the same flask. It has been demonstrated that Proteins secreted by normal fibroblasts are taken up by the patient's fibroblasts, enabling the latter to degrade the accumulated polysaccharide. In Hurler syndrome, this correcting factor was identified as a-L-iduronidase. Missing enzymes in several other disorders have been identified in a similar manner. For instance, Hunter syndrome is characterized by the excessive accumulation of dermatan sulfate and heparan sulfate due to a deficiency in sulfatase, an enzyme that cleaves sulfated iduronic acid residues [23]. In Sanfilippo syndrome type A, the correcting factor is heparan sulfatase (possibly N-sulfatase), whereas in type B it is N-acetyl-a-glucosaminidase. Another form of mucopolysaccharidosis is characterized by a deficiency of ß-glucuronidase. This Overview somewhat simplifies the actual clinical picture. For example, many lysosomal storage diseases present with both moderate and severe forms; some manifest exclusively in infancy or childhood, while others appear in adulthood. Several enzymes exhibit multiple isoenzymatic forms. In some cases, the enzyme is either entirely absent or present in insufficient concentrations. Furthermore, certain forms of these disorders may stem from a deficiency of regulatory proteins.