Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Lipid Biosynthesis
Numerous lysosomal storage diseases exist

Tay-Sachs disease, Niemann-Pick disease, and many other Genetic Disorders characterized by the incomplete degradation of Sphingolipids and Proteoglycans are collectively known as lysosomal storage diseases (Table 21-3). They are so named because many steps in the enzymatic breakdown of sphingolipids and proteoglycans take place within Lysosomes—small, membrane-enclosed cytoplasmic vesicles responsible for digesting certain cellular components. Lysosomes engulf macromolecules and insoluble cellular components, breaking them down via hydrolytic Enzymes into smaller, Water-soluble products that then diffuse into the Cytosol for further METABOLISM. Lysosomes contain over 50 different hydrolytic enzymes capable of degrading Lipids, mucopolysaccharides, Glycogen, and Proteins. The internal environment of lysosomes is mildly acidic (pH around 5.5). In genetic disorders affecting lysosomal enzymes, incompletely degraded macromolecules or insoluble lipids accumulate within the lysosomes, causing them to swell and enlarge to such an extent that normal cellular function is disrupted. Lysosomal storage diseases characterized by defective sphingolipid breakdown typically present with mental retardation, as the Brain is exceptionally rich in sphingolipids compared to other Tissues. When sphingolipid degradation is blocked, normal brain Cell function is severely impaired.

Class="center">Table 21-3. Selected Lysosomal Storage Diseases

Most lysosomal storage diseases are caused by enzymatic defects involved in the Hydrolysis or breakdown of Complex Lipids, glycogen, Glycoproteins, and proteoglycans

Another example of a lysosomal storage disease is Hurler syndrome, or gargoylism. This condition involves a defect in the enzyme responsible for cleaving the mucopolysaccharide portion of certain proteoglycans (Section 11.13), leading to the accumulation of their partial degradation products. Children with this disorder exhibit severe facial deformities, coarse Skin folds with a high proteoglycan content, mental retardation, and blindness. Early childhood mortality is inevitable.

Numerous studies are currently underway to explore the possibility of correcting genetic deficiencies of lysosomal enzymes using biochemical engineering techniques. A primary goal of this research is to find a way to replace the defective enzyme with a normal, catalytically active one. For instance, in living Cells derived from patients with Hurler syndrome, the genetically defective enzyme can be "corrected" in vitro by adding an active enzyme isolated from normal cells. However, introducing a normal exogenous enzyme into a patient's body to replace the defective one is challenging. Ideally, the normal enzyme should be of human origin; if an enzyme from another species is used, its immunological compatibility with the patient must be ensured. Furthermore, the enzyme must be administered in such a way that it reaches the lysosomes of the specific cells affected by the genetic defect. Another approach, described in Chapter 30, involves integrating a normal, active Gene—responsible for the Synthesis of the deficient enzyme—into the Chromosomes of cells that produce the defective enzyme, enabling them to synthesize a normal, active enzyme based on the introduced Genetic Code and ensure its proper delivery to the lysosomes.