Biochemistry - Chemical Reactions in Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Intracellular Degradation of Polysaccharides and Glycolipids
Can Lysosomal Storage Diseases Be Cured?

The issue of enzyme replacement therapy in patients with lysosomal enzyme deficiencies has been attracting close attention from specialists [22]. Indeed, Cells possess The ability to take up Enzymes from the extracellular environment, as demonstrated in tissue culture. In all likelihood, during pinocytosis, the outer membrane invaginates into The Cell, forming pinocytotic vacuoles that subsequently fuse with Lysosomes. Lysosomal Hydrolases then break down Cell wall Polysaccharides, which appears necessary for normal cellular function. On the other hand, pinocytosis serves as a mechanism for cells to acquire enzymes from the extracellular milieu, and this very process forms the basis for the feasibility of enzyme replacement therapy. However, enzyme replacement therapy is complicated by the risk of allergic reactions to the Introduction of foreign Proteins into the bloodstream. In cases where excessively accumulated substances enter the Circulation, a potential approach to solving this problem could be The Development of a method for administering enzymes in the form of microcapsules—specifically, by encapsulating the missing enzyme within the ghosts of the patient's own erythrocytes [22]. In Gaucher and Fabry diseases, Brain dysfunction can presumably be prevented if Treatment is initiated at a very early age. The literature already contains reports of certain successes in the treatment of Fabry disease. As for Tay-Sachs disease, in this case, the accumulation of GM₂ ganglioside occurs primarily in the ganglia and glial Cells of the brain; due to the presence of the Blood-brain barrier and the severity of the resulting damage, it seems unlikely that this condition can be successfully treated.

To prevent these disorders, current efforts are focused on identifying carriers of highly undesirable genetic traits and providing appropriate Genetic Counseling¹⁾. If both the father and the mother are carriers of the defective Gene, the risk of having a child with Tay-Sachs disease is 1 : 4. For instance, in a group of 32 pregnant women who had previously had a child with Tay-Sachs disease, the genetic status of the fetus was determined using amniocentesis²⁾. In accordance with theoretical prediction, 8 out of the 32 fetuses carried the hereditary defect. Within this group, 7 women chose to have an abortion; in the case of the eighth, the Diagnosis was made too late, and a child with Tay-Sachs disease was born [27].

Other diseases caused by impaired carbohydrate breakdown are also known. For example, alpha-fucosidase deficiency develops when the ability to cleave fucose residues from cell surface polysaccharides is lost [29–31]. As is clear from the foregoing, the catabolic processes of body components are fraught with A number of problems. At the same time, deficiencies in biosynthetic enzymes are much rarer. This is probably because an inborn error in Biosynthesis is more often entirely lethal, resulting in Spontaneous Abortion. Nevertheless, specific mutant mouse strains exist—designated Jimpy, Quaking, and msd (myelin synthesis deficient)—in which cerebroside biosynthesis is blocked [32–34]. These animals are characterized by reduced (though not completely absent) activity of the transferases that catalyze reactions 11 and 12 in Fig. 12-5. Concurrently, marked neurological disorders and defective myelination of nerve fibers in the brain are observed. Relatively recently, a report was published describing a human disorder in which The conversion of GM₃ to GM₂ is impaired (accompanied by the accumulation of GM₃; reaction 13 in Fig. 12-5).

Since it is evident that Intercellular Communication is lost between tumor cells, a biochemical study of their Structure/108.html">Surface Properties was undertaken to elucidate The Mechanism of this phenomenon. This revealed an alteration in ganglioside composition driven by a decrease in The activity of specific Glycosyltransferases [35, 36].

Ganglioside GM₁ (Fig. 12-5) appears to be the natural receptor for cholera toxin (Ch. 6, Sect. E, 5) [36a]. The binding of the B-subunit of this toxic protein to the free oligosaccharide chains of several ganglioside molecules triggers a cascade of reactions that results in the release of the toxin's A-subunit, which in turn activates adenylate cyclase [36b].

¹⁾ However, in many cases, tests for identifying heterozygous carriers are still lacking.

²⁾ A sample of the Amniotic Fluid surrounding the fetus is taken at the 16th–18th week of Pregnancy. Amniotic fluid contains fibroblasts sloughed off from the embryonic Skin. These cells are cultured for 2–3 weeks, and once they have proliferated in sufficient numbers, the activity of the corresponding enzymes is measured.