Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Lipid Biosynthesis
Genetic Defects in Lipid Metabolism

All membrane polar Lipids undergo constant metabolic turnover. Under normal cellular conditions, a dynamic steady state is established in which The rate of lipid synthesis equals the rate of degradation. Lipid breakdown is catalyzed by hydrolytic Enzymes capable of cleaving strictly specific covalent bonds. For instance, the degradation of phosphatidylcholine, the major membrane lipid, involves several distinct phospholipases, the mechanisms of which are illustrated in Fig. 21-20.

The METABOLISM of membrane Sphingolipids—including sphingomyelin, cerebrosides, and gangliosides (Section 12.6)—is particularly susceptible to disorders caused by genetic defects in the enzymes responsible for their degradation. Because sphingolipid synthesis proceeds normally while their breakdown is impaired, these lipids or their partial degradation products accumulate in Tissues in large quantities. For example, in Niemann-Pick disease, a rare genetic disorder, sphingomyelin accumulates in the Brain, Spleen, and Liver. Manifesting shortly after birth, the disease leads to mental retardation and early death. Niemann-Pick disease is caused by a genetic deficiency of sphingomyelinase, the enzyme that cleaves phosphorylcholine from sphingomyelin (the structures of these compounds are shown in Fig. 12-11).

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Fig. 21-20. Sites of phospholipase action on phosphatidylcholine. R₁ and R₂ represent long-chain fatty acid residues.

Much more common is Tay-Sachs disease, caused by a deficiency of the lysosomal enzyme N-acetylhexosaminidase. This enzyme normally catalyzes the Hydrolysis of the specific bond between the N-acetyl-D-galactosamine and D-galactose residues in the polar HEAD group of a ganglioside (Fig. 21-21). Its absence leads to the accumulation of specific types of gangliosides in the brain and spleen. Because ganglioside degradation halts at an intermediate stage, partially degraded gangliosides accumulate in large amounts, triggering neurodegenerative processes that result in mental retardation, blindness, and early death (Fig. 21-22).

Although Tay-Sachs disease is rare in the general population (about 1 case per 300,000 births), its incidence is notably high among Ashkenazi Jews (descendants of Central European Jews, who comprise 90% of the Jewish population in America), where about 1 in 3,600 newborns is affected, and roughly 1 in 28 individuals is a carrier of the recessive defective Gene. If both parents carry the defective gene, the probability of the child developing Tay-Sachs disease increases significantly. Given the irreversible and severely disabling Nature of the disease, Genetic Counseling for prospective parents is of paramount importance. Screening tests have been developed to identify carriers of the recessive gene. Carriers can be identified by measuring hexosaminidase A activity in Skin fibroblast cultures obtained via skin biopsy. The genetic status of a fetus can also be determined by assaying enzyme activity in Cells obtained from Amniotic Fluid, a Procedure known as amniocentesis.

Fig. 21-21. Genetic defect in Tay-Sachs disease. Under normal conditions, the lysosomal enzyme N-acetylhexosaminidase degrades ganglioside G_М2 to yield N-acetyl-D-galactosamine and ganglioside G_М3. In Tay-Sachs disease, this enzyme is defective, causing ganglioside G_М2 to accumulate in Lysosomes, predominantly within brain cells.

Fig. 21-22. A. A one-year-old child with Tay-Sachs disease. Brain damage has already begun, which will soon be followed by blindness. Few children with this condition survive past the age of five. B. Electron micrograph of a portion of an affected brain Cell, showing abnormal accumulations of gangliosides within lysosomes.