17.21:
Lysosomal Hydrolases
Lysosomes contain different enzymes which help degrade macromolecules.
These enzymes are optimally active in an acidic pH of 5 and use water molecules to break down the chemical bonds in their substrates. Thus, lysosomal enzymes are called acid hydrolases.
Lysosomal hydrolases are produced in the rough ER and transported to the Golgi apparatus. There, the hydrolases are tagged with Mannose-6-Phosphate groups or M6P that are added to the N-linked oligosaccharides on the enzymes.
Transmembrane receptors specifically recognize the M6P markers and anchor the hydrolases on the lumenal side of the membrane, while Clathrin coat assembles on the cytosolic side.
The receptor-bound enzymes bud out as clathrin-coated vesicles from the trans-Golgi network and move to the early endosome.
Because the M6P receptors cannot bind the hydrolases at a pH lower than 6, the acidic pH of the endosome prompts the release of the enzymes in the endosomal lumen.
The early endosome matures to the late endosome and fuses with the lysosome delivering the enzymes to their final destination,the endolysosome.
17.21:
Lysosomal Hydrolases
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane, counting discharged materials.
Lysosomal storage Diseases
Genetic defects in lysosomal function cause lysosomal storage diseases. In these diseases, the absence of lysosomal hydrolases results in undigested molecules accumulating in the lysosome. Organs containing such defective lysosomes malfunction, which can even lead to death. More than 40 of such diseases are known, affecting one in every 8000 infants. The symptoms of lysosomal storage diseases can range from very severe to barely detectable, depending on the degree of enzyme dysfunction. For example, Taysachs, the best-studied lysosomal storage disease, occurs due to the deficiency of an enzyme degrading ganglioside called N-hexosaminidase. In Hurler’s disease, the enzyme involved in glycosaminoglycan chain breakdown is either defective or missing. Undigested glycogen accumulates in lysosomes in the absence of enzyme glucosidase. This causes swelling of the organelles and irreversible damage to the cells and tissues in a fatal disease called Pompe disease. I- cell disease or inclusion-cell disease is one of the most severe and rare forms of lysosomal storage disease. In this inherited metabolic disorder, the lysosomes of various cell types do not have most hydrolytic enzymes due to a recessive single gene defect resulting in the accumulation of undigested substrates in the lysosomes. These result in large inclusions in the cells that pathologically affect all organ systems, skeletal integrity, and mental development.
Suggested Reading
- Parkinson-Lawrence, E. J., Shandala, T., Prodoehl, M., Plew, R., Borlace, G. N., & Brooks, D. A. (2010). Lysosomal storage disease: revealing lysosomal function and physiology. Physiology, 25(2), 102-115.
- Fukuda T, Ewan L, Bauer M, Mattaliano RJ, Zaal K, Ralston E, Plotz PH, Raben N. Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2006 Apr;59(4):700-8.