Cellular Biology 7. Describe the process by which lysosomal enzymes are targeted

Question

Cellular Biology

7. Describe the process by which lysosomal enzymes are targeted to lysosomes following their synthesis on the ER. Begin your description with the enzymes exiting the ER and end your description at lysosomes, where the enzymes are fully active.

8. For each of the following lysosomal storage diseases describe the enzyme that is defective that gives rise to each disease, its normal function and why the defect causes the phenotype. a. I cell disease b. Tay-Sachs disease c. Pompe disease d. Batten disease

Explanation / Answer

Lysosomes are cellular organelles that contain acid hydrolase enzymes that break down waste materials and cellular debris. They can be described as the stomach of the cell. Lysosomes digest excess or worn-out organelles, food particles, and engulfed viruses or bacteria. The membrane around a lysosome allows the digestive enzymes to work at the pH they require. Lysosomes fuse with autophagic vacuoles (phagosomes) and dispense their enzymes into the autophagic vacuoles, digesting their contents. They are frequently nicknamed "suicide bags" or "suicide sacs" by cell biologists due to their autolysis.

The size of lysosomes varies from 0.1–1.2 m.[12] At pH 4.8, the interior of the lysosomes is acidic compared to the slightly basic cytosol (pH 7.2). The lysosome maintains this pH differential by pumping in protons (H+ ions) from the cytosol across the membrane via proton pumps and chloride ion channels. Vacuolar H+-ATPases are responsible for transport of protons, while the counter transport of chloride ions is performed by ClC-7 Cl/H+ antiporter. In this way a steady acidic environment is maintained.[13][14] The lysosomal membrane protects the cytosol, and therefore the rest of the cell, from the degradative enzymes within the lysosome. The cell is additionally protected from any lysosomal acid hydrolases that drain into the cytosol, as these enzymes are pH-sensitive and do not function well or at all in the alkaline environment of the cytosol. This ensures that cytosolic molecules and organelles are not destroyed in case there is leakage of the hydrolytic enzymes from the lysosome.

Lysosomotropism

Weak bases with lipophilic properties accumulate in acidic intracellular compartments like lysosomes. While the plasma and lysosomal membranes are permeable for neutral and uncharged species of weak bases, the charged protonated species of weak bases do not permeate biomembranes and accumulate within lysosomes. The concentration within lysosomes may reach levels 100 to 1000 fold higher than extracellular concentrations. This phenomenon is called "lysosomotropism"[23] or "acid trapping". The amount of accumulation of lysosomotropic compounds may be estimated using a cell-based mathematical model.[24]

A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties. This explains a number of pharmacological properties of these drugs, such as high tissue-to-blood concentration gradients or long tissue elimination half-lifes; these properties have been found for drugs such as haloperidol,[25] levomepromazine,[26] and amantadine.[27] However, high tissue concentrations and long elimination half-lives are explained also by lipophilicity and absorption of drugs to fatty tissue structures. Important lysosomal enzymes, such as acid sphingomyelinase, may be inhibited by lysosomally accumulated drugs.[28][29] Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase)[30] and include for example fluoxetine, sertraline, or amitriptyline.

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