BIOCHEMISTRY AND MOLECULAR BIOLOGY - W. ELLIOTT - 2002

CHAPTER 16. INTRACELLULAR WASTE-DISPOSAL ORGANELLES

While this role may seem unglamorous, its critical importance is underscored by the fact that over forty Genetic Disorders are linked to defects in lysosomal Enzymes.

In addition, we will discuss Peroxisomes, Organelles that bear a striking morphological resemblance to lysosomes yet serve a somewhat different function: they are dedicated to the chemical Processing of substances that the cell's broader metabolic machinery cannot handle.

Lysosomes

Lysosomes are membrane-bounded organelles present in the Cytoplasm of all Eukaryotic Cells (see Fig. 3.15, a).

Liver cells contain several hundred of them. Figuratively speaking, lysosomes can be described as "bags of mass destruction weaponry"! Indeed, they enclose a diverse array of hydrolytic enzymes capable of dismantling virtually any cellular component. The cell is protected from self-destruction not only by the lysosomal membrane itself, but also by the fact that lysosomal enzymes operate in an acidic environment (pH 4.5). This acidity is maintained within the lysosome by an ATP-dependent proton pump (Fig. 16.1). If a lysosomal membrane is ruptured, its enzymes spill into an environment with a pH of ~7.3, where they are virtually inactive (the buffering capacity of the cytoplasm vastly exceeds that of the lysosomal contents).

Class="center">Fig. 16.1. Primary lysosome budding off from the Golgi apparatus (schematic representation). A primary lysosome is a transport vesicle that delivers hydrolytic enzymes to endosomes.

Primary lysosomes bud off from the Golgi apparatus as vesicles packed with enzymes. Newly synthesized enzymes are packaged into lysosomes during their formation (discussed in detail in Chapter 22). These include proteinases, Phosphatases, esterases, DNases, RNases, and enzymes that degrade Polysaccharides and mucopolysaccharides. This arsenal is more than sufficient to hydrolyze any biological molecule, and Hydrolysis in an aqueous medium is irreversible.

How do substances destined for destruction enter lysosomes?

Because lysosomal enzymes cannot function in the cytoplasm, their substrates must gain entry into the lysosomes. The objects targeted for degradation may originate either inside or outside the cell. Intracellular targets include Mitochondria. The lifespan of a mitochondrion in a liver cell is about ten days, after which these aged organelles are somehow recognized and enclosed within a vesicle formed from The Endoplasmic reticulum membrane. Such vesicles are called autophagosomes (Fig. 16.2) to distinguish them from phagosomes, which are formed when phagocytes engulf Bacteria or other foreign particles.

Fig. 16.2. Digestion of the contents of clathrin-coated vesicles (endosomes and autophagosomes). Bacteria captured during phagocytosis are digested in a similar manner.

The phagocytosis of bacteria is carried out by white Blood Cells, but most cells in our bodies can also internalize external particles via receptor-mediated endocytosis. A prime example is the uptake of LDL and chylomicron remnants (see p. 96). The Mechanism of this process is illustrated in Fig. 16.2. Receptors on The Plasma Membrane are clustered in regions containing the protein clathrin. Following the binding of a Ligand, such as LDL, to its receptor, these regions invaginate and pinch off from the membrane, enclosing the LDL within a clathrin-coated vesicle. The clathrin is subsequently recycled back to the plasma membrane. Membrane vesicles containing endocytosed extracellular particles are termed endosomes.

Receptor-mediated endocytosis also accounts for the clearance of aged erythrocytes by The Liver and Spleen. The carbohydrate chains On the surface of erythrocytes terminate in sialic acid residues. Over time, these terminal groups are lost, exposing underlying galactose residues, which serves as a signal for erythrocyte destruction (their average lifespan in the blood is 120 days). Lysosomes also play a vital role in the lysis of Lipoproteins, such as LDL, taken up via endocytosis.

Autophagosomes, phagosomes, and endosomes fuse with primary lysosomes (which bud off from the Golgi apparatus), bringing the enzymes and their target substrates together within a single vesicle known as a secondary lysosome (terminology here is still somewhat fluid; lysosomes are sometimes equated specifically with secondary lysosomes). It is believed that The surface of primary lysosomes bears specialized Proteins that bind to complementary proteins on the membrane of the target particle with which the lysosome is to fuse. The fusion of a lysosome with its target is an energy-dependent process requiring GTP hydrolysis.

Lysosomes participate not only in the degradation of organelles and endocytosed structures, but also in The breakdown of certain proteins, Nucleic Acids, Lipids, and even Glycogen. How all these compounds cross into the enzyme-laden vesicles remains unclear, as does the mechanism by which breakdown products are returned to the cytoplasm. Presumably, dedicated membrane transport systems—specific Membrane Proteins—mediate these processes.

Certain membrane components are also degraded within lysosomes. For instance, a whole family of genetic disorders known as sphingolipidoses (with Tay-Sachs disease being a classic example) arises from the inability of lysosomal enzymes to break down gangliosides (see p. 56).

Structure/19.html">The Importance of Lysosomal Digestion

The deficiency of one or more lysosomal enzymes leads to severe pathology, causing lysosomes to become engorged with undigested material.

The Role of lysosomes in glycogen breakdown remains somewhat enigmatic. As you know from Chapter 6, glycogen is normally broken down by Glycogen phosphorylase. However, There is a condition known as Pompe disease, which is caused by a deficiency in a lysosomal enzyme that hydrolyzes α-(1—>4)-glycosidic bonds in glycogen. This leads to a massive accumulation of glycogen within cells, resulting in infant mortality. Lysosomes do not neatly fit into the classic pathway of glycogen degradation. It is possible that glycogen molecules are scavenged by lysosomes as a final clearance step; however, the physiological significance of this pathway remains poorly understood.

Peroxisomes

These membrane-bound vesicles, found in mammalian cells, contain enzymes belonging to the oxidase class. Oxidases utilize molecular oxygen to oxidize various

substrates, with the product of oxygen reduction being not Water, but hydrogen peroxide:

R′Н₂ + O₂ —> R′ + Н₂O₂.

Hydrogen peroxide, in turn, oxidizes other substrates itself (including a portion of the alcohol introduced into the body):

RН₂ + Н₂O₂ —> R + 2Н₂O.

Peroxisomes oxidize certain phenols, D-Amino Acids, as well as very long-chain Fatty acids that cannot be oxidized in mitochondria until they are shortened. Peroxisomes are also involved in the synthesis of certain Complex Lipids. There is reason to believe that they play a role in The conversion of Cholesterol into Bile acids. Interestingly, clofibrate, a cholesterol-lowering drug, causes a significant increase in the number of peroxisomes.

As with lysosomes, the BIOLOGICAL Functions OF peroxisomes are not yet fully understood, but their significance can be inferred from the consequences of genetic defects. For example, a rare, fatal genetic disease is known to be caused by the accumulation of C₂₄ and C₂₆ fatty acids, as well as bile acid precursors.

Questions for Chapter 16

1. What is the purpose of lysosomes?

2. What are primary lysosomes and where are they formed?

3. How do lysosomal enzymes come into contact with their substrates?

4. What evidence suggests that lysosomes are involved in the degradation of individual cellular components?

5. What is the underlying cause of Pompe disease?

6. What are peroxisomes and what are their functions?