Chapter 10:  Peroxisomes

Functions of Peroxisomes

Peroxisomes contain at least 50 different enzymes, which are involved in a variety of biochemical pathways in different types of cells. Peroxisomes originally were defined as organelles that carry out oxidation reactions leading to the production of hydrogen peroxide. Because hydrogen peroxide is harmful to the cell, peroxisomes also contain the enzyme catalase, which decomposes hydrogen peroxide either by converting it to water or by using it to oxidize another organic compound. A variety of substrates are broken down by such oxidative reactions in peroxisomes, including uric acid, amino acids, and fatty acids. The oxidation of fatty acids (Figure 10.25) is a particularly important example, since it provides a major source of metabolic energy. In animal cells, fatty acids are oxidized in both peroxisomes and mitochondria, but in yeasts and plants fatty acid oxidation is restricted to peroxisomes.

In addition to providing a compartment for oxidation reactions, peroxisomes are involved in lipid biosynthesis. In animal cells, cholesterol and dolichol are synthesized in peroxisomes as well as in the ER. In the liver, peroxisomes are also involved in the synthesis of bile acids, which are derived from cholesterol. In addition, peroxisomes contain enzymes required for the synthesis of plasmalogens—a family of phospholipids in which one of the hydrocarbon chains is joined to glycerol by an ether bond rather than an ester bond (Figure 10.26). Plasmalogens are important membrane components in some tissues, particularly heart and brain, although they are absent in others.

Peroxisomes play two particularly important roles in plants. First, peroxisomes in seeds are responsible for the conversion of stored fatty acids to carbohydrates, which is critical to providing energy and raw materials for growth of the germinating plant. This occurs via a series of reactions termed the glyoxylate cycle, which is a variant of the citric acid cycle (Figure 10.27). The peroxisomes in which this takes place are sometimes called glyoxysomes.

Second, peroxisomes in leaves are involved in photorespiration, which serves to metabolize a side product formed during photosynthesis (Figure 10.28). CO₂ is converted to carbohydrates during photosynthesis via a series of reactions called the Calvin cycle (see Figure 2.39). The first step is the addition of CO₂ to the five-carbon sugar ribulose-1,5-bisphosphate, yielding two molecules of 3-phosphoglycerate (three carbons each). However, the enzyme involved (ribulose bisphosphate carboxylase or rubisco) sometimes catalyzes the addition of O₂ instead of CO₂, producing one molecule of 3-phosphoglycerate and one molecule of phosphoglycolate (two carbons). This is a side reaction, and phosphoglycolate is not a useful metabolite. It is first converted to glycolate and then transferred to peroxisomes, where it is oxidized and converted to glycine. Glycine is then transferred to mitochondria, where two molecules of glycine are converted to one molecule of serine, with the loss of CO₂ and NH₃. The serine is then returned to peroxisomes, where it is converted to glycerate. Finally, the glycerate is transferred back to chloroplasts, where it reenters the Calvin cycle. Photorespiration does not appear to be beneficial for the plant, since it is essentially the reverse of photosynthesis—O₂ is consumed and CO₂ is released without any gain of ATP. However, the occasional utilization of O₂ in place of CO₂ appears to be an inherent property of rubisco, so photorespiration is a general accompaniment of photosynthesis. Peroxisomes thus play an important role by allowing most of the carbon in glycolate to be recovered and utilized.

Peroxisome Assembly

As already noted, the assembly of peroxisomes is fundamentally similar to that of mitochondria and chloroplasts, rather than to that of the endoplasmic reticulum, Golgi apparatus, and lysosomes. Proteins destined for peroxisomes are translated on free cytosolic ribosomes and then transported into peroxisomes as completed polypeptide chains (Figure 10.29). Phospholipids are also imported to peroxisomes, via phospholipid transfer proteins, from their major site of synthesis in the ER. The import of proteins and phospholipids results in peroxisome growth, and new peroxisomes are then formed by division of old ones.

Proteins are targeted to the interior of peroxisomes by at least two pathways, which are conserved from yeasts to humans. Most proteins are targeted to peroxisomes by the simple amino acid sequence Ser-Lys-Leu at their carboxy terminus (peroxisome targeting signal 1, or PTS1). Other proteins are targeted by a sequence of nine amino acids (PTS2) at their amino terminus, and some proteins may be targeted by alternative signals that have not yet been well defined.

PTS1 and PTS2 are recognized by distinct receptors and then transferred to a translocation complex that mediates their transport across the peroxisome membrane. However, the mechanism of protein import into peroxisomes is less well characterized than the mechanisms of protein translocation across the membranes of other subcellular organelles. In contrast to the translocation of polypeptide chains across the membranes of the endoplasmic reticulum, mitochondria, and chloroplasts, targeting signals are usually not cleaved during the import of proteins into peroxisomes. Cytosolic Hsp70 has been implicated in protein import to peroxisomes, but the possible role of molecular chaperones within peroxisomes is unclear. Moreover, it appears that proteins can be transported into peroxisomes in at least partially folded conformations, rather than as extended polypeptide chains.

Some peroxisome membrane proteins are similarly synthesized on cytosolic ribosomes and targeted to the peroxisome membrane by distinct internal signals. However, other experiments suggest that some peroxisomal membrane proteins may be synthesized on membrane-bound polysomes of the endoplasmic reticulum and then transported to peroxisomes, suggesting a role for the endoplasmic reticulum in peroxisome maintenance. The import of proteins into peroxisomes thus appears to have several novel features, making it an active area of investigation.

Interestingly, some components of peroxisome import pathways have been identified not only as mutants of yeasts but also as mutations associated with serious human diseases involving disorders of peroxisomes. In some such diseases, only a single peroxisomal enzyme is deficient. However, in other diseases resulting from defects in peroxisome function, multiple peroxisomal enzymes fail to be imported to peroxisomes, instead being localized in the cytosol. The latter group of diseases results from deficiencies in the PTS1 or PTS2 pathways responsible for peroxisomal protein import. The prototypical example is Zellweger syndrome, which is lethal within the first ten years of life. Zellweger syndrome can result from mutations in at least ten different genes affecting peroxisomal protein import, one of which has been identified as the gene encoding the receptor for the peroxisome targeting signal PTS1.