Peroxisomes’ mechanisms of action

Peroxisomes differ from mitochondria and chloroplasts in many ways. Most notably, they are surrounded by only a single membrane, and they do not contain DNA or ribosomes. Like mitochondria and chloroplasts, however, peroxisomes are thought to acquire their proteins by selective import from the cytosol. But because they have no genomeall of their proteins must be imported. Peroxisomes thus resemble the ER in being a self-replicating, membrane-enclosed organelle that exists without a genome of its own.

Image ch12fu4.jpg

Because we do not discuss peroxisomes elsewhere, we shall digress to consider some of the functions of this diverse family of organelles, before discussing their biosynthesis. Peroxisomes are found in all eucaryotic cells. They contain oxidative enzymes, such as catalase and urate oxidase, at such high concentrations that in some cells the peroxisomes stand out in electron micrographs because of the presence of a crystalloid core.

Like mitochondria, peroxisomes are major sites of oxygen utilization. One hypothesis is that peroxisomes are a vestige of an ancient organelle that performed all the oxygen metabolism in the primitive ancestors of eucaryotic cells. When the oxygen produced by photosynthetic bacteria first began to accumulate in the atmosphere, it would have been highly toxic to most cells. Peroxisomes might have served to lower the intracellular concentration of oxygen, while also exploiting its chemical reactivity to perform useful oxidative reactions. According to this view, the later development of mitochondria rendered peroxisomes largely obsolete because many of the same reactions—which had formerly been carried out in peroxisomes without producing energy—were now coupled to ATP formation by means of oxidative phosphorylation. The oxidative reactions performed by peroxisomes in present-day cells would therefore be those that have important functions not taken over by mitochondria.

Peroxisomes Use Molecular Oxygen and Hydrogen Peroxide to Perform Oxidative Reactions

Peroxisomes are so named because they usually contain one or more enzymes that use molecular oxygen to remove hydrogen atoms from specific organic substrates (designated here as R) in an oxidative reaction that produces hydrogen peroxide (H2O2):

Image ch12e1.jpg

Catalase utilizes the H2O2 generated by other enzymes in the organelle to oxidize a variety of other substrates—including phenols, formic acid, formaldehyde, and alcohol—by the “peroxidative” reaction: H2O2 + R′ H2 → R′ + 2H2O. This type of oxidative reaction is particularly important in liver and kidney cells, where the peroxisomes detoxify various toxic molecules that enter the bloodstream. About 25% of the ethanol we drink is oxidized to acetaldehyde in this way. In addition, when excess H2O2 accumulates in the cell, catalase converts it to H2O through the reaction:

Image ch12e2.jpg

A major function of the oxidative reactions performed in peroxisomes is the breakdown of fatty acid molecules. In a process called β oxidation, the alkyl chains of fatty acids are shortened sequentially by blocks of two carbon atoms at a time, thereby converting the fatty acids to acetyl CoA. The acetyl CoA is then exported from the peroxisomes to the cytosol for reuse in biosynthetic reactions. In mammalian cells, β oxidation occurs in both mitochondria and peroxisomes; in yeast and plant cells, however, this essential reaction occurs exclusively in peroxisomes.

An essential biosynthetic function of animal peroxisomes is to catalyze the first reactions in the formation of plasmalogens, which are the most abundant class of phospholipids in myelin (Figure 12-32). Deficiency of plasmalogens causes profound abnormalities in the myelination of nerve cells, which is one reason why many peroxisomal disorders lead to neurological disease.

The structure of a plasmalogen. Plasmalogens are very abundant in the myelin sheaths that insulate the axons of nerve cells. They make up some 80–90% of the myelin membrane phospholipids. In addition to an ethanolamine head group and a long-chain (more…)

Peroxisomes are unusually diverse organelles, and even in the various cell types of a single organism they may contain different sets of enzymes. They can also adapt remarkably to changing conditions. Yeast cells grown on sugar, for example, have small peroxisomes. But when some yeasts are grown on methanol, they develop large peroxisomes that oxidize methanol; and when grown on fatty acids, they develop large peroxisomes that break down fatty acids to acetyl CoA by β oxidation.

Peroxisomes are also important in plants. Two different types have been studied extensively. One type is present in leaves, where it catalyzes the oxidation of a side product of the crucial reaction that fixes CO2 in carbohydrate (Figure 12-33A). As discussed in Chapter 14, this process is called photorespiration because it uses up O2 and liberates CO2. The other type of peroxisome is present in germinating seeds, where it has an essential role in converting the fatty acids stored in seed lipids into the sugars needed for the growth of the young plant. Because this conversion of fats to sugars is accomplished by a series of reactions known as the glyoxylate cycle, these peroxisomes are also called glyoxysomes (Figure 12-33B). In the glyoxylate cycle, two molecules of acetyl CoA produced by fatty acidbreakdown in the peroxisome are used to make succinic acid, which then leaves the peroxisome and is converted into glucose. The glyoxylate cycle does not occur in animal cells, and animals are therefore unable to convert the fatty acids in fats into carbohydrates.

Electron micrographs of two types of peroxisomes found in plant cells. (A) A peroxisome with a paracrystalline core in a tobacco leaf mesophyll cell. Its close association with chloroplasts is thought to facilitate the exchange of materials between these (more…)

A Short Signal Sequence Directs the Import of Proteins into Peroxisomes

A specific sequence of three amino acids located at the C terminus of many peroxisomal proteins functions as an import signal (see Table 12-3). Other peroxisomal proteins contain a signal sequence near the N terminus. If either of these sequences is experimentally attached to a cytosolic protein, the protein is imported into peroxisomes. The import process is still poorly understood, although it is known to involve soluble receptor proteins in the cytosol that recognize the targeting signals, as well as docking proteins on the cytosolic surface of the peroxisome. At least 23 distinct proteins, called peroxins, participate as components in the process, which is driven by ATP hydrolysis. Oligomeric proteins do not have to unfold to be imported into peroxisomes, indicating that the mechanism is distinct from that used by mitochondria and chloroplasts and at least one soluble import receptor, the peroxin Pex5, accompanies its cargo all the way into peroxisomes and, after cargo release, cycles back out into the cytosol. These aspects of peroxisomal protein import resemble protein tranport into the nucleus.

The importance of this import process and of peroxisomes is demonstrated by the inherited human disease Zellweger syndrome, in which a defect in importing proteins into peroxisomes leads to a severe peroxisomal deficiency. These individuals, whose cells contain “empty” peroxisomes, have severe abnormalities in their brain, liver, and kidneys, and they die soon after birth. One form of this disease has been shown to be due to a mutation in the gene encoding a peroxisomal integral membrane protein, the peroxin Pex2, involved in protein import. A milder inherited peroxisomal disease is caused by a defective receptor for the N-terminal import signal.

Most peroxisomal membrane proteins are made in the cytosol and then insert into the membrane of preexisting peroxisomes. Thus, new peroxisomes are thought to arise from preexisting ones, by organelle growth and fission—as mentioned earlier for mitochondria and plastids, and as we describe below for the ER

A model for how new peroxisomes are produced. The peroxisome membrane contains import receptor proteins. Peroxisomal proteins, including new copies of the import receptor, are synthesized by cytosolic ribosomes and then imported into the organelle. Presumably, (more…)

Summary

Peroxisomes are specialized for carrying out oxidative reactions using molecular oxygen. They generate hydrogen peroxide, which they use for oxidative purposes—destroying the excess by means of the catalase they contain. Peroxisomes also have an important role in the synthesis of specialized phospholipids required for nerve cellmyelination. Like mitochondria and plastids, peroxisomes are thought to be self-replicating organelles. Because they contain no DNA or ribosomes, however, they have to import their proteins from the cytosol. A specific sequence of three amino acids near the C terminus of many of these proteins functions as a peroxisomal import signal. The mechanism of protein import is distinct from that of mitochondria and chloroplasts, and oligomeric proteins can be transported into peroxisomes without unfolding.

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Peroxisome

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Basic structure of a peroxisome

File:Distribution of peroxisomes labelled with a monomeric eqFP611 variant in HEK293 cells during mitosis - pone.0004391.s005.ogv

Distribution of peroxisomes (white) in HEK 293 cells during mitosis

Peroxisome in rat neonatal cardiomyocyte staining The SelectFX Alexa Fluor 488 Peroxisome Labeling Kit directed against peroxisomal membrane protein 70 (PMP 70)

Peroxisome in rat neonatal cardiomyocyte

peroxisome (IPA: [pɛɜˈɹɒksɪˌsoʊm])[1] is a type of organelle known as a microbody, found in virtually all eukaryotic cells.[2] They are involved in catabolism of very long chain fatty acidsbranched chain fatty acidsD-amino acids, and polyaminesreduction of reactive oxygen species – specifically hydrogen peroxide[3] – and biosynthesis of plasmalogens, i.e., ether phospholipids critical for the normal function of mammalian brains and lungs.[4] They also contain approximately 10% of the total activity of two enzymes in the pentose phosphate pathway, which is important for energy metabolism.[4] It is vigorously debated whether peroxisomes are involved in isoprenoid and cholesterol synthesis in animals.[4] Other known peroxisomal functions include the glyoxylate cycle in germinating seeds (“glyoxysomes“), photorespiration in leaves,[5]glycolysis in trypanosomes (“glycosomes“), and methanol and/or amine oxidation and assimilation in some yeasts.

History[edit]

Peroxisomes were identified as organelles by the Belgian cytologist Christian de Duve in 1967[6] after they had been first described by a Swedish doctoral student, J. Rhodin in 1954.[7]

Metabolic functions[edit]

A major function of the peroxisome is the breakdown of very long chain fatty acids through beta-oxidation. In animal cells, the long fatty acids are converted to medium chain fatty acids, which are subsequently shuttled to mitochondria where they are eventually broken down to carbon dioxide and water. In yeast and plant cells, this process is carried out exclusively in peroxisomes.[8]

The first reactions in the formation of plasmalogen in animal cells also occur in peroxisomes. Plasmalogen is the most abundant phospholipid in myelin. Deficiency of plasmalogens causes profound abnormalities in the myelination of nerve cells, which is one reason why many peroxisomal disorders affect the nervous system.[8] Peroxisomes also play a role in the production of bile acids important for the absorption of fats and fat-soluble vitamins, such as vitamins A and K. Skin disorders are features of genetic disorders affecting peroxisome function as a result.

Peroxisomes contain oxidative enzymes, such as D-amino acid oxidase and uric acid oxidase.[9] However the last enzyme is absent in humans, explaining the disease known as gout, caused by the accumulation of uric acid. Certain enzymes within the peroxisome, by using molecular oxygen, remove hydrogen atoms from specific organic substrates (labeled as R), in an oxidative reaction, producing hydrogen peroxide (H2O2, itself toxic):

RH2O2RH2O2{\mathrm {RH}}_{{\mathrm {2}}}+{\mathrm {O}}_{{\mathrm {2}}}\rightarrow {\mathrm {R}}+{\mathrm {H}}_{2}{\mathrm {O}}_{2}

Catalase, another peroxisomal enzyme, uses this H2O2 to oxidize other substrates, including phenolsformic acidformaldehyde, and alcohol, by means of the peroxidation reaction:

H2O2RH2R2H2O{\mathrm {H}}_{2}{\mathrm {O}}_{2}+{\mathrm {R'H}}_{2}\rightarrow {\mathrm {R'}}+2{\mathrm {H}}_{2}{\mathrm {O}}, thus eliminating the poisonous hydrogen peroxide in the process.

This reaction is important in liver and kidney cells, where the peroxisomes detoxify various toxic substances that enter the blood. About 25% of the ethanolalcohol humans drink is oxidized to acetaldehyde in this way.[8] In addition, when excess H2O2 accumulates in the cell, catalase converts it to H2O through this reaction:

2H2O22H2OO22{\mathrm {H}}_{2}{\mathrm {O}}_{2}\rightarrow 2{\mathrm {H}}_{2}{\mathrm {O}}+{\mathrm {O}}_{2}

In higher plants, peroxisomes contain also a complex battery of antioxidative enzymes such as superoxide dismutase, the components of the ascorbate-glutathione cycle, and the NADP-dehydrogenases of the pentose-phosphate pathway. It has been demonstrated that peroxisomes generate superoxide (O2•−) and nitric oxide (NO) radicals.[10][11]

The peroxisome of plant cells is polarised when fighting fungal penetration. Infection causes a glucosinolate molecule to play an antifungal role to be made and delivered to the outside of the cell through the action of the peroxisomal proteins (PEN2 and PEN3).[12]

Peroxisome assembly[edit]

Peroxisomes can be derived from the endoplasmic reticulum and replicate by fission.[13] Peroxisome matrix proteins are translated in the cytoplasm prior to import. Specific amino acid sequences (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins signals them to be imported into the organelle. There are at least 32 known peroxisomal proteins, called peroxins,[14] which participate in the process of peroxisome assembly. Proteins do not have to unfold to be imported into the peroxisome. The protein receptors, the peroxins PEX5 and PEX7, accompany their cargoes (containing a PTS1 or a PTS2 amino acid sequence, respectively) all the way into the peroxisome where they release the cargo and then return to the cytosol – a step named recycling. A model describing the import cycle is referred to as the extended shuttle mechanism.[15] There is now evidence that ATP hydrolysis is required for the recycling of receptors to the cytosol. Also, ubiquitination appears to be crucial for the export of PEX5 from the peroxisome, to the cytosol.

Associated medical conditions[edit]

Peroxisomal disorders are a class of medical conditions that typically affect the human nervous system as well as many other organ systems. Two common examples are X-linked adrenoleukodystrophy and peroxisome biogenesis disorders.[16][17]

Genes[edit]

PEX genes encode the protein machinery (“peroxins”) required for proper peroxisome assembly, as described above. Membrane assembly and maintenance requires three of these (peroxins 3, 16, and 19) and may occur without the import of the matrix (lumen) enzymes. Proliferation of the organelle is regulated by Pex11p.

Genes that encode peroxin proteins include: PEX1PEX2 (PXMP3), PEX3PEX5PEX6PEX7PEX10PEX11APEX11BPEX11GPEX12PEX13PEX14PEX16PEX19PEX26PEX28PEX30, and PEX31.

Evolutionary origins[edit]

The protein content of peroxisomes varies across species or organism, but the presence of proteins common to many species has been used to suggest an endosymbiotic origin; that is, peroxisomes evolved from bacteria that invaded larger cells as parasites, and very gradually evolved a symbiotic relationship.[18]However, this view has been challenged by recent discoveries.[19] For example, peroxisome-less mutants can restore peroxisomes upon introduction of the wild-type gene.

Two independent evolutionary analyses of the peroxisomal proteome found homologies between the peroxisomal import machinery and the ERAD pathway in the endoplasmic reticulum,[20][21] along with a number of metabolic enzymes that were likely recruited from the mitochondria.[21] Recently, it has been suggested that the peroxisome may have had an actinobacterial origin,[22] however, this is controversial.[23]

Other related organelles[edit]

Other organelles of the microbody family related to peroxisomes include glyoxysomes of plants and filamentous fungiglycosomes of kinetoplastids,[24] and Woronin bodies of filamentous fungi.

References[edit]

  1. Jump up ^ “Peroxisome”Online DIctionary. Merriam-Webster. Retrieved 19 June2013.
  2. Jump up ^ Gabaldón T (Mar 2010). “Peroxisome diversity and evolution”Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences365 (1541): 765–73. doi:10.1098/rstb.2009.0240PMC 2817229Freely accessiblePMID 20124343.
  3. Jump up ^ Bonekamp NA, Völkl A, Fahimi HD, Schrader M (2009). “Reactive oxygen species and peroxisomes: struggling for balance”. BioFactors35 (4): 346–55. doi:10.1002/biof.48PMID 19459143.
  4. Jump up to: a b c Wanders RJ, Waterham HR (2006). “Biochemistry of mammalian peroxisomes revisited”. Annual Review of Biochemistry75: 295–332. doi:10.1146/annurev.biochem.74.082803.133329PMID 16756494.
  5. Jump up ^ Evert RF, Eichhorn SE (2006). Esau’s Plant Anatomy: Meristems, Cells, and Tissues of the Plant Body: Their Structure, Function, and Development. John Wiley & Sons. ISBN 9780471738435.
  6. Jump up ^ de Duve C (Apr 1969). “The peroxisome: a new cytoplasmic organelle”. Proceedings of the Royal Society of London. Series B, Biological Sciences173 (1030): 71–83. doi:10.1098/rspb.1969.0039PMID 4389648.
  7. Jump up ^ Rhodin, J (1954). “Correlation of ultrastructural organization and function in normal and experimentally changed proximal tubule cells of the mouse kidney”. Doctorate Thesis. Karolinska Institutet, Stockholm.
  8. Jump up to: a b c Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). “Chapter 12: Peroxisomes”. Molecular Biology of the Cell (Fourth ed.). New York: Garland Science. ISBN 0-8153-3218-1.
  9. Jump up ^ del Río LA, Sandalio LM, Palma JM, Bueno P, Corpas FJ (Nov 1992). “Metabolism of oxygen radicals in peroxisomes and cellular implications”. Free Radical Biology & Medicine13 (5): 557–80. doi:10.1016/0891-5849(92)90150-FPMID 1334030.
  10. Jump up ^ Corpas FJ, Barroso JB, del Río LA (Apr 2001). “Peroxisomes as a source of reactive oxygen species and nitric oxide signal molecules in plant cells”. Trends in Plant Science6 (4): 145–50. doi:10.1016/S1360-1385(01)01898-2PMID 11286918.
  11. Jump up ^ Corpas FJ, Barroso JB, Carreras A, Quirós M, León AM, Romero-Puertas MC, Esteban FJ, Valderrama R, Palma JM, Sandalio LM, Gómez M, del Río LA (Sep 2004). “Cellular and subcellular localization of endogenous nitric oxide in young and senescent pea plants”Plant Physiology136 (1): 2722–33. doi:10.1104/pp.104.042812PMC 523336Freely accessiblePMID 15347796.
  12. Jump up ^ Bednarek P, Pislewska-Bednarek M, Svatos A, Schneider B, Doubsky J, Mansurova M, Humphry M, Consonni C, Panstruga R, Sanchez-Vallet A, Molina A, Schulze-Lefert P (Jan 2009). “A glucosinolate metabolism pathway in living plant cells mediates broad-spectrum antifungal defense”. Science323(5910): 101–6. doi:10.1126/science.1163732PMID 19095900.
  13. Jump up ^ Hoepfner D, Schildknegt D, Braakman I, Philippsen P, Tabak HF (Jul 2005). “Contribution of the endoplasmic reticulum to peroxisome formation”Cell122 (1): 85–95. doi:10.1016/j.cell.2005.04.025PMID 16009135.
  14. Jump up ^ Saleem RA, Smith JJ, Aitchison JD (Dec 2006). “Proteomics of the peroxisome”Biochimica et Biophysica Acta1763 (12): 1541–51. doi:10.1016/j.bbamcr.2006.09.005PMC 1858641Freely accessiblePMID 17050007.
  15. Jump up ^ Dammai V, Subramani S (Apr 2001). “The human peroxisomal targeting signal receptor, Pex5p, is translocated into the peroxisomal matrix and recycled to the cytosol”. Cell105 (2): 187–96. doi:10.1016/s0092-8674(01)00310-5PMID 11336669.
  16. Jump up ^ Depreter M, Espeel M, Roels F (Jun 2003). “Human peroxisomal disorders”. Microscopy Research and Technique61 (2): 203–23. doi:10.1002/jemt.10330PMID 12740827.
  17. Jump up ^ Depreter M, Espeel M, Roels F (Jun 2003). “Human peroxisomal disorders”Microscopy Research and Technique61 (2): 203–23. doi:10.1002/jemt.10330PMID 12740827.
  18. Jump up ^ Lazarow PB, Fujiki Y (1985). “Biogenesis of peroxisomes”. Annual Review of Cell Biology1: 489–530. doi:10.1146/annurev.cb.01.110185.002421PMID 3916321.
  19. Jump up ^ Fagarasanu A, Fagarasanu M, Rachubinski RA (2007). “Maintaining peroxisome populations: a story of division and inheritance”. Annual Review of Cell and Developmental Biology23: 321–44. doi:10.1146/annurev.cellbio.23.090506.123456PMID 17506702.
  20. Jump up ^ Schlüter A, Fourcade S, Ripp R, Mandel JL, Poch O, Pujol A (Apr 2006). “The evolutionary origin of peroxisomes: an ER-peroxisome connection”. Molecular Biology and Evolution23 (4): 838–45. doi:10.1093/molbev/msj103PMID 16452116.
  21. Jump up to: a b Gabaldón T, Snel B, van Zimmeren F, Hemrika W, Tabak H, Huynen MA (2006). “Origin and evolution of the peroxisomal proteome”Biology Direct1: 8. doi:10.1186/1745-6150-1-8PMC 1472686Freely accessiblePMID 16556314.
  22. Jump up ^ Duhita N, Le HA, Satoshi S, Kazuo H, Daisuke M, Takao S (Jan 2010). “The origin of peroxisomes: The possibility of an actinobacterial symbiosis”. Gene450 (1-2): 18–24. doi:10.1016/j.gene.2009.09.014PMID 19818387.
  23. Jump up ^ Gabaldón T, Capella-Gutiérrez S (Oct 2010). “Lack of phylogenetic support for a supposed actinobacterial origin of peroxisomes”. Gene465 (1–2): 61–5. doi:10.1016/j.gene.2010.06.004PMID 20600706.
  24. Jump up ^ Blattner J, Swinkels B, Dörsam H, Prospero T, Subramani S, Clayton C (Dec 1992). “Glycosome assembly in trypanosomes: variations in the acceptable degeneracy of a COOH-terminal microbody targeting signal”The Journal of Cell Biology119 (5): 1129–36. doi:10.1083/jcb.119.5.1129PMC 2289717Freely accessiblePMID 1447292.

Further reading[edit]

  • Corpas FJ (2015). “What is the role of hydrogen peroxide in plant peroxisomes?”. Plant Biol (Stuttg)17 (6): 1099–103. doi:10.1111/plb.12376PMID 26242708.

External links[edit]

 This article incorporates public domain material from the NCBI document “Science Primer”This article incorporates text from the public domain Pfam and InterPro IPR006708

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