Peroxisomes PDF

Peroxisomes Suresh Subramani University of California, San Diego, California, USA Peroxisomes are among the simplest of the subcellular include the induction of prolif...

Peroxisomes Suresh Subramani University of California, San Diego, California, USA Peroxisomes are among the simplest of the subcellular include the induction of proliferation of hepatic peroxi- organelles that are characteristic of all eukaryotic cells. With somes by fibrate drugs, phthalate plasticizers and , 60 known enzymes in the matrix and ,45 documented xenobiotics, or the induction of peroxisomes in the integral or peripheral membrane proteins, it is a reasonable methylotrophic yeast, Pichia pastoris, by methanol or guess that this organelle has only , 125 proteins, which makes it oleate. The contents of the organelle are also responsive much less complex than other organelles. The peroxisome to the environment, as illustrated by the fact that derives its name from the fact that many metabolic enzymes that peroxisomes of yeasts grown on oleate have induced generate hydrogen peroxide as a by-product are sequestered levels of the fatty acid b-oxidation enzymes, whereas here because peroxides are toxic to cells. Within peroxisomes, methylotrophic yeasts grown on methanol have elevated hydrogen peroxide is degraded by the enzyme, catalase, to water levels of alcohol oxidase and dihydroxyacetone and oxygen. Peroxisomes are surrounded by a single membrane synthase. Peroxisome volume can also be regulated by and they range in diameter from 0.1 to 1 mm. They exist either in proteins such as Pex11p and Pex25p. Some mechanism the form of a network of interconnected tubules (peroxisome must also exist for monitoring the need for peroxisomes reticulum), as in liver cells, or as individual microperoxisomes in and their function, because excess peroxisomes can be other cells such as tissue culture fibroblasts. turned over by autophagic mechanisms involving the lysosome in mammals, or its yeast equivalent, the vacuole. Peroxisome-Like Organelles Peroxisomes are related to specialized peroxisomes called glycosomes in parasites such as Trypanosomes, Functions of Peroxisomes and to plant glyoxysomes, but are unrelated to hydro- genosomes, mitochondria, and chloroplasts. Collec- The principal function of peroxisomes is to house many tively, peroxisomes, glyoxysomes, and glycosomes are metabolic pathways that are involved in various aspects also referred to as microbodies. of lipid metabolism. These include the following: 1. enzymes involved in the degradative oxidation Peroxisome Distribution (e.g., b-oxidation of very long chain fatty acids, 2-methyl-branched fatty acids, dicarboxylic acids, leuko- and Origin trienes, bile acid intermediates and cholesterol side chains, and both a- and b-oxidation of 3-methyl- Peroxisomes exist in all eukaryotes from single- and multi- branched chain fatty acids); cellular microorganisms, to plants and animals. Unlike 2. the early steps in the synthesis of ether glycero- mitochondria, nuclei, and chloroplasts, peroxisomes lipids or plasmalogens; have no DNA. Consequently all their proteins are 3. the formation of bile acids, dolichol, and choles- encoded by nuclear genes. They are proposed to have terol; and originated from endosymbionts that subsequently lost 4. the catabolism of purines, polyamines, and amino their DNA, but the evidence for an endosymbiont origin is acids, and the detoxification of reactive oxygen species much weaker than it is for mitochondria and chloroplasts. such as hydrogen peroxide, superoxide anions, and epoxides. In methylotrophic yeasts, peroxisomes are Regulation of Peroxisome Number, also involved in the metabolism of methanol and methyl amines. Volume, and Contents Glycosomes contain the glycolytic enzymes, in Peroxisomes can be induced to proliferate in many addition to enzymes common to most peroxisomes, organisms in response to metabolic needs. Examples whereas plant gloxysomes have some or all of the Encyclopedia of Biological Chemistry, Volume 3. q 2004, Elsevier Inc. All Rights Reserved. 246  PEROXISOMES 247 glyoxylate pathway enzymes. Peroxisomes in the leaves Most of proteins that reside in the peroxisome matrix of plants also participate in photorespiration. and membrane are synthesized in the cytosol and then Despite the fragility of the organelle during bio- imported posttranslationally to the organelle. About 25 chemical purification, the peroxisome membrane is PEX genes, encoding proteins named peroxins, are impermeable to small molecules such as NAD(H), necessary for the biogenesis of the organelle. Most of NADP(H), acetyl-CoA, and even protons in vivo. these genes are found in multiple organisms and 13 are Consequently, it is not surprising that the peroxisomal conserved in humans (Table II). The general principles of membrane has a number of transporters for fatty acids, biogenesis appear to be common to organisms across the fatty-acyl-CoA esters, metabolites, and ATP. evolutionary spectrum, but there are indeed organism- specific variations. More recently, additional PEX genes (PEX23 – PEX32) have been defined and many of these Involvement in Human Disease are involved in the control of peroxisome division and number, rather than in protein import. There are , 20 peroxisomal disorders, many of which are fatal. These diseases affect either a single metabolic enzyme, or the assembly of the organelle itself (Table I). PEROXISOMAL MATRIX PROTEIN IMPORT Almost all of the genes involved in the human Proteins destined for the peroxisome matrix have a few peroxisome biogenesis disorders (PBDs) are now peroxisome targeting signals (PTSs). Most matrix known – they fall within the 25 PEX genes required polypeptides have a conserved, C-terminal, tripeptide for peroxisome biogenesis. Mouse models for human PTS1 (-SKL in the one letter amino-acid code, or its PBDs offer the promise of better insights into the conserved variants). Others have an N-terminal or symptoms of these diseases, their diagnoses, and internal sequence termed PTS2 [(R/K) (L/V/I))X5(H/Q) eventually for therapeutic intervention. (L/A)]. A few proteins, such Saccharomyces cerevisiae acyl-CoA oxidase, either have no canonical PTS1 sequence or have one that is dispensable, suggesting Biogenesis of Peroxisomes that they may possess other, as yet undefined, features that allow them to be targeted to the peroxisome lumen. Because peroxisomes have no DNA, all their proteins Matrix proteins synthesized in the cytosol are bound must be imported from genes encoded in the nucleus. by cytosolic receptors – Pex5p in the case of PTS1, and TABLE I Human Peroxisomal Disorders Involving Metabolism and Biogenesis Disease Peroxisomal metabolic disorders Peroxisomal enzyme affected Pseudoneonatal adrenoleukodystrophy Acyl-CoA oxidase (Acox1) Multifunctional protein 2 (MFP2) deficiency MFP2 involved in b-oxidation of very long chain and 2-methylbranched fatty acids Peroxisomal thiolase deficiency 3-ketoacyl-CoA-thiolase X-linked adrenoleukodystrophy ALDp (transporter) Rhizomelic chondrodysplasia punctata Type 2 Dihydroxyacetonephosphate acyltransferase Rhizomelic chondrodysplasia punctata Type 3 Alkyl-dihydroxyacetonephosphate synthase Refsum’s disease (classical) Phytanoyl-CoA hydroxylase Glutaric aciduria Type 3 Glutaryl-CoA oxidase Hyperoxaluria Type I Alanine:glyoxylate aminotransferase Acatalasaemia Catalase Mevalonic aciduria Mevalonate kinase Di/trihydroxycholestanoic acidaemia Trihydroxycholestanoyl-CoA oxidase (Acox2) Mulibrey nanism TRIM37 Adult-onset sensory motor neuropathy 2-methylacyl-CoA racemase Disease Peroxisome biogenesis disorders Peroxin affected Zellweger syndrome Pex1, Pex2, Pex3, Pex5, Pex6, Pex10, Pex12, Pex13, Pex16, Pex19 Neonatal adrenoleukodystrophy Several peroxins (Pex1, Pex5, Pex6, Pex10, Pex12, Pex13) Infantile Refsum’s disease Several peroxins (Pex1, Pex2, Pex5, Pex12) Rhizomelic chondrodysplasia punctata Type I Pex7 248 PEROXISOMES TABLE II Proteins Involved in Peroxisome Biogenesis Pex1 A 100 –50 kDa ATPase (AAA family) in yeasts and humans. Interacts with Pex6 and other peroxins. Defects in Pex1 are the most common cause of the PBDs (CGI). Pex2 A ,40 kDa integral PMP with a carboxy-terminal, cytoplasmically exposed, zinc-binding RING domain. Has been identified in yeasts and humans, interacts with Pex3, Pex10 and Pex12 and is defective in CG10 of the PBDs. Pex3 A ,40 kDa integral PMP in yeast and humans that binds Pex19 and is defective in CG12 of the PBDs. Needed for assembly/stability of the RING–domain subcomplex comprised of Pex2, Pex10, Pex12 in yeast. Pex4 A 20–24 kDa peroxisome-associated ubiquitin-conjugating enzyme that interacts with Pex22. Has been identified in several yeast species, but not in any metazoan. Pex5 A ,70 kDa, predominantly cytoplasmic/partly peroxisomal protein that is found in yeasts, plants and humans. Contains a PTS1- binding, tetratricopeptide-repeat (TPR) domain in its carboxy-terminal half, interacts with several peroxins (Pex7, Pex8, Pex10, Pex12, Pex13 and Pex14) and is defective in CG2 of the PBDs. Pex6 A ,100 kDa (AAA family) ATPase found in yeasts, plants and humans. Interacts with Pex1 and is defective in CG4 of the PBDs. Pex7 A ,40 kDa, WD40-repeat-containing protein that binds the PTS2. Defective in CG11 of the PBDs. Pex8 A variably sized (60–80 kDa), peripheral, but intraperoxisomal, PMP that interacts with Pex5 and the docking subcomplex, found only in yeast. It is an intraperoxisomal organizer of the peroxisomal import machinery in S. cerevisiae. Pex9 A 44 kDa integral PMP found only in the yeast Yarrowia lipolytica. Pex10 A ,35 kDa integral PMP with a carboxy-terminal, cytoplasmically-exposed, zinc binding RING domain. Has been identified in yeasts and humans, interacts with Pex2, Pex3, Pex5 and Pex12, and is defective in CG7 of the PBDs. Pex11 A ,25 kDa integral PMP required for normal peroxisome abundance. Many species contain several Pex11 genes. Pex12 A ,40 kDa integral PMP with a carboxy-terminal, cytoplasmically-exposed, zinc-binding RING domain. Has been identified in yeasts and humans, interacts with Pex2, Pex3, Pex5 and Pex10, and is defective in CG3 of the PBDs. Pex13 A ,44 kDa integral PMP with a carboxy-terminal, cytoplasmically-exposed SH3 domain. Identified in yeasts and humans, interacts with Pex5 and Pex14, and is defective in CG13 of the PBDs. Pex14 A ,40 kDa PMP of yeasts, plants and humans that interacts with Pex5, Pex8, Pex13 and Pex17. Pex15 A 44 kDa integral PMP identified only in Saccharomyces cerevisiae. Interacts with Pex6 in yeast. Pex16 In humans, Pex16 is a 36 kDa integral PMP that binds Pex19 and is defective in CG9 of the PBDs. Pex17 A ,25 kDa integral PMP that interacts with Pex14. Has been identified only in S. cerevisiae and P. pastoris. Pex18 A 31 kDa soluble protein involved only in PTS2-protein import. It is highly similar to Pex21, and might act as a Pex7 chaperone. Identified only in S. cerevisiae. Pex19 A 33 kDa farnesylated protein of yeasts and humans. Predominantly cytoplasmic/partly peroxisomal, binds all known integral PMPs and recognizes some, but not all, mPTSs. It is defective in CG14 of the PBDs. Pex20 A 46 kDa soluble protein involved only in PTS2-protein import. Identified only in Y. lipolytica. Substitutes functionally for Pex18/Pex21 in S. cerevisiae. Pex21 A 31 kDa soluble protein involved only in PTS2-protein import, is highly similar to Pex18 and might act as a Pex7 chaperone. Identified only in S. cerevisiae. Pex22 A 20 kDa integral PMP of yeasts that interacts with Pex4 and anchors it on the peroxisomal membrane. Pex23 A 46 kDa integral PMP. Identified only in Y. lipolytica. Pex24 A 61 kDa integral PMP found in yeasts required for the proper localization of some, but not all, PMPs and matrix proteins. Pex25 A 45 kDa PMP found in S. cerevisiae that regulates peroxisome size and maintenance. CG, complementation group; SH3, Src-Homology 3. Pex7p in the case of PTS2 (see Figure 1). These of the organelle, where they release their cargo, before receptor– cargo complexes then move to the peroxisome they return back to the cytosol for another round of membrane where they dock with protein subcomplexes import. This is referred to as the extended shuttle model that are in or on the membrane. Two such complexes are for matrix protein import. It is unclear at present a docking subcomplex, comprised minimally of peroxins whether the RING – protein subcomplex (also called the Pex8p, Pex13p, Pex14p, and Pex17p, and a really translocation complex in the literature) is involved interesting new gene (RING) – protein subcomplex, directly in the translocation of proteins into peroxi- consisting of three RING – proteins Pex2p, Pex10p, somes, or in the shuttling of receptors (e.g., Pex5p) back and Pex12p (and other yeast peroxins, such as Pex3p to the cytosol. Many other peroxins and chaperones and Pex8p). The RING – proteins have a characteristic such as Djp1p, hsp70, and hsp40 are implicated in zinc-binding domain and are members of a protein matrix protein import, but their precise roles are still family whose first member was called RING. There is under investigation. evidence that the protein subcomplexes are dynamic, The PTS2 pathway, which is dependent on the e.g., the docking and RING –protein subcomplexes can receptor, Pex7p, requires different additional proteins come together as a larger complex during import. The depending on the organism of its origin. In S. cerevisiae, PTS receptors, Pex5p and Pex7p, are believed to shuttle the redundant proteins, Pex18p and Pex21p, fulfill this from the cytosol to the peroxisome membrane or lumen function, whereas in Yarrowia lipolytica, Pex20p is  PEROXISOMES 249 IMPORT OF PEROXISOMAL MEMBRANE PROTEINS These proteins have one or more sequences (mPTSs) that direct them to the peroxisomal membrane with the correct topology. Although a dozen or so mPTSs have been defined in several yeast and mammalian perox- isomal membrane proteins (PMPs), they have no simple consensus sequence. The PMP receptor(s), the mechan- ism of insertion of PMPs into the peroxisomal mem- brane, and the rules that govern their topology are not completely known, although several peroxins that play a role in PMP biogenesis are defined. Most mutants affecting the import of either peroxisomal matrix or membrane proteins have organelle remnants, in some but perhaps not all, organisms. FIGURE 1 Model of peroxisomal matrix enzyme import. Numbers indicate the corresponding Pex protein. Three main steps are outlined: (1) Binding of PTS-containing proteins (yellow and blue circles depict PTS1- and multimeric PTS2-containing proteins, respectively) to the Division and Proliferation import receptors (Pex5p and Pex7p); (2) transport of receptor–cargo complexes to the peroxisome membrane and interactions with PMPs, of Peroxisomes such as Pex14p and, perhaps Pex13p, which are in a subcomplex with Pex17p and Pex8p; (3) receptor– cargo translocation through a The division of peroxisomes is compatible with two proteinaceous pore formed either by the docking subcomplex (Pex14p, Pex13p, Pex17p, Pex8p) or the RING–peroxins subcomplex models. One of these proposes that peroxisomes arise by (Pex2p, Pex10p, Pex12p). PTS receptors may deliver cargo while budding and fission from pre-existing peroxisomes, and inserted in the peroxisomal membrane or after entry into the lumen. may be the one that is used in normal, mitotically Pex3p and Pex8p have been proposed to bridge proteins in the docking dividing cells. The other model is that peroxisomes arise and RING–peroxins subcomplexes. either de novo or from some other reservoir of membranes such as the endoplasmic reticulum. Mature needed, and in mammals an alternatively spliced form of peroxisomes are then generated from this membrane Pex5p (Pex5pL) is necessary for PTS2 import. However, reservoir via a variety of biogenesis intermediates. This the docking and RING – proteins are required in model may be more applicable to proliferating peroxi- common for both PTS1 and PTS2 import pathways, somes and to the regeneration of peroxisomes in pex leading to the current view that a common translocation mutants complemented by the affected gene. machinery is involved for both these pathways. Examples of organism-specific variations in the general scheme of biogenesis include the apparent lack Acknowledgments of the entire PTS2 pathway (PTS2 proteins and Pex7p, the PTS2 receptor) in worms (Caenorhabditis elegans), This work was supported by grants NIH DK41737 and and the dependence of the PTS2 import pathway on the NIH DK59844. The author thanks Dr. Sebastien Leon PTS1 receptor, Pex5p, in mammals, but not in yeasts. for his help in assembling Table II and Figure 1. He However, even where such differences exist, the under- regrets that the format of this article does not permit lying molecular mechanism is similar. This is illustrated citation of the many original contributors to this field. by the point that the proteins Pex18p and Pex21p from S. cerevisiae, Pex20p from Y. lipolytica, and Pex5pL in mammals all have a conserved motif that allows them to SEE ALSO THE FOLLOWING ARTICLES interact with Pex7p and/or PTS2 cargo to facilitate the Fatty Acid Oxidation † Fatty Acid Receptors † PTS2 import pathway. Fatty Acid Synthesis and its Regulation † Flavins Unlike the transport of unfolded proteins into other organelles, such as the endoplasmic reticulum and mitochondria, folded and oligomeric proteins can be GLOSSARY transported across the peroxisomal membrane. How autophagy Degradation of cytosol and organelles by protein turnover such large multi-subunit complexes are transported involving the yeast vacuole or the lysosome in mammals. across the membrane is unknown, because the trans- biogenesis The process of assembly. locon in the peroxisomal membrane has not been microbodies Another name for peroxisomes and similar organelles characterized. (glyoxysomes, glycosomes). 250 PEROXISOMES organelle A subcellular, membrane-enclosed compartment perform- Subramani, S., Koller, A., and Snyder, W. B. (2000). Import of ing specialized functions. peroxisomalmatrix and membrane proteins. Annu. Rev. Biochem. peroxisomal matrix Lumen of the peroxisome. 69, 399 –418. peroxisome A subcellular organelle involved in many lipid metabolic Titorenko, V. I., and Rachubinski, R. A. (1998). The endoplasmic pathways. reticulum plays an essential role in peroxisome biogenesis. Trends vacuole or lysosome Organelle in which protein turnover and Biochem. Sci. 23, 231–233. recycling occurs. The organelle is called the vacuole in yeast and Van den Bosch, H., Schutgens, R. B., Wanders, R. J., and Tager, J. M. the lysosome in mammalian cells. (1992). Biochemistry of peroxisomes. Annu. Rev. Biochem. 61, 157–197. BIOGRAPHY FURTHER READING Suresh Subramani is a Professor in the Section of Molecular Biology, Baumgartner, M. R., and Saudubray, J. M. (2002). Peroxisomal Division of Biological Sciences, University of California at San Diego. disorders. Semin. Neonatol. 7, 85–94. His current research interest is in organelle homeostasis. He holds a Hettema, E. H., and Tabak, H. F. (2000). Transport of fatty acids and doctoral degree in biochemistry from the University of California, metabolites across the peroxisomal membrane. Biochim. Biophys. Berkeley, and did his postdoctoral work at Stanford University. He has Acta 1486, 18–27. been on the faculty at UCSD since 1982. He and his colleagues have Purdue, P. E., and Lazarow, P. B. (2001). Peroxisome biogenesis. Annu. made many important contributions to the field of peroxisome Rev. Cell Develop. Biol. 17, 701– 752. biogenesis and turnover.