In humans, the catabolism of phytanate, pristanate, and very long chain fatty acids as well as the first four steps of the biosynthesis of plasmalogens are catalyzed by peroxisomal enzymes. Defects in any of these enzymes or in the assembly of peroxisomes are associated with severe developmental disorders (Wanders and Watherham 2006).
View original pathway at Reactome.
Schmitz W, Albers C, Fingerhut R, Conzelmann E.; ''Purification and characterization of an alpha-methylacyl-CoA racemase from human liver.''; PubMedEurope PMCScholia
van Roermund CW, Visser WF, Ijlst L, van Cruchten A, Boek M, Kulik W, Waterham HR, Wanders RJ.; ''The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters.''; PubMedEurope PMCScholia
Chu R, Varanasi U, Chu S, Lin Y, Usuda N, Rao MS, Reddy JK.; ''Overexpression and characterization of the human peroxisomal acyl-CoA oxidase in insect cells.''; PubMedEurope PMCScholia
Bloisi W, Colombo I, Garavaglia B, Giardini R, Finocchiaro G, Didonato S.; ''Purification and properties of carnitine acetyltransferase from human liver.''; PubMedEurope PMCScholia
Houten SM, Denis S, Argmann CA, Jia Y, Ferdinandusse S, Reddy JK, Wanders RJ.; ''Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids.''; PubMedEurope PMCScholia
Chen GL, Balfe A, Erwa W, Hoefler G, Gaertner J, Aikawa J, Chen WW.; ''Import of human bifunctional enzyme into peroxisomes of human hepatoma cells in vitro.''; PubMedEurope PMCScholia
Wylin T, Baes M, Brees C, Mannaerts GP, Fransen M, Van Veldhoven PP.; ''Identification and characterization of human PMP34, a protein closely related to the peroxisomal integral membrane protein PMP47 of Candida boidinii.''; PubMedEurope PMCScholia
Jones JM, Nau K, Geraghty MT, Erdmann R, Gould SJ.; ''Identification of peroxisomal acyl-CoA thioesterases in yeast and humans.''; PubMedEurope PMCScholia
Sacksteder KA, Morrell JC, Wanders RJ, Matalon R, Gould SJ.; ''MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency.''; PubMedEurope PMCScholia
Ferdinandusse S, Denis S, Hogenhout EM, Koster J, van Roermund CW, IJlst L, Moser AB, Wanders RJ, Waterham HR.; ''Clinical, biochemical, and mutational spectrum of peroxisomal acyl-coenzyme A oxidase deficiency.''; PubMedEurope PMCScholia
Baumgart E, Vanhooren JC, Fransen M, Marynen P, Puype M, Vandekerckhove J, Leunissen JA, Fahimi HD, Mannaerts GP, van Veldhoven PP.; ''Molecular characterization of the human peroxisomal branched-chain acyl-CoA oxidase: cDNA cloning, chromosomal assignment, tissue distribution, and evidence for the absence of the protein in Zellweger syndrome.''; PubMedEurope PMCScholia
Ferdinandusse S, Denis S, Van Roermund CW, Wanders RJ, Dacremont G.; ''Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids.''; PubMedEurope PMCScholia
Amery L, Fransen M, De Nys K, Mannaerts GP, Van Veldhoven PP.; ''Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans.''; PubMedEurope PMCScholia
Jiang LL, Miyazawa S, Souri M, Hashimoto T.; ''Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein.''; PubMedEurope PMCScholia
Reilly SJ, Tillander V, Ofman R, Alexson SE, Hunt MC.; ''The nudix hydrolase 7 is an Acyl-CoA diphosphatase involved in regulating peroxisomal coenzyme A homeostasis.''; PubMedEurope PMCScholia
Verhoeven NM, Roe DS, Kok RM, Wanders RJ, Jakobs C, Roe CR.; ''Phytanic acid and pristanic acid are oxidized by sequential peroxisomal and mitochondrial reactions in cultured fibroblasts.''; PubMedEurope PMCScholia
Visser WF, van Roermund CW, Waterham HR, Wanders RJ.; ''Identification of human PMP34 as a peroxisomal ATP transporter.''; PubMedEurope PMCScholia
Keller MA, Watschinger K, Golderer G, Maglione M, Sarg B, Lindner HH, Werner-Felmayer G, Terrinoni A, Wanders RJ, Werner ER.; ''Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal.''; PubMedEurope PMCScholia
Osumi T, Hashimoto T.; ''Peroxisomal beta oxidation system of rat liver. Copurification of enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase.''; PubMedEurope PMCScholia
Ferdinandusse S, Denis S, IJlst L, Dacremont G, Waterham HR, Wanders RJ.; ''Subcellular localization and physiological role of alpha-methylacyl-CoA racemase.''; PubMedEurope PMCScholia
De Nys K, Meyhi E, Mannaerts GP, Fransen M, Van Veldhoven PP.; ''Characterisation of human peroxisomal 2,4-dienoyl-CoA reductase.''; PubMedEurope PMCScholia
Ferdinandusse S, Mulders J, IJlst L, Denis S, Dacremont G, Waterham HR, Wanders RJ.; ''Molecular cloning and expression of human carnitine octanoyltransferase: evidence for its role in the peroxisomal beta-oxidation of branched-chain fatty acids.''; PubMedEurope PMCScholia
McDonough MA, Kavanagh KL, Butler D, Searls T, Oppermann U, Schofield CJ.; ''Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.''; PubMedEurope PMCScholia
Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K.; ''Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing.''; PubMedEurope PMCScholia
Zha S, Ferdinandusse S, Hicks JL, Denis S, Dunn TA, Wanders RJ, Luo J, De Marzo AM, Isaacs WB.; ''Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer.''; PubMedEurope PMCScholia
Geisbrecht BV, Zhang D, Schulz H, Gould SJ.; ''Characterization of PECI, a novel monofunctional Delta(3), Delta(2)-enoyl-CoA isomerase of mammalian peroxisomes.''; PubMedEurope PMCScholia
Jones JM, Morrell JC, Gould SJ.; ''Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases.''; PubMedEurope PMCScholia
Van Veldhoven PP.; ''Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism.''; PubMedEurope PMCScholia
Hunt MC, Solaas K, Kase BF, Alexson SE.; ''Characterization of an acyl-coA thioesterase that functions as a major regulator of peroxisomal lipid metabolism.''; PubMedEurope PMCScholia
Croes K, Van Veldhoven PP, Mannaerts GP, Casteels M.; ''Production of formyl-CoA during peroxisomal alpha-oxidation of 3-methyl-branched fatty acids.''; PubMedEurope PMCScholia
Jansen GA, van den Brink DM, Ofman R, Draghici O, Dacremont G, Wanders RJ.; ''Identification of pristanal dehydrogenase activity in peroxisomes: conclusive evidence that the complete phytanic acid alpha-oxidation pathway is localized in peroxisomes.''; PubMedEurope PMCScholia
Bout A, Franse MM, Collins J, Blonden L, Tager JM, Benne R.; ''Characterization of the gene encoding human peroxisomal 3-oxoacyl-CoA thiolase (ACAA). No large DNA rearrangement in a thiolase-deficient patient.''; PubMedEurope PMCScholia
Rizzo WB, Lin Z, Carney G.; ''Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analysis in Sjögren-Larsson syndrome.''; PubMedEurope PMCScholia
Ofman R, Speijer D, Leen R, Wanders RJ.; ''Proteomic analysis of mouse kidney peroxisomes: identification of RP2p as a peroxisomal nudix hydrolase with acyl-CoA diphosphatase activity.''; PubMedEurope PMCScholia
Nazarko TY, Ozeki K, Till A, Ramakrishnan G, Lotfi P, Yan M, Subramani S.; ''Peroxisomal Atg37 binds Atg30 or palmitoyl-CoA to regulate phagophore formation during pexophagy.''; PubMedEurope PMCScholia
Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE.; ''Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs.''; PubMedEurope PMCScholia
Vanhove GF, Van Veldhoven PP, Fransen M, Denis S, Eyssen HJ, Wanders RJ, Mannaerts GP.; ''The CoA esters of 2-methyl-branched chain fatty acids and of the bile acid intermediates di- and trihydroxycoprostanic acids are oxidized by one single peroxisomal branched chain acyl-CoA oxidase in human liver and kidney.''; PubMedEurope PMCScholia
Steinberg SJ, Wang SJ, Kim DG, Mihalik SJ, Watkins PA.; ''Human very-long-chain acyl-CoA synthetase: cloning, topography, and relevance to branched-chain fatty acid metabolism.''; PubMedEurope PMCScholia
Das AK, Uhler MD, Hajra AK.; ''Molecular cloning and expression of mammalian peroxisomal trans-2-enoyl-coenzyme A reductase cDNAs.''; PubMedEurope PMCScholia
Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T.; ''Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis.''; PubMedEurope PMCScholia
Lalwani ND, Reddy MK, Mangkornkanok-Mark M, Reddy JK.; ''Induction, immunochemical identity and immunofluorescence localization of an 80 000-molecular-weight peroxisome-proliferation-associated polypeptide (polypeptide PPA-80) and peroxisomal enoyl-CoA hydratase of mouse liver and renal cortex.''; PubMedEurope PMCScholia
Hua T, Wu D, Ding W, Wang J, Shaw N, Liu ZJ.; ''Studies of human 2,4-dienoyl CoA reductase shed new light on peroxisomal β-oxidation of unsaturated fatty acids.''; PubMedEurope PMCScholia
Vanhooren JC, Marynen P, Mannaerts GP, Van Veldhoven PP.; ''Evidence for the existence of a pristanoyl-CoA oxidase gene in man.''; PubMedEurope PMCScholia
Foulon V, Antonenkov VD, Croes K, Waelkens E, Mannaerts GP, Van Veldhoven PP, Casteels M.; ''Purification, molecular cloning, and expression of 2-hydroxyphytanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-methyl-branched fatty acids.''; PubMedEurope PMCScholia
Gasmi L, McLennan AG.; ''The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives.''; PubMedEurope PMCScholia
Onwukwe GU, Kursula P, Koski MK, Schmitz W, Wierenga RK.; ''Human Δ³,Δ²-enoyl-CoA isomerase, type 2: a structural enzymology study on the catalytic role of its ACBP domain and helix-10.''; PubMedEurope PMCScholia
Gloerich J, Ruiter JP, van den Brink DM, Ofman R, Ferdinandusse S, Wanders RJ.; ''Peroxisomal trans-2-enoyl-CoA reductase is involved in phytol degradation.''; PubMedEurope PMCScholia
Jiang LL, Kobayashi A, Matsuura H, Fukushima H, Hashimoto T.; ''Purification and properties of human D-3-hydroxyacyl-CoA dehydratase: medium-chain enoyl-CoA hydratase is D-3-hydroxyacyl-CoA dehydratase.''; PubMedEurope PMCScholia
Ferdinandusse S, Kostopoulos P, Denis S, Rusch H, Overmars H, Dillmann U, Reith W, Haas D, Wanders RJ, Duran M, Marziniak M.; ''Mutations in the gene encoding peroxisomal sterol carrier protein X (SCPx) cause leukencephalopathy with dystonia and motor neuropathy.''; PubMedEurope PMCScholia
Ferdinandusse S, Denis S, van Berkel E, Dacremont G, Wanders RJ.; ''Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein X (SCPx). Activity measurements in liver and fibroblasts using a newly developed method.''; PubMedEurope PMCScholia
Wu D, Govindasamy L, Lian W, Gu Y, Kukar T, Agbandje-McKenna M, McKenna R.; ''Structure of human carnitine acetyltransferase. Molecular basis for fatty acyl transfer.''; PubMedEurope PMCScholia
Nazarko TY.; ''Atg37 regulates the assembly of the pexophagic receptor protein complex.''; PubMedEurope PMCScholia
Peroxisomal ALDH3A2-2 (fatty aldehyde dehydrogenase family 3 member A2, isoform 2) catalyzes the NAD-dependent dehydrogenation of pristanal to form pristanate (Jansen et al. 2001; Kelson et al. 1997; Rizzo et al. 2001). Structural studies suggest that the enzyme is a homodimer (Keller et al. 2010), and expression studies of the homologous mouse proteins in cultured cells indicate that ALDH3A2 isoform 2 is localized to peroxisomes while isoform 1 is localized to the endoplasmic reticulum (Ashibe et al. 2007).
Peroxisomal HACL1 catalyzes the reaction of 2-hydroxyphytanoyl-CoA to form pristanal and formyl-CoA. The active form of the enzyme is a homotetramer, with one Mg++ and one molecule of thiamin pyrophosphate bound to each monomer (Croes et al. 1997; Foulon et al. 1999).
VLCS (very long chain acyl-CoA synthetase), associated with the inner surface of the peroxisomal membrane, cayalyzes the reaction of phytanate, CoA-SH, and ATP to form phytanoyl-CoA, AMP, and pyrophosphate (Steinberg et al. 1999).
VLCS (very long chain acyl-CoA synthetase), associated with the inner surface of the peroxisomal membrane, catalyzes the reaction of pristanate, CoA-SH and ATP to form pristanoyl-CoA, AMP and pyrophosphate (Steinberg et al. 1999).
Peroxisomal phytanoyl-CoA dioxygenase catalyzes the reaction of phytanoyl-CoA, 2-oxoglutarate, and O2 to form 2-hydroxyphytanoyl-CoA, succinate, and CO2. The mature form of the enzyme lacks the first 30 amino acid residues of the full-length polypeptide and is complexed with Fe++. Mutations in this enzyme are the commonest cause of Refsum disease (Mukherji et al. 2001; McDonough et al. 2005).
The peroxisomal membrane transport protein PMP34 mediates the exchange of adenine nucleotides between the cytosol and the peroxisomal matrix. The localization of PMP34 has been established by immunofluoresence studies (Wylin et al. 1998). The cloned human protein restores adenine nucleotide transport in yeast whose endogenous peroxisomal transporter has been disrupted, and has adenine nucleotide transport activity in reconstituted lipid vesicles in vitro (Visser et al. 2002), consistent with its hypothesized role in vivo (Wanders and Waterham 2006).
In human liver and kidney tissue, monomeric peroxisomal ACOX2 (bound to FAD cofactor) catalyzes the reaction of (2S)-pristanoyl-CoA and O2 to form trans-2,3-dehydropristanoyl-CoA and H2O2 (Vanhove et al. 1993; Baumgart et al. 1996). A putative acyl-coenzyme A oxidase-like protein ACOXL could catalyse this type of reaction but its activity has not yet been determined.
Peroxisomal ACOX3 catalyzes the reaction of (2S)-pristanoyl-CoA and O2 to form trans-2,3-dehydropristanoyl-CoA and H2O2. ACOX3 protein and enzyme activity have been observed in prostate tumors, but are undetectable in normal prostate tissue as well as in liver and kidney (where ACOX2 catalyzes the oxidation of pristanoyl-CoA) (Zha et al. 2005; Vanhooren et al. 1997). The physiological consequences of this differential gene expression are unknown.
Peroxisomal 2-methylacyl-CoA racemase (AMACR) catalyzes the isomerization of (2R)-pristanoyl-CoA to form (2S)-pristanoyl-CoA. The active form of the enzyme is a monomer (Schmitz et al. 1995; Amery et al. 2000; Ferdinandusse et al. 2000).
Peroxisomal HSD17B4 dimer catalyzes the reaction of trans-2,3-dehydropristanoyl-CoA and H2O to form 3-hydroxypristanoyl-CoA. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's, the reaction annotated here (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006).
Peroxisomal HSD17B4 dimer catalyzes the reaction of 3-hydroxypristanoyl-CoA and NAD+ to form 3-ketoxypristanoyl-CoA and NADH + H+. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's, the reaction annotated here, and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006).
Peroxisomal SCPx (Non-specific lipid transfer protein; SCP2) catalyzes the reaction of 3-ketopristanoyl-CoA and CoASH to form 4,8,12-trimethyltridecanoyl-CoA and propionyl-CoA. Both intact SCPx and an SCPx fragment corresponding to approximately the 430 aminoterminal residues of the protein are catalytically active in vitro; the latter form may predominate in vivo. Consistent with the role of SCPx in the beta-oxidation of branched-chain fatty acids in vitro, mutations in the protein are associated with elevated levels of pristanic acid in the blood in vivo and the development of neurological defects (Ferdinandusse et al. 2000, 2006).
Peroxisomal HSD17B4 dimer catalyzes the reaction of 3-hydroxyhexacosanoyl-CoA and NAD+ to form 3-ketohexacosanoyl-CoA and NADH + H+. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's, the reaction annotated here, and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006).
Peroxisomal HSD17B4 dimer catalyzes the reaction of trans-2,3-dehydrohexacosanoyl-CoA and H2O to form 3-hydroxyhexacosanoyl-CoA. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's, the reaction annotated here (Jiang et al. 1996, 1997). Defects in the enzyme are associated with a severe disorder of peroxisomal fatty acid metabolism in humans (Ferdinandusse et al. 2006).
Peroxisomal ACOX1 catalyzes the reaction of hexacosanoyl-CoA and O2 to form trans-2,3-dehydrohexacosanoyl-CoA and H2O2. The active form of the enzyme is a homodimer with FAD as a cofactor (Chu et al. 1995). Mutations in the ACOX1 gene are asociated with accumulation of very long chain fatty acids. Two isoforms of ACOX1, generated by alternative splicing are known; a mutation affecting specifically the second isoform blocks the oxidation of very long chain fatty acids (Ferdinandusse et al. 2007).
In two cycles of beta-oxidation mediated by the same enzyme activities responsible for the conversion of pristanoyl-CoA to 4,8,12-trimethyltridecanoyl-CoA, the latter molecule is converted to 4,8-dimethylnonanoyl-CoA. Two molecules each of O2, H2O, NAD+, and CoASH are consumed in the process and two molecules of H2O2 and NADH + H+ are generated, together with single molecules of acetyl-CoA and propionyl-CoA (Verhoeven et al. 1998).
Peroxisomal CROT catalyzes the reaction of 4,8-dimethylnonanoyl-CoA and carnitine to form 4,8-dimethylnonanoylcarnitine and CoASH (Ferdinandusse et al. 1999).
Peroxisomal carnitineacetyltransferase (CRAT) catalyzes the reaction of propionyl-CoA and carnitine to form propionylcarnitine and CoASH. The active form of the enzyme is a monomer (Bloisi et al. 1990; Wu et al. 2003).
Peroxisomal carnitineacetyltransferase (CRAT) catalyzes the reaction of acetyl-CoA and carnitine to form acetylcarnitine and CoASH. The active form of the enzyme is a monomer (Bloisi et al. 1990; Wu et al. 2003).
In eight cycles of beta-oxidation mediated by the same enzyme activities responsible for the conversion of hexacosanoyl-CoA to tetracosenoyl-CoA, the latter molecule is converted to octanoyl-CoA. Eight molecules each of O2, H2O, NAD+, and CoASH are consumed in the process and eight molecules of H2O2 and NADH + H+ are generated, together with eight molecules of acetyl-CoA (Wanders and Waterham 2006).
Homodimeric ABCD1 associated with the peroxisomal membrane mediates the uptake of cytosolic very long chain fatty acyl CoAs such as hexacosanoyl-CoA into the peroxisomal matrix. While the requirement for this uptake step in the catabolism of very long chain fatty acids is well-established, direct evidence for the function of ABCD1 as a transporter comes only from studies of its ability to restore peroxisomal long chain fatty acid catabolism in yeast strains whose endogenous transporters have been disrupted by mutation. ABCD1 is inferred to function as a dimer like other members of the ABCD transporter family. The energy requirements of peroxisomal fatty acid uptake (other ABCD transporter-mediated reactions are coupled to ATP hydrolysis) have not been established (van Roermund et al. 2008).
The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health.
Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A (CoA) thioesterases (ACOTs) hydrolyse medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFA-CoA, LCFA-CoA) to their corresponding free fatty acids (MCFA, LCFA) and CoASH. ACOTs located in peroxisomes are ACOT4, 6 and 8 (Hunt et al. 2006, Hunt et al. 2002).
Saturated and unsaturated fats can undergo beta-oxidation in the mitochondrion and peroxisomes. The only major difference known so far is that peroxisomes can process linear as well as branched unsaturated fatty acid enoyl-CoA esters with much longer chains (>C20) when compared with the mitochondrion. Peroxisomal 2,4-dienoyl-CoA reductase (DECR2) mediates the reduction of long-chain enoyl-CoA esters (LCtE-CoA) to form trans-3-enoyl-CoA esters (t3enoyl-CoA) (De Nys et al. 2001, Hua et al. 2012). DECR2 functions as an auxiliary enzyme for fatty acid beta-oxidation where very long-chain and long-chain fatty acids are shortened in peroxisomes and shuttled to the mitochondrion for complete degradation.
Fatty acids can be metabolised by two distinct pathways; alpha- and beta-oxidation. Peroxisomal hydroxyacid oxidase 2 (HAO2) is thought to take part in alpha-oxidation of long chain fatty acids such as 2-hydroxypalmitate (2OH-PALM). HAO2 functions as a homotetramer and is highly expressed in liver and kidney (Jones et al. 2000).
Peroxisomal EHHADH catalyzes the reaction of trans-2,3-dehydrohexacosanoyl-CoA and H2O to form 3-hydroxyhexacosanoyl-CoA. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's, the reaction annotated here. The properties of the human enzyme are inferred from studies of its mouse and rat homologues and from enzymatic stdies of mutant yeast cells expressing the cloned human enzyme (Chen et al. 1991, Ferdinandusse et al. 2004; Houten et al. 2012; Lalwani et al. 1981; Osumi & Hashimoto 1979). The enzyme can also act on fatty dicarboxylic acids (not annotated here) (Houten et al, 2012).
Peroxisomal EHHADH catalyzes the reaction of 3-hydroxyhexacosanoyl-CoA and NAD+ to form 3-ketohexacosanoyl-CoA and NADH + H+. The enzyme is bifunctional - an aminoterminal domain catalyzes the dehydrogenation of a variety of 3-hydroxyacyl-CoA's, the reaction annotated here, and a carboxyterminal domain catalyzes the hydration of a variety of trans-2,3-dehydroacyl-CoA's. The properties of the human enzyme are inferred from studies of its mouse and rat homologues and from enzymatic stdies of mutant yeast cells expressing the cloned human enzyme (Chen et al. 1991, Ferdinandusse et al. 2004; Houten et al. 2012; Lalwani et al. 1981; Osumi & Hashimoto 1979). The enzyme can also act on fatty dicarboxylic acids (not annotated here) (Houten et al, 2012).
Coenzyme A (CoASH) is a necessary cofactor for the oxidation of lipids in peroxisomes. Peroxisomal coenzyme A diphosphatase (NUDT7) mediates the cleavage of CoA (and CoA esters and oxidised CoA) to produce 3',5'-ADP and 4'-phosphopantetheine (PPANT) and is suggested to be involved in the regulation of peroxisomal CoASH levels. Human NUDT7 activity is inferred from mouse Nudt7 activity (Gasmi et al. 2001, Reilly et al. 2008).
ECI2 in the peroxisome matrix catalyzes the isomerizeation of 3Z-enoyl-CoA to 2E-enoyl-CoA. The active form of the enzyme is a homotrimer (Onwukwe et al. 2015). The reaction annotated here, involving octenoyl-CoA isomers is the one originally characterized by Geisbreacht et al. (1999), although the enzyme is active on enoyl-CoAs of a range of chain lengths.
PECR associated with the peroxisomal membrane catalyzes the NADPH-dependent reduction of 2E-phytenoyl-CoA to form phytanoyl-CoA (Das et al. 2000; Gloerich et al. 2006). The active form of the enzyme is inferred to be a homotetramer from unpublished data deposited in PDB (accession 1YXM). This reaction is part of the process by which dietary phytol, ultimately derived from chlorophyll, is catabolized (Van Veldhoven 2010).
Coenzyme A (CoA-SH) and acyl-coenzyme A (acyl-CoA) can be degraded in peroxisomes by two members of the Nudix (nucleoside diphosphates linked to some moiety X) hydrolase superfamily; NUDT7 and NUDT19. NUDT19 hydrolyses free fatty acyl-CoA to form acyl-phosphopantetheine (acyl-PPANT) and 3′,5′-ADP. Human NUDT19 activity is inferred from mouse Nudt19 activity (Ofman et al. 2006).
The selective autophagy of peroxisomes (pexophagy) is controlled by autophagy receptors through the assembly of a receptor protein complex (RPC). These receptors can recruit specific proteins required for pexophagy to occur. The human orthologue of the fungal acyl-CoA-binding protein Atg37, ACBD5, is a positive regulator of the pexophagic RPC process. Palmitoyl-CoA competes with autophagy receptors thus may affect the pexophagic RPC process. Acyl-CoA-binding domain-containing proteins 4 and 5 (ACBD4,5) are peroxisomal membrane-bound proteins and thought to bind medium- and long-chain acyl-CoA esters (MCFA-CoA, LCFA-CoA) (Nazarko et al. 2014, Nazarko 2014). The function of ACBD4 has not yet been determined.
Carboxylation of acetyl-CoA and decarboxylation of malonyl-CoA are two processes that can control the amount of the signal transducer malonyl-CoA in the cell. The decarboxylation is catalysed by MCD enzyme in the peroxisomal matrix (Sacksteder et al, 1999).
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