This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: cerotate biosynthesis, hexacosanoate biosynthesis
|Superclasses:||Biosynthesis → Fatty Acid and Lipid Biosynthesis → Fatty Acid Biosynthesis|
Fatty acids are carboxylic acids with a long unbranched aliphatic tail. Even though fatty acids derived from natural fats and oils are usually at least 8 carbon atoms long, carboxylic acids as short as butanoate (4 carbon atoms) are considered to be fatty acids.
Fatty acids are often classified into four groups by their lengths:
Short-chain fatty acids (SCFA) are fatty acids with aliphatic tails of fewer than six carbons.
Medium-chain fatty acids (MCFA) are fatty acids with aliphatic tails of 6-12 carbons.
Long-chain fatty acids (LCFA) are fatty acids with aliphatic tails of 13-21 carbons.
Very-long-chain fatty acids (VLCFA) are fatty acids with aliphatic tails of 22 carbons or longer.
Very-long-chain fatty acids are components of eukaryotic cells and are involved in many different physiological functions in different organisms. They are abundant in some tissues, for example as constituents of myelin in the brain or of storage triacylglycerols in plant seeds, and are components of plant cuticular waxes [Westerberg04] (see cuticular wax biosynthesis), of sphingolipids [Dickson06], and of the lipid barrier of the skin. They are also involved in the pathways for protein trafficking and for the synthesis of the glycosylphostphatidylinositol (GPI) lipid anchor [Gaigg06].
About This Pathway
VLCFAs are synthesized in eukaryotes in the endoplasmic reticulum (ER) by a membrane-bound enzyme complex known as the elongase [Domergue00]. This complex catalyzes the sequential additions of C2 moieties from malonyl-CoA to preformed C18 acyl groups derived from the de novo fatty acid biosynthesis pathway. Each elongation cycle is composed of 4 reactions: condensation of a long-chain acyl-CoA and malonyl-CoA to form a 3-oxoacyl-CoA, reduction to a 3-hydroxyacyl-CoA, dehydration to a trans-2-enoyl-CoA, and a final reduction to yield a chain-elongated fatty acyl-CoA [Tehlivets07, Jakobsson06].
While the reactions catalyzed by the elongase are similar to those of de novo fatty acid biosynthesis (see palmitate biosynthesis I (animals and fungi) and palmitate biosynthesis II (bacteria and plants)), there are several differences between the elongase complex and the fatty acid synthase (FAS) complex. In animals and yeast all of the functions of FAS are present in either one (mammals) or two (yeast) large multidomain subunits (see human fatty acid synthase and yeast fatty acid synthase). The elongase, on the other hand, is composed of four enzymes that catalyze independent reactions, similarly to the bacterial/plants FAS systems. In addition, the elongase always utilizes malonyl-CoA as the C2 donor unit, while FAS uses either malonyl-CoA (in yeast and animals) or malonyl-[acp] in bacteria and plants.
The elongase accepts long-chain fatty acids [usually palmitate (C16) or stearate (C18)] made by the cytosolic fatty acid synthase complex, and produces arachidate (C20), behenate (C22), lignocerate (C24), cerotate (26) or even longer acids.
The four enzymes that form the elongase complex are very-long-chain 3-oxoacyl-CoA synthase or condensing enzyme [Ghanevati01], very-long-chain 3-oxoacyl-CoA reductase, very-long-chain 3-hydroxyacyl-CoA dehydratase and very-long-chain enoyl-CoA reductase. While only one enzyme catalyzes each of the last three reactions of the cycle (respectively), the first step (the condensation of the 2 carbons from malonyl-CoA to the nascent acyl-CoA) is catalyzed by several different enzymes, each of which has a different preference for its substrates (for example, in yeast both the ELO2 and ELO3 genes encode condensing enzymes that participate in the elongase complex). These enzymes, which are also the rate-limiting step in the cycle, thus determine the length of the final acyl-CoA produced by the complex they participate in [Kohlwein01].
Domergue00: Domergue F, Chevalier S, Creach A, Cassagne C, Lessire R (2000). "Purification of the acyl-CoA elongase complex from developing rapeseed and characterization of the 3-ketoacyl-CoA synthase and the 3-hydroxyacyl-CoA dehydratase." Lipids 35(5);487-94. PMID: 10907783
Gaigg06: Gaigg B, Toulmay A, Schneiter R (2006). "Very long-chain fatty acid-containing lipids rather than sphingolipids per se are required for raft association and stable surface transport of newly synthesized plasma membrane ATPase in yeast." J Biol Chem 281(45);34135-45. PMID: 16980694
Ghanevati01: Ghanevati M, Jaworski JG (2001). "Active-site residues of a plant membrane-bound fatty acid elongase beta-ketoacyl-CoA synthase, FAE1 KCS." Biochim Biophys Acta 2001;1530(1);77-85. PMID: 11341960
Kohlwein01: Kohlwein SD, Eder S, Oh CS, Martin CE, Gable K, Bacikova D, Dunn T (2001). "Tsc13p is required for fatty acid elongation and localizes to a novel structure at the nuclear-vacuolar interface in Saccharomyces cerevisiae." Mol Cell Biol 21(1);109-25. PMID: 11113186
Westerberg04: Westerberg R, Tvrdik P, Unden AB, Mansson JE, Norlen L, Jakobsson A, Holleran WH, Elias PM, Asadi A, Flodby P, Toftgard R, Capecchi MR, Jacobsson A (2004). "Role for ELOVL3 and fatty acid chain length in development of hair and skin function." J Biol Chem 279(7);5621-9. PMID: 14581464
Adamski95: Adamski J, Normand T, Leenders F, Monte D, Begue A, Stehelin D, Jungblut PW, de Launoit Y (1995). "Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV." Biochem J 311 ( Pt 2);437-43. PMID: 7487879
Airenne03: Airenne TT, Torkko JM, Van den plas S, Sormunen RT, Kastaniotis AJ, Wierenga RK, Hiltunen JK (2003). "Structure-function analysis of enoyl thioester reductase involved in mitochondrial maintenance." J Mol Biol 327(1);47-59. PMID: 12614607
Amery01: Amery L, Mannaerts GP, Subramani S, Van Veldhoven PP, Fransen M (2001). "Identification of a novel human peroxisomal 2,4-dienoyl-CoA reductase related protein using the M13 phage protein VI phage display technology." Comb Chem High Throughput Screen 4(7);545-52. PMID: 11669066
Bach08: Bach L, Michaelson LV, Haslam R, Bellec Y, Gissot L, Marion J, Da Costa M, Boutin JP, Miquel M, Tellier F, Domergue F, Markham JE, Beaudoin F, Napier JA, Faure JD (2008). "The very-long-chain hydroxy fatty acyl-CoA dehydratase PASTICCINO2 is essential and limiting for plant development." Proc Natl Acad Sci U S A 105(38);14727-31. PMID: 18799749
Baes00: Baes M, Huyghe S, Carmeliet P, Declercq PE, Collen D, Mannaerts GP, Van Veldhoven PP (2000). "Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids." J Biol Chem 275(21);16329-36. PMID: 10748062
Beaudoin02: Beaudoin F, Gable K, Sayanova O, Dunn T, Napier JA (2002). "A Saccharomyces cerevisiae gene required for heterologous fatty acid elongase activity encodes a microsomal beta-keto-reductase." J Biol Chem 277(13);11481-8. PMID: 11792704
Beaudoin09: Beaudoin F, Wu X, Li F, Haslam RP, Markham JE, Zheng H, Napier JA, Kunst L (2009). "Functional characterization of the Arabidopsis beta-ketoacyl-coenzyme A reductase candidates of the fatty acid elongase." Plant Physiol 150(3);1174-91. PMID: 19439572
Chen91b: Chen GL, Balfe A, Erwa W, Hoefler G, Gaertner J, Aikawa J, Chen WW (1991). "Import of human bifunctional enzyme into peroxisomes of human hepatoma cells in vitro." Biochem Biophys Res Commun 178(3);1084-91. PMID: 1651711
deLaunoit99: de Launoit Y, Adamski J (1999). "Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome." J Mol Endocrinol 22(3);227-40. PMID: 10343282
DieuaideNoubhan96: Dieuaide-Noubhani M, Novikov D, Baumgart E, Vanhooren JC, Fransen M, Goethals M, Vandekerckhove J, Van Veldhoven PP, Mannaerts GP (1996). "Further characterization of the peroxisomal 3-hydroxyacyl-CoA dehydrogenases from rat liver. Relationship between the different dehydrogenases and evidence that fatty acids and the C27 bile acids di- and tri-hydroxycoprostanic acids are metabolized by separate multifunctional proteins." Eur J Biochem 240(3);660-6. PMID: 8856068
Dittrich98: Dittrich F, Zajonc D, Huhne K, Hoja U, Ekici A, Greiner E, Klein H, Hofmann J, Bessoule JJ, Sperling P, Schweizer E (1998). "Fatty acid elongation in yeast--biochemical characteristics of the enzyme system and isolation of elongation-defective mutants." Eur J Biochem 252(3);477-85. PMID: 9546663
Ferdinandusse04: Ferdinandusse S, Denis S, Van Roermund CW, Wanders RJ, Dacremont G (2004). "Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids." J Lipid Res 45(6);1104-11. PMID: 15060085
Ferdinandusse05: Ferdinandusse S, Denis S, Overmars H, Van Eeckhoudt L, Van Veldhoven PP, Duran M, Wanders RJ, Baes M (2005). "Developmental changes of bile acid composition and conjugation in L- and D-bifunctional protein single and double knockout mice." J Biol Chem 280(19);18658-66. PMID: 15769750
Ferdinandusse06: Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T (2006). "Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis." Am J Hum Genet 78(1);112-24. PMID: 16385454
Fiebig00: Fiebig A, Mayfield JA, Miley NL, Chau S, Fischer RL, Preuss D (2000). "Alterations in CER6, a gene identical to CUT1, differentially affect long-chain lipid content on the surface of pollen and stems." Plant Cell 2000;12(10);2001-8. PMID: 11041893
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