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: de novo fatty acid biosynthesis, initial reactions
|Superclasses:||Biosynthesis → Fatty Acid and Lipid Biosynthesis → Fatty Acid Biosynthesis|
Fatty acids are key building blocks for the phospholipid components of cell membranes and are determinants of intracellular communication, in the form of lipid second messengers [Prieschl00], and fatty acyl moieties of proteins that modify their location and function [Resh99].
There are two basic types of fatty acid (FAS) biosynthesis mechanisms. The type I system is found in mammals and lower eukaryotes. The mammalian system consists of a single gene product that contains all of the reaction centers required to produce a fatty acid (see fatty acid synthase from Homo sapiens), while the system of lower eukaryotes (such as yeast) consists of two genes, whose polypeptide products combine to form a multifunctional complex (see fatty acid synthase from Saccharomyces cerevisiae).
Type II systems are found in bacteria, plants [White05], parasites of the Apicomplexa phylum [Ferguson07] and mitochondria [Zhang03h, Miinalainen03]. The reactions in these systems are catalyzed by a series of individual soluble proteins that are each encoded by a discrete gene, and the pathway intermediates are transferred between the enzymes as thioesters of a holo-[acyl-carrier protein].
The best studied pathway is that of Escherichia coli K-12, from which all the enzymes have been purified and crystalized. In plants fatty acid synthesis occurs mainly in plastids of leaf mesophyll cells, seeds, and oil-accumulating fruits. Although most of the synthesis occurrs in plastids, it has been shown that mitochondria are also capable of synthesizing fatty acids [Yasuno04].
Fatty acid biosynthesis starts with an initiation sequence that produces an acetoacetyl-[acp], an activated molecule that is used for subsequent elongation reactions, which ultimately produce the final fatty acid products. This pathway describes only the initiation sequnce, subsequent elongation reactions are described in the pathways fatty acid elongation -- saturated and (5Z)-dodec-5-enoate biosynthesis.
About This Pathway
Escherichia coli K-12 has several different routes in which it can produce acetoacetyl-ACP, and this pathway describes the major route. In it, one acetyl-CoA molecule is converted to malonyl-CoA, which is then activated to a malonyl-[acp] that is condensed with a second acetyl-CoA molecule to form an acetoacetyl-[acp].
The first enzyme in this pathway, acetyl-CoA carboxylase, is the controlling point for the flux of carbon into lipids. It is a biotin-containing multi-enzyme complex with two activities, biotin carboxylase and acetyl-CoA carboxyltransferase, catalyzing two half reactions that combined condense hydrogen carbonate with acetyl-CoA to yield malonyl-CoA. Further discussion of this enzyme is available in the pathway biotin-carboxyl carrier protein assembly. In plants this reaction is catalyzed by the plastidic heteromeric acetyl-CoA carboxylase. A second, homomeric form of the enzyme is cytosolic and is involved in very-long-chain fatty acid biosynthesis and synthesis of flavonoids.
The last step of the pathway, the condensation of a second acetyl-CoA with malonyl-[acp], is carried out by the condensing enzyme β-ketoacyl-ACP synthase (KAS). Escherichia coli K-12, as well as most plants, has three β-ketoacyl-ACP synthases: KASI, KASII and KASIII, encoded by fabB, fabF and fabH, respectively. KASIII is the key enzyme in the initiation of fatty acids biosynthesis. It selectively catalyzes the formation of acetoacetyl-ACP and specifically uses CoA thioesters rather than acyl-ACP as the primer. The products tend to be shorter than the products of KASI and II, which are involved primarily in elongation reactions. Unlike the other two enzymes, KASIII cannot participate in the terminal elongation steps of fatty acid biosynthesis [White05].
KASIII is inhibited by long-chain acyl-ACPs, indicating a role in feedback regulation of fatty acid synthesis. Since it catalyzes the first condensation step in fatty acid synthesis, it is able to control the rate of fatty acid initiation.
The substrate specificity of KASIII is a major determining factor in membrane fatty acid composition of an organism. In Escherichia coli the enzyme is highly selective for acetyl-CoA, and thus only straight-chain fatty acids are produced in this organism. In many gram-positive bacteria, such as Bacillus subtilis, the enzyme prefers branched-chain acyl-CoA substrates derived from amino acid metabolism, leading to the production of primarily iso- and anteisobranched fatty acids [Choi00a].
Superpathways: superpathway of fatty acids biosynthesis (E. coli) , superpathway of mycolate biosynthesis , superpathway of fatty acid biosynthesis II (plant) , superpathway of fatty acid biosynthesis initiation (E. coli) , superpathway of fatty acid biosynthesis I (E. coli)
Choi00a: Choi KH, Heath RJ, Rock CO (2000). "beta-ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis." J Bacteriol 182(2);365-70. PMID: 10629181
Clough92: Clough RC, Matthis AL, Barnum SR, Jaworski JG (1992). "Purification and characterization of 3-ketoacyl-acyl carrier protein synthase III from spinach. A condensing enzyme utilizing acetyl-coenzyme A to initiate fatty acid synthesis." J Biol Chem 267(29);20992-8. PMID: 1328217
Ferguson07: Ferguson DJ, Campbell SA, Henriquez FL, Phan L, Mui E, Richards TA, Muench SP, Allary M, Lu JZ, Prigge ST, Tomley F, Shirley MW, Rice DW, McLeod R, Roberts CW (2007). "Enzymes of type II fatty acid synthesis and apicoplast differentiation and division in Eimeria tenella." Int J Parasitol 37(1);33-51. PMID: 17112527
Miinalainen03: Miinalainen IJ, Chen ZJ, Torkko JM, Pirila PL, Sormunen RT, Bergmann U, Qin YM, Hiltunen JK (2003). "Characterization of 2-enoyl thioester reductase from mammals. An ortholog of YBR026p/MRF1'p of the yeast mitochondrial fatty acid synthesis type II." J Biol Chem 278(22);20154-61. PMID: 12654921
Yasuno04: Yasuno R, von Wettstein-Knowles P, Wada H (2004). "Identification and molecular characterization of the beta-ketoacyl-[acyl carrier protein] synthase component of the Arabidopsis mitochondrial fatty acid synthase." J Biol Chem 279(9);8242-51. PMID: 14660674
Yuan12: Yuan Y, Sachdeva M, Leeds JA, Meredith TC (2012). "Fatty acid biosynthesis in Pseudomonas aeruginosa is initiated by FabY: A new class of β-ketoacyl acyl carrier protein synthases." J Bacteriol. PMID: 22753059
Zhang03h: Zhang L, Joshi AK, Smith S (2003). "Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. Malonyltransferase and acyl carrier protein." J Biol Chem 278(41);40067-74. PMID: 12882974
AbdelHamid07: Abdel-Hamid AM, Cronan JE (2007). "Coordinate expression of the acetyl coenzyme A carboxylase genes, accB and accC, is necessary for normal regulation of biotin synthesis in Escherichia coli." J Bacteriol 189(2);369-76. PMID: 17056747
Alhamadsheh07: Alhamadsheh MM, Musayev F, Komissarov AA, Sachdeva S, Wright HT, Scarsdale N, Florova G, Reynolds KA (2007). "Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes." Chem Biol 14(5);513-24. PMID: 17524982
Alhamadsheh08: Alhamadsheh MM, Waters NC, Sachdeva S, Lee P, Reynolds KA (2008). "Synthesis and biological evaluation of novel sulfonyl-naphthalene-1,4-diols as FabH inhibitors." Bioorg Med Chem Lett 18(24);6402-5. PMID: 18996691
Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699
Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
Benson08: Benson BK, Meades G, Grove A, Waldrop GL (2008). "DNA inhibits catalysis by the carboxyltransferase subunit of acetyl-CoA carboxylase: implications for active site communication." Protein Sci 17(1);34-42. PMID: 18156466
Bilder06: Bilder P, Lightle S, Bainbridge G, Ohren J, Finzel B, Sun F, Holley S, Al-Kassim L, Spessard C, Melnick M, Newcomer M, Waldrop GL (2006). "The structure of the carboxyltransferase component of acetyl-coA carboxylase reveals a zinc-binding motif unique to the bacterial enzyme." Biochemistry 45(6);1712-22. PMID: 16460018
Blanchard99: Blanchard CZ, Chapman-Smith A, Wallace JC, Waldrop GL (1999). "The biotin domain peptide from the biotin carboxyl carrier protein of Escherichia coli acetyl-CoA carboxylase causes a marked increase in the catalytic efficiency of biotin carboxylase and carboxyltransferase relative to free biotin." J Biol Chem 1999;274(45);31767-9. PMID: 10542197
Bognar87: Bognar AL, Osborne C, Shane B (1987). "Primary structure of the Escherichia coli folC gene and its folylpolyglutamate synthetase-dihydrofolate synthetase product and regulation of expression by an upstream gene." J Biol Chem 262(25);12337-43. PMID: 3040739
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
Choi95a: Choi JK, Yu F, Wurtele ES, Nikolau BJ (1995). "Molecular cloning and characterization of the cDNA coding for the biotin-containing subunit of the chloroplastic acetyl-coenzyme A carboxylase." Plant Physiol 109(2);619-25. PMID: 7480350
Colbert10: Colbert CL, Kim CW, Moon YA, Henry L, Palnitkar M, McKean WB, Fitzgerald K, Deisenhofer J, Horton JD, Kwon HJ (2010). "Crystal structure of Spot 14, a modulator of fatty acid synthesis." Proc Natl Acad Sci U S A 107(44);18820-5. PMID: 20952656
Daines03: Daines RA, Pendrak I, Sham K, Van Aller GS, Konstantinidis AK, Lonsdale JT, Janson CA, Qiu X, Brandt M, Khandekar SS, Silverman C, Head MS (2003). "First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling." J Med Chem 46(1);5-8. PMID: 12502353
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