If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
|Superclasses:||Biosynthesis → Fatty Acids and Lipids Biosynthesis → Fatty Acid Biosynthesis|
Fatty acids are key building blocks for lipids and lipoproteins in Escherichia coli and Salmonella enterica subsp. enterica serovar Typhimurium. The overall mechanism of fatty acid biosynthesis is conserved in bacteria and eukaryotes and involves initiation and cyclic elongation stages. Intermediates of the E. coli pathway are used to form specific derivatives such as unsaturated fatty acids, the fatty acids of lipid A, and octanoyl-ACP.
There are two basic types of fatty acid 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, while the system of lower eukaryotes (such as yeast) consists of two genes, whose polypeptide products combine to form a multifunctional complex. Type II systems are found in bacteria, plants [White05], parasites of the phylum Apicomplexa [Ferguson07], and mitochondria [Zhang03e, 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 ACP.
The best studied pathway is that of Escherichia coli K-12, from which all the enzymes have been purified and crystallized. In plants fatty acid synthesis occurs mainly in plastids of leaf mesophyll cells, seeds, and oil-accumulating fruits. Although most of the synthesis occurs 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 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 sequence, subsequent elongation reactions are described in the pathways fatty acid elongation -- saturated and cis-dodecenoyl biosynthesis.
About This Pathway
Escherichia coli K-12 has several different routes in which it can produce acetoacetyl-ACP, using different combinations of its three β-ketoacyl-ACP synthases (KAS). KASI, KASII and KASIII are encoded by fabB, fabF and fabH respectively. In general, the fabH-encoded enzyme is responsible for the initiation of fatty acid elongation, utilizing acyl-CoA primers, while the fabB/fabF products are responsible for the subsequent rounds of elongation, condensing malonyl-ACP with different length acyl-ACPs to extend the acyl chain by two carbons [White05, Schujman08].
In this theoretical pathway all three β-ketoacyl-ACP synthases participate. In the first reaction acetyl-CoA is transacylated to a holo-ACP by acetyl-CoA:ACP transacylase activity. This activity has been attributed to KASIII, although it is a minor activity of the enzyme (the trans-acylation specific activity is only about 200-fold less than the enzyme's condensation activity). It is possible that another acetyl transacylase exists in E. coli, although this has not been verified [Lowe88, Tsay92].
The product of this reaction, acetyl-ACP, can be condensed with malonyl-ACP by either KASI or KASII to form acetoacetyl-ACP. While these reactions have been verified in vitro [Garwin80a, Garwin80], the importance of this route in vivo is not clear, since these enzymes are believed to be primarily responsible for elongation reactions [White05].
Review: Cronan, J.E. and C.O. Rock (2008) "Biosynthesis of Membrane Lipids" EcoSal 3.6.4 [ECOSAL]
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Garwin80: Garwin JL, Klages AL, Cronan JE (1980). "Structural, enzymatic, and genetic studies of beta-ketoacyl-acyl carrier protein synthases I and II of Escherichia coli." J Biol Chem 1980;255(24);11949-56. PMID: 7002930
Garwin80a: Garwin JL, Klages AL, Cronan JE (1980). "Beta-ketoacyl-acyl carrier protein synthase II of Escherichia coli. Evidence for function in the thermal regulation of fatty acid synthesis." J Biol Chem 1980;255(8);3263-5. PMID: 6988423
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
Tsay92: Tsay JT, Oh W, Larson TJ, Jackowski S, Rock CO (1992). "Isolation and characterization of the beta-ketoacyl-acyl carrier protein synthase III gene (fabH) from Escherichia coli K-12." J Biol Chem 1992;267(10);6807-14. PMID: 1551888
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
Zhang03e: 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
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
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
Cao10: Cao Y, Yang J, Xian M, Xu X, Liu W (2010). "Increasing unsaturated fatty acid contents in Escherichia coli by coexpression of three different genes." Appl Microbiol Biotechnol 87(1);271-80. PMID: 20135119
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
Davies00: Davies C, Heath RJ, White SW, Rock CO (2000). "The 1.8 A crystal structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli." Structure 8(2);185-95. PMID: 10673437
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Edwards97: Edwards P, Nelsen JS, Metz JG, Dehesh K (1997). "Cloning of the fabF gene in an expression vector and in vitro characterization of recombinant fabF and fabB encoded enzymes from Escherichia coli." FEBS Lett 402(1);62-6. PMID: 9013860
Feng09a: Feng Y, Cronan JE (2009). "Escherichia coli unsaturated fatty acid synthesis: complex transcription of the fabA gene and in vivo identification of the essential reaction catalyzed by FabB." J Biol Chem 284(43);29526-35. PMID: 19679654
Gajiwala09: Gajiwala KS, Margosiak S, Lu J, Cortez J, Su Y, Nie Z, Appelt K (2009). "Crystal structures of bacterial FabH suggest a molecular basis for the substrate specificity of the enzyme." FEBS Lett 583(17);2939-46. PMID: 19665020
Greenspan69: Greenspan MD, Alberts AW, Vagelos PR (1969). "Acyl carrier protein. 13. Beta-ketoacyl acyl carrier protein synthetase from Escherichia coli." J Biol Chem 1969;244(23);6477-85. PMID: 4901371
Heath96: Heath RJ, Rock CO (1996). "Inhibition of beta-ketoacyl-acyl carrier protein synthase III (FabH) by acyl-acyl carrier protein in Escherichia coli." J Biol Chem 1996;271(18);10996-1000. PMID: 8631920
Heath96b: Heath RJ, Rock CO (1996). "Roles of the FabA and FabZ beta-hydroxyacyl-acyl carrier protein dehydratases in Escherichia coli fatty acid biosynthesis." J Biol Chem 1996;271(44);27795-801. PMID: 8910376
Huang98a: Huang W, Jia J, Edwards P, Dehesh K, Schneider G, Lindqvist Y (1998). "Crystal structure of beta-ketoacyl-acyl carrier protein synthase II from E.coli reveals the molecular architecture of condensing enzymes." EMBO J 17(5);1183-91. PMID: 9482715
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