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Escherichia coli K-12 substr. MG1655 Pathway: fatty acid biosynthesis initiation II

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Locations of Mapped Genes:

Genetic Regulation Schematic: ?

Superclasses: Biosynthesis Fatty Acids and Lipids Biosynthesis Fatty Acid Biosynthesis

General Background

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 [Zhang03a, 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 [Garwin80, Garwin80a], the importance of this route in vivo is not clear, since these enzymes are believed to be primarily responsible for elongation reactions [White05].

Other mechanisms for fatty acid biosynthesis initiation in E. coli K-12 are described in fatty acid biosynthesis initiation I and fatty acid biosynthesis initiation III.

Review: Cronan, J.E. and C.O. Rock (2008) "Biosynthesis of Membrane Lipids" EcoSal 3.6.4 [ECOSAL]

Superpathways: superpathway of fatty acid biosynthesis initiation (E. coli) , superpathway of fatty acid biosynthesis I (E. coli)

Created 07-Jul-2008 by Caspi R , SRI International
Last-Curated ? 10-Jun-2011 by Fulcher C , SRI International


ECOSAL: "Escherichia coli and Salmonella: Cellular and Molecular Biology." Online edition.

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

Garwin80: 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

Garwin80a: 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

Lowe88: Lowe PN, Rhodes S (1988). "Purification and characterization of [acyl-carrier-protein] acetyltransferase from Escherichia coli." Biochem J 1988;250(3);789-96. PMID: 3291856

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

Schujman08: Schujman GE, Altabe S, de Mendoza D (2008). "A malonyl-CoA-dependent switch in the bacterial response to a dysfunction of lipid metabolism." Mol Microbiol 68(4);987-96. PMID: 18384517

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

White05: White SW, Zheng J, Zhang YM, Rock (2005). "The structural biology of type II fatty acid biosynthesis." Annu Rev Biochem 74;791-831. PMID: 15952903

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

Zhang03a: 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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

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

Byers07: Byers DM, Gong H (2007). "Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family." Biochem Cell Biol 85(6);649-62. PMID: 18059524

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

DAgnolo75: D'Agnolo G, Rosenfeld IS, Vagelos PR (1975). "Multiple forms of beta-ketoacyl-acyl carrier protein synthetase in Escherichia coli." J Biol Chem 250(14);5289-94. PMID: 237914

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

Feng09: 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

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA01a: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

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). "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

Heath96a: Heath RJ, Rock CO (1996). "Regulation of fatty acid elongation and initiation by acyl-acyl carrier protein in Escherichia coli." J Biol Chem 1996;271(4);1833-6. PMID: 8567624

Heath96b: 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

Huang98: 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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Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
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