MetaCyc Pathway: fatty acid biosynthesis initiation II
Inferred from experiment

Enzyme View:

Pathway diagram: fatty acid biosynthesis initiation II

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.

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisFatty Acid Biosynthesis

Some taxa known to possess this pathway include : Escherichia coli K-12 substr. MG1655, Homo sapiens, Saccharomyces cerevisiae

Expected Taxonomic Range: Bacteria , Entamoebidae, Fungi, Metazoa

General Background

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 [Zhang03b, 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, 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-[acyl-carrier protein] 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 the organism, although this has not been verified [Lowe88, Tsay92].

The product of this reaction, an acetyl-[acp], can be condensed with a malonyl-[acp] by either KASI or KASII to form an 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].

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

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

Unification Links: EcoCyc:PWY-5966

Created 07-Jul-2008 by Caspi R, SRI International


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). "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

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

Prieschl00: Prieschl EE, Baumruker T (2000). "Sphingolipids: second messengers, mediators and raft constituents in signaling." Immunol Today 21(11);555-60. PMID: 11094259

Resh99: Resh MD (1999). "Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins." Biochim Biophys Acta 1451(1);1-16. PMID: 10446384

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

Zhang03b: 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

Brink02: Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W (2002). "Quaternary structure of human fatty acid synthase by electron cryomicroscopy." Proc Natl Acad Sci U S A 99(1);138-43. PMID: 11756679

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

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

Edwards97a: 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

Field02: Field FJ, Born E, Murthy S, Mathur SN (2002). "Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport." Biochem J 368(Pt 3);855-64. PMID: 12213084

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

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

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

Harington93: Harington A, Herbert CJ, Tung B, Getz GS, Slonimski PP (1993). "Identification of a new nuclear gene (CEM1) encoding a protein homologous to a beta-keto-acyl synthase which is essential for mitochondrial respiration in Saccharomyces cerevisiae." Mol Microbiol 9(3);545-55. PMID: 8412701

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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