|Gene:||fabH||Accession Numbers: EG10277 (MetaCyc), b1091, ECK1077|
Synonyms: β-ketoacyl-acyl carrier protein synthase III, β-ketoacyl-ACP synthase III, 3-oxoacyl-ACP synthase III, KASIII
Species: Escherichia coli K-12 substr. MG1655
Subunit composition of KASIII = [FabH]2
There are three β-ketoacyl-ACP synthases (KAS) in E. coli: KASI, KASII and KASIII, encoded by fabB, fabF and fabH, respectively. All three are genetically and biochemically distinct. Each of the three enzymes is capable of initiating fatty acid biosynthesis.
KASIII is a 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.
KASIII is inhibited by acyl-ACP, indicating a role in feedback regulation of fatty acid synthesis. As KASIII catalyzes the first condensation step in fatty acid synthesis, it is ideally situated in the pathway to control the rate of fatty acid initiation [Heath96, Heath96a, Jackowski89, Tsay92, Magnuson93].
The enzyme has also been shown to possess acetyl-CoA:ACP transacylase activity, although to a much lesser extent than its main function. Its condensation reaction has a specific activity 200 times higher than the transacylation reaction [Tsay92].
The essentially of bacterial FabH to fatty acid biosynthesis in vivo has been demonstrated using mutant strains of Lactococcus lactis and E. coli. In E. coli, the essentiality of FabH to cell growth could be shown by a genetic method that utilized a plasmid-based gene insertion/deletion system (the CRIM plasmid system) [Lai03].
The β-ketoacyl-ACP synthase (KAS) enzymes of the bacterial type II fatty acid biosynthesis pathway are of interest as drug targets. Many novel compounds that inhibit E. coli FabH have been identified and studied. Recent examples include [Alhamadsheh08, Lee09a, Lv09, Lv10, Shi10, Li11, Zhang11a]. Several crystal structures of this enzyme have been solved [Gajiwala09, Alhamadsheh07, Daines03, Qiu01, Davies00]. In addition to X-ray crystallography, molecular dynamics simulations and molecular docking studies have been used to explore the conformation of both unliganded E. coli FabH and an enzyme-inhibitor complex, to allow more accurate inhibitor modeling [PerezCastillo11].
Review: Cronan, J.E. and C.O. Rock (2008) "Biosynthesis of Membrane Lipids" EcoSal 3.6.4 [ECOSAL]
|Map Position: [1,147,982 -> 1,148,935]|
Molecular Weight of Polypeptide: 33.515 kD (from nucleotide sequence)
Unification Links: ASAP:ABE-0003696 , CGSC:31860 , DIP:DIP-48255N , EchoBASE:EB0273 , EcoGene:EG10277 , EcoliWiki:b1091 , Mint:MINT-1263292 , ModBase:P0A6R0 , OU-Microarray:b1091 , PortEco:fabH , PR:PRO_000022564 , Pride:P0A6R0 , Protein Model Portal:P0A6R0 , RefSeq:NP_415609 , RegulonDB:EG10277 , SMR:P0A6R0 , String:511145.b1091 , UniProt:P0A6R0
Relationship Links: InterPro:IN-FAMILY:IPR004655 , InterPro:IN-FAMILY:IPR013747 , InterPro:IN-FAMILY:IPR013751 , InterPro:IN-FAMILY:IPR016038 , InterPro:IN-FAMILY:IPR016039 , PDB:Structure:1EBL , PDB:Structure:1HN9 , PDB:Structure:1HND , PDB:Structure:1HNH , PDB:Structure:1HNJ , PDB:Structure:1HNK , PDB:Structure:1MZS , PDB:Structure:2EFT , PDB:Structure:2GYO , PDB:Structure:3IL9 , Pfam:IN-FAMILY:PF08541 , Pfam:IN-FAMILY:PF08545
|Biological Process:|| GO:0006631 - fatty acid metabolic process
GO:0006629 - lipid metabolic process [UniProtGOA11]
GO:0006633 - fatty acid biosynthetic process [UniProtGOA12, UniProtGOA11, GOA06, GOA01]
GO:0008152 - metabolic process [UniProtGOA11, GOA01]
GO:0008610 - lipid biosynthetic process [GOA01]
|Molecular Function:|| GO:0033818 - beta-ketoacyl-acyl-carrier-protein synthase III activity
[GOA06, GOA01a, Tsay92]
GO:0042803 - protein homodimerization activity [Lowe88]
GO:0003824 - catalytic activity [UniProtGOA11, GOA01]
GO:0004315 - 3-oxoacyl-[acyl-carrier-protein] synthase activity [GOA01]
GO:0016740 - transferase activity [UniProtGOA11]
GO:0016746 - transferase activity, transferring acyl groups [UniProtGOA11]
GO:0016747 - transferase activity, transferring acyl groups other than amino-acyl groups [GOA01]
|Cellular Component:|| GO:0005737 - cytoplasm
[UniProtGOA11a, UniProtGOA11, GOA06]
GO:0005829 - cytosol
|MultiFun Terms:||metabolism → biosynthesis of building blocks → fatty acids and phosphatidic acid|
Enzymatic reaction of: β-ketoacyl-ACP synthase (KASIII)
Synonyms: 3-oxoacyl-ACP synthase, acetoacetyl-ACP synthase, acyl-[acyl carrier protein]:malonyl-[acyl carrier protein] C-acyltransferase (decarboxylating), β-ketoacyl-acyl carrier protein synthase
EC Number: 220.127.116.11
The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.
The reaction is favored in the direction shown.
In Pathways: superpathway of fatty acid biosynthesis I (E. coli) , superpathway of fatty acid biosynthesis initiation (E. coli) , superpathway of fatty acids biosynthesis (E. coli) , fatty acid biosynthesis initiation I
Primary Physiological Regulators of Enzyme Activity: an acyl-[acyl-carrier protein]
Enzymatic reaction of: acetyl-CoA:ACP transacylase (KASIII)
Synonyms: [acyl-carrier-protein] S-acetyltransferase, acetyl-CoA:[ACP] S-acetyltransferase, acetyl-CoA:ACP transacylase
EC Number: 18.104.22.168
The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction of enzyme catalysis.
This reaction is reversible.
Acetyl-CoA can be converted into acetyl-ACP by the ACP S-acetyltransferase enzyme. The resulting acetyl-ACP can serve as the primer when alternative condensing enzymes such as KASI participate in the initiation of fatty acid production [Magnuson93]. Both transacylase and KASIII activities are carried out by the same protein, coded for by the fabH gene [Tsay92].
|Protein-Segment||245 -> 249|
|Mutagenesis-Variant||256 -> 257|
10/20/97 Gene b1091 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10277; confirmed by SwissProt match.
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
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
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
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
Lee09a: Lee JY, Jeong KW, Lee JU, Kang DI, Kim Y (2009). "Novel E. coli beta-ketoacyl-acyl carrier protein synthase III inhibitors as targeted antibiotics." Bioorg Med Chem 17(4);1506-13. PMID: 19185501
Li11: Li HQ, Luo Y, Zhu HL (2011). "Discovery of vinylogous carbamates as a novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors." Bioorg Med Chem 19(15);4454-9. PMID: 21742506
Lv09: Lv PC, Wang KR, Yang Y, Mao WJ, Chen J, Xiong J, Zhu HL (2009). "Design, synthesis and biological evaluation of novel thiazole derivatives as potent FabH inhibitors." Bioorg Med Chem Lett 19(23);6750-4. PMID: 19836235
Lv10: Lv PC, Sun J, Luo Y, Yang Y, Zhu HL (2010). "Design, synthesis, and structure-activity relationships of pyrazole derivatives as potential FabH inhibitors." Bioorg Med Chem Lett 20(15);4657-60. PMID: 20594840
Neidhardt96: Neidhardt FC, Curtiss III R, Ingraham JL, Lin ECC, Low Jr KB, Magasanik B, Reznikoff WS, Riley M, Schaechter M, Umbarger HE "Escherichia coli and Salmonella, Cellular and Molecular Biology, Second Edition." American Society for Microbiology, Washington, D.C., 1996.
PerezCastillo11: Perez-Castillo Y, Froeyen M, Cabrera-Perez MA, Nowe A (2011). "Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling." J Comput Aided Mol Des 25(4);371-93. PMID: 21516317
Shi10: Shi L, Fang RQ, Zhu ZW, Yang Y, Cheng K, Zhong WQ, Zhu HL (2010). "Design and synthesis of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III (FabH) as potential antibacterial agents." Eur J Med Chem 45(9);4358-64. PMID: 20557983
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
Zhang01: Zhang YM, Rao MS, Heath RJ, Price AC, Olson AJ, Rock CO, White SW (2001). "Identification and analysis of the acyl carrier protein (ACP) docking site on beta-ketoacyl-ACP synthase III." J Biol Chem 276(11);8231-8. PMID: 11078736
Zhang11a: Zhang HJ, Zhu DD, Li ZL, Sun J, Zhu HL (2011). "Synthesis, molecular modeling and biological evaluation of β-ketoacyl-acyl carrier protein synthase III (FabH) as novel antibacterial agents." Bioorg Med Chem 19(15);4513-9. PMID: 21741250
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