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MetaCyc Enzyme: KASIII

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

Summary:
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, Lee09f, Lv09, Lv10, Shi10a, Li11f, Zhang11e]. Several crystal structures of this enzyme have been solved [Gajiwala09, Alhamadsheh07, Daines03, Qiu01b, Davies00a]. 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]

Review: [White05]

Locations: cytosol

Map Position: [1,147,982 -> 1,148,935]

Molecular Weight of Polypeptide: 33.515 kD (from nucleotide sequence)

pI: 5.33 [Neidhardt96], 4.85 [Tsay92]

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

Gene-Reaction Schematic: ?

GO Terms:

Biological Process: GO:0006631 - fatty acid metabolic process Inferred from experiment Inferred by computational analysis [UniProtGOA11, Tsay92]
GO:0006629 - lipid metabolic process Inferred by computational analysis [UniProtGOA11]
GO:0006633 - fatty acid biosynthetic process Inferred by computational analysis [UniProtGOA12, UniProtGOA11, GOA06, GOA01]
GO:0008152 - metabolic process Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0008610 - lipid biosynthetic process Inferred by computational analysis [GOA01]
Molecular Function: GO:0033818 - beta-ketoacyl-acyl-carrier-protein synthase III activity Inferred from experiment Inferred by computational analysis [GOA06, GOA01a, Tsay92]
GO:0042803 - protein homodimerization activity Inferred from experiment [Lowe88]
GO:0003824 - catalytic activity Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0004315 - 3-oxoacyl-[acyl-carrier-protein] synthase activity Inferred by computational analysis [GOA01]
GO:0016740 - transferase activity Inferred by computational analysis [UniProtGOA11]
GO:0016746 - transferase activity, transferring acyl groups Inferred by computational analysis [UniProtGOA11]
GO:0016747 - transferase activity, transferring acyl groups other than amino-acyl groups Inferred by computational analysis [GOA01]
Cellular Component: GO:0005829 - cytosol Inferred from experiment Inferred by computational analysis [DiazMejia09, Ishihama08, LopezCampistrou05]
GO:0005737 - cytoplasm Inferred by computational analysis [UniProtGOA11a, UniProtGOA11, GOA06]

MultiFun Terms: metabolism biosynthesis of building blocks fatty acids and phosphatidic acid

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International


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: 2.3.1.180

acetyl-CoA + a malonyl-[acp] + H+ <=> an acetoacetyl-[acp] + CO2 + coenzyme A

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.

Alternative Substrates for acetyl-CoA: butanoyl-CoA [Heath96 ] , propanoyl-CoA [Heath96 ]

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

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International

Inhibitors (Competitive): an acyl-[acyl-carrier protein] [Comment 1]

Inhibitors (Other): an acyl-[acyl-carrier protein] [Heath96, Comment 2]

Inhibitors (Unknown Mechanism): thiolactomycin [Jackowski89]

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: 2.3.1.38

acetyl-CoA + a holo-[acyl-carrier protein] <=> an acetyl-[acp] + coenzyme A

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.

In Pathways: superpathway of fatty acid biosynthesis I (E. coli) , superpathway of fatty acid biosynthesis initiation (E. coli) , fatty acid biosynthesis initiation II

Credits:
Imported from EcoCyc 16-Sep-2014 by Paley S , SRI International

Summary:
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].

Inhibitors (Competitive): coenzyme A [Lowe88, Comment 3] , pantetheine [Lowe88, Comment 4]

Inhibitors (Unknown Mechanism): thiolactomycin [Tsay92] , iodoacetamide [Lowe88] , N-ethylmaleimide [Lowe88]


Sequence Features

Feature Class Location Citations Comment
Mutagenesis-Variant 112
[UniProt10]
Alternate sequence: S; UniProt: Loss of activity;
Active-Site 112
[UniProt10]
Mutagenesis-Variant 214
[Zhang01d, UniProt11a]
Alternate sequence: A; UniProt: Strongly reduces the binding to malonyl-ACP but not that of the substrate.
Alternate sequence: E; UniProt: Strongly reduces the binding to malonyl-ACP but not that of the substrate.
Mutagenesis-Variant 244
[UniProt10]
Alternate sequence: A; UniProt: Loss of activity;
Active-Site 244
[UniProt10]
Protein-Segment 245 -> 249
[UniProt10a]
UniProt: ACP-binding; Sequence Annotation Type: region of interest;
Mutagenesis-Variant 249
[Zhang01d, UniProt11a]
Alternate sequence: A; UniProt: Abolishes the binding to malonyl- ACP but not that of the substrate.
Alternate sequence: E; UniProt: Abolishes the binding to malonyl- ACP but not that of the substrate.
Mutagenesis-Variant 253
[Zhang01d, UniProt11a]
Alternate sequence: Y; UniProt: Abolishes both binding to malonyl- ACP and binding to substrate.
Mutagenesis-Variant 256 -> 257
[UniProt10]
Alternate sequence: EE; UniProt: Abolishes the binding to malonyl- ACP but not that of the substrate;
Alternate sequence: AA; UniProt: Strongly reduces both binding to malonyl-ACP and binding to substrate;
Mutagenesis-Variant 274
[UniProt10]
Alternate sequence: A; UniProt: Loss of activity;
Active-Site 274
[UniProt10]

History:
10/20/97 Gene b1091 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10277; confirmed by SwissProt match.


References

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

Davies00a: 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.

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."

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

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

Ishihama08: Ishihama Y, Schmidt T, Rappsilber J, Mann M, Hartl FU, Kerner MJ, Frishman D (2008). "Protein abundance profiling of the Escherichia coli cytosol." BMC Genomics 9;102. PMID: 18304323

Jackowski89: Jackowski S, Murphy CM, Cronan JE, Rock CO (1989). "Acetoacetyl-acyl carrier protein synthase. A target for the antibiotic thiolactomycin." J Biol Chem 1989;264(13);7624-9. PMID: 2651445

Lai03: Lai CY, Cronan JE (2003). "Beta-ketoacyl-acyl carrier protein synthase III (FabH) is essential for bacterial fatty acid synthesis." J Biol Chem 278(51);51494-503. PMID: 14523010

Lee09f: 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

Li11f: 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

LopezCampistrou05: Lopez-Campistrous A, Semchuk P, Burke L, Palmer-Stone T, Brokx SJ, Broderick G, Bottorff D, Bolch S, Weiner JH, Ellison MJ (2005). "Localization, annotation, and comparison of the Escherichia coli K-12 proteome under two states of growth." Mol Cell Proteomics 4(8);1205-9. PMID: 15911532

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

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

Magnuson93: Magnuson K, Jackowski S, Rock CO, Cronan JE (1993). "Regulation of fatty acid biosynthesis in Escherichia coli." Microbiol Rev 1993;57(3);522-42. PMID: 8246839

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

Qiu01b: Qiu X, Janson CA, Smith WW, Head M, Lonsdale J, Konstantinidis AK (2001). "Refined structures of beta-ketoacyl-acyl carrier protein synthase III." J Mol Biol 307(1);341-56. PMID: 11243824

Shi10a: 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

UniProt10: UniProt Consortium (2010). "UniProt version 2010-11 released on 2010-11-02 00:00:00." Database.

UniProt10a: UniProt Consortium (2010). "UniProt version 2010-07 released on 2010-06-15 00:00:00." Database.

UniProt11a: UniProt Consortium (2011). "UniProt version 2011-06 released on 2011-06-30 00:00:00." Database.

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on the manual assignment of UniProtKB Subcellular Location terms in UniProtKB/Swiss-Prot entries."

UniProtGOA12: UniProt-GOA (2012). "Gene Ontology annotation based on UniPathway vocabulary mapping."

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

Zhang01d: 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

Zhang11e: 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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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Thu Nov 27, 2014, biocyc11.