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Escherichia coli K-12 substr. MG1655 Polypeptide: FadR DNA-binding transcriptional dual regulator



Gene: fadR Accession Numbers: EG10281 (EcoCyc), b1187, ECK1175

Synonyms: dec, ole, oleR, thdB

Regulation Summary Diagram: ?

Component of: FadR-acyl-CoA (summary available)

Summary:
FadR, Fatty acid degradation Regulon [Overath69], is a multifunctional dual regulator [DiRusso88] that exerts negative control over the fatty acid degradative regulon [Simons80, Simons80a] and acetate metabolism [Maloy81], whereas it is responsible for maximal expression of unsaturated fatty acid biosynthesis [Nunn83]. FadR coordinately regulates fatty acid biosynthesis and fatty acid degradation at the level of transcription [DiRusso93]. In this way, FadR functions as a switch between fatty acid β-oxidation and fatty acid biosynthesis [Xu01].

FadR is a global regulator of lipid metabolism, as it activates multiple operons responsible for fatty acid synthesis [My13]. FadR activates the fabH promoter in the absence of long-chain fatty acids [My13].

FadR belongs to the GntR family [vanAalten00, Haydon91]. However, Xu et al. (2001) reported that homologies to CAP and the Tet repressor based on structure are more relevant and they have categorized FadR as a chimera of two motifs [Xu01].

FadR appears to be a two-domain dimeric molecule in which the N-terminal domains [Raman95, Raman97, DiRusso92, DiRusso88] bind to DNA, whereas the C-terminal domain binds the fatty acyl coenzyme A (acyl-CoA) [Xu01]. In addition, there is a linker that connects both the N-terminal and C-terminal. FadR binds DNA as an apo-protein, and it is released when it binds long-chain acyl-CoA [Cronan98]. The binding of the acyl-CoA disrupts a buried network of charged and polar residues in the C-terminal domain, and the resulting conformational change is transmitted to the N-terminal domain via a domain-spanning α-helix CoA [Xu01]; in this way there is loss of DNA binding [vanAalten00a], since acyl-CoA regulates DNA binding by FadR [DiRusso92, Cronan97].

The α/β N-terminal domain (α1-β1-α2-α3-β2-β3) has a winged-helix motif, and the α-helical C-terminal domain (α6-α7-α8-α9-α10-α11-α12) resembles the sensor domain of the Tet repressor [Xu01] and PAS domain, in particular the photoactive yellow protein [vanAalten00a], and finally the linker comprising two short α-helices (α4-α5) [Xu01].

The binding of FadR to DNA is determined by the localization of the α3 recognition helices that are paired together at the dimer interface [Xu01].

The DNA-binding domain is very highly conserved among FadR-containing bacteria, whereas the C-terminal acyl-CoA-binding domain shows only weak conservation [Iram05].

A FadR-type regulator has been identified in Vibrio vulnificus [Brown08a], Corynebacterium glutamicum [Georgi08], Salmonella enterica, Vibrio cholerae, Pasteurella multocida, and Hemophilus influenzae [Iram05].

FadR is a homodimer [Raman97, Xu01] that recognizes a palindromic sequence, 5'-TGGNNNNNCCA-3' [Xu01].

Overexpression of FadR improves fatty acid production by 5- to 7.5-fold over that of strains in which it is not overexpressed [Zhang12c]. Genes related to the stress response proteins and fatty acid biosynthetic pathways are upregulated by FadR [Zhang12c]. An increase of organic solvent tolerances (OSTs) was shown by using the fadR and marR double mutant of those two transcriptional regulators [Oh12].

Review: [Marrakchi02, Cronan98].

Locations: cytosol

Map Position: [1,234,161 -> 1,234,880] (26.6 centisomes)
Length: 720 bp / 239 aa

Molecular Weight of Polypeptide: 26.969 kD (from nucleotide sequence)

pI: 6.84

Unification Links: ASAP:ABE-0003988 , CGSC:789 , EchoBASE:EB0277 , EcoGene:EG10281 , EcoliWiki:b1187 , Mint:MINT-1264978 , ModBase:P0A8V6 , OU-Microarray:b1187 , PortEco:fadR , PR:PRO_000022573 , Pride:P0A8V6 , Protein Model Portal:P0A8V6 , RefSeq:NP_415705 , RegulonDB:EG10281 , SMR:P0A8V6 , String:511145.b1187 , UniProt:P0A8V6

Relationship Links: InterPro:IN-FAMILY:IPR000524 , InterPro:IN-FAMILY:IPR008920 , InterPro:IN-FAMILY:IPR011991 , InterPro:IN-FAMILY:IPR014178 , InterPro:IN-FAMILY:IPR027376 , InterPro:IN-FAMILY:IPR028374 , PDB:Structure:1E2X , PDB:Structure:1H9G , PDB:Structure:1H9T , PDB:Structure:1HW1 , PDB:Structure:1HW2 , Pfam:IN-FAMILY:PF00392 , Pfam:IN-FAMILY:PF07840 , Prints:IN-FAMILY:PR00035 , Prosite:IN-FAMILY:PS50949 , Smart:IN-FAMILY:SM00345

In Paralogous Gene Group: 38 (9 members) , 541 (2 members)

In Reactions of unknown directionality:

Not in pathways:
FadR + an acyl-CoA = FadR-acyl-CoA

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

GO Terms:

Biological Process: GO:0019217 - regulation of fatty acid metabolic process Inferred from experiment Inferred by computational analysis [GOA06, GOA01a, Campbell01]
GO:0019395 - fatty acid oxidation Inferred from experiment [Xu01]
GO:0045723 - positive regulation of fatty acid biosynthetic process Inferred from experiment [Campbell01]
GO:0006351 - transcription, DNA-templated Inferred by computational analysis [UniProtGOA11a]
GO:0006355 - regulation of transcription, DNA-templated Inferred by computational analysis [UniProtGOA11a, GOA06, GOA01a]
GO:0006629 - lipid metabolic process Inferred by computational analysis [UniProtGOA11a]
GO:0006631 - fatty acid metabolic process Inferred by computational analysis [UniProtGOA11a]
GO:0045892 - negative regulation of transcription, DNA-templated Inferred by computational analysis [Xu01]
GO:0045893 - positive regulation of transcription, DNA-templated Inferred by computational analysis [Xu01]
Molecular Function: GO:0000062 - fatty-acyl-CoA binding Inferred by computational analysis [GOA01a]
GO:0003677 - DNA binding Inferred by computational analysis [UniProtGOA11a, GOA06, GOA01a]
GO:0003700 - sequence-specific DNA binding transcription factor activity Inferred by computational analysis [GOA06, GOA01a, Xu01]
Cellular Component: GO:0005829 - cytosol Inferred from experiment Inferred by computational analysis [DiazMejia09, Ishihama08]
GO:0005737 - cytoplasm Inferred by computational analysis [UniProtGOA11, UniProtGOA11a, GOA06]

MultiFun Terms: information transfer RNA related Transcription related
metabolism carbon utilization fatty acids
regulation genetic unit regulated operon
regulation genetic unit regulated regulon
regulation type of regulation transcriptional level activator
regulation type of regulation transcriptional level repressor

DNA binding site length: 17 base-pairs

Symmetry: Inverted Repeat

Consensus DNA Binding Sequence: aaCTGGTCnGACCAGtt

Regulated Transcription Units (12 total): ?

Notes:

Essentiality data for fadR knockouts: ?

Growth Medium Growth? T (°C) O2 pH Osm/L Growth Observations
LB enriched Yes 37 Aerobic 6.95   Yes [Gerdes03, Comment 1]
LB Lennox Yes 37 Aerobic 7   Yes [Baba06, Comment 2]
M9 medium with 1% glycerol Yes 37 Aerobic 7.2 0.35 Yes [Joyce06, Comment 3]
MOPS medium with 0.4% glucose Yes 37 Aerobic 7.2 0.22 Yes [Baba06, Comment 2]

Credits:
Last-Curated ? 03-Apr-2009 by Santos-Zavaleta A , UNAM
Revised 23-May-2011 by Brito D


Subunit of: FadR-acyl-CoA

Synonyms: B1187, Ole, Dec, ThdB, OleR, FadR

Subunit composition of FadR-acyl-CoA = [FadR][an acyl-CoA]
         FadR DNA-binding transcriptional dual regulator = FadR (extended summary available)

Summary:

Sequence Length: 239 AAs

Molecular Weight: 26.969 kD (from nucleotide sequence)

Relationship Links: PDB:STRUCTURE:1HW2 , Pfam:IN-FAMILY:PF00392

In Reactions of unknown directionality:

Not in pathways:
FadR + an acyl-CoA = FadR-acyl-CoA

MultiFun Terms: information transfer RNA related Transcription related
metabolism carbon utilization fatty acids
regulation genetic unit regulated operon
regulation genetic unit regulated regulon
regulation type of regulation transcriptional level activator
regulation type of regulation transcriptional level repressor

Regulated Transcription Units (1 total): ?

Notes:


Sequence Features

Feature Class Location Citations Comment
Cleavage-of-Initial-Methionine 1
[UniProt10]
UniProt: Removed;
Chain 2 -> 239
[UniProt09]
UniProt: Fatty acid metabolism regulator protein;
Conserved-Region 6 -> 74
[UniProt09]
UniProt: HTH gntR-type;
DNA-Binding-Region 34 -> 53
[UniProt10a]
UniProt: H-T-H motif; Non-Experimental Qualifier: potential;


Gene Local Context (not to scale): ?

Transcription Units:

Notes:

History:
10/20/97 Gene b1187 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10281; confirmed by SwissProt match.


References

Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554

Bateman00: Bateman A, Birney E, Durbin R, Eddy SR, Howe KL, Sonnhammer EL (2000). "The Pfam protein families database." Nucleic Acids Res 28(1);263-6. PMID: 10592242

Brown08a: Brown RN, Gulig PA (2008). "Regulation of fatty acid metabolism by FadR is essential for Vibrio vulnificus to cause infection of mice." J Bacteriol 190(23);7633-44. PMID: 18835990

Campbell01: Campbell JW, Cronan JE (2001). "Escherichia coli FadR positively regulates transcription of the fabB fatty acid biosynthetic gene." J Bacteriol 183(20);5982-90. PMID: 11566998

Cronan97: Cronan JE (1997). "In vivo evidence that acyl coenzyme A regulates DNA binding by the Escherichia coli FadR global transcription factor." J Bacteriol 179(5);1819-23. PMID: 9045847

Cronan98: Cronan JE, Subrahmanyam S (1998). "FadR, transcriptional co-ordination of metabolic expediency." Mol Microbiol 29(4);937-43. PMID: 9767562

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

DiRusso88: DiRusso CC (1988). "Nucleotide sequence of the fadR gene, a multifunctional regulator of fatty acid metabolism in Escherichia coli." Nucleic Acids Res 1988;16(16);7995-8009. PMID: 2843809

DiRusso92: DiRusso CC, Heimert TL, Metzger AK (1992). "Characterization of FadR, a global transcriptional regulator of fatty acid metabolism in Escherichia coli. Interaction with the fadB promoter is prevented by long chain fatty acyl coenzyme A." J Biol Chem 1992;267(12);8685-91. PMID: 1569108

DiRusso93: DiRusso CC, Metzger AK, Heimert TL (1993). "Regulation of transcription of genes required for fatty acid transport and unsaturated fatty acid biosynthesis in Escherichia coli by FadR." Mol Microbiol 1993;7(2);311-22. PMID: 8446033

Georgi08: Georgi T, Engels V, Wendisch VF (2008). "Regulation of L-lactate utilization by the FadR-type regulator LldR of Corynebacterium glutamicum." J Bacteriol 190(3);963-71. PMID: 18039772

Gerdes03: Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL (2003). "Experimental determination and system level analysis of essential genes in Escherichia coli MG1655." J Bacteriol 185(19);5673-84. PMID: 13129938

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."

Haydon91: Haydon DJ, Guest JR (1991). "A new family of bacterial regulatory proteins." FEMS Microbiol Lett 63(2-3);291-5. PMID: 2060763

Iram05: Iram SH, Cronan JE (2005). "Unexpected functional diversity among FadR fatty acid transcriptional regulatory proteins." J Biol Chem 280(37);32148-56. PMID: 16027119

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

Joyce06: Joyce AR, Reed JL, White A, Edwards R, Osterman A, Baba T, Mori H, Lesely SA, Palsson BO, Agarwalla S (2006). "Experimental and computational assessment of conditionally essential genes in Escherichia coli." J Bacteriol 188(23);8259-71. PMID: 17012394

Maloy81: Maloy SR, Nunn WD (1981). "Role of gene fadR in Escherichia coli acetate metabolism." J Bacteriol 148(1);83-90. PMID: 7026540

Marrakchi02: Marrakchi H, Zhang YM, Rock CO (2002). "Mechanistic diversity and regulation of Type II fatty acid synthesis." Biochem Soc Trans 30(Pt 6);1050-5. PMID: 12440970

My13: My L, Rekoske B, Lemke JJ, Viala JP, Gourse RL, Bouveret E (2013). "Transcription of the Escherichia coli Fatty Acid Synthesis Operon fabHDG Is Directly Activated by FadR and Inhibited by ppGpp." J Bacteriol 195(16);3784-95. PMID: 23772072

Nunn83: Nunn WD, Giffin K, Clark D, Cronan JE (1983). "Role for fadR in unsaturated fatty acid biosynthesis in Escherichia coli." J Bacteriol 154(2);554-60. PMID: 6341354

Oh12: Oh HY, Lee JO, Kim OB (2012). "Increase of organic solvent tolerance of Escherichia coli by the deletion of two regulator genes, fadR and marR." Appl Microbiol Biotechnol 96(6);1619-27. PMID: 23053109

Overath69: Overath P, Pauli G, Schairer HU (1969). "Fatty acid degradation in Escherichia coli. An inducible acyl-CoA synthetase, the mapping of old-mutations, and the isolation of regulatory mutants." Eur J Biochem 7(4);559-74. PMID: 4887396

Raman95: Raman N, DiRusso CC (1995). "Analysis of acyl coenzyme A binding to the transcription factor FadR and identification of amino acid residues in the carboxyl terminus required for ligand binding." J Biol Chem 270(3);1092-7. PMID: 7836365

Raman97: Raman N, Black PN, DiRusso CC (1997). "Characterization of the fatty acid-responsive transcription factor FadR. Biochemical and genetic analyses of the native conformation and functional domains." J Biol Chem 272(49);30645-50. PMID: 9388199

Simons80: Simons RW, Egan PA, Chute HT, Nunn WD (1980). "Regulation of fatty acid degradation in Escherichia coli: isolation and characterization of strains bearing insertion and temperature-sensitive mutations in gene fadR." J Bacteriol 142(2);621-32. PMID: 6247326

Simons80a: Simons RW, Hughes KT, Nunn WD (1980). "Regulation of fatty acid degradation in Escherichia coli: dominance studies with strains merodiploid in gene fadR." J Bacteriol 143(2);726-30. PMID: 7009562

UniProt09: UniProt Consortium (2009). "UniProt version 15.8 released on 2009-10-01 00:00:00." Database.

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.

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

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

vanAalten00: van Aalten DM, DiRusso CC, Knudsen J, Wierenga RK (2000). "Crystal structure of FadR, a fatty acid-responsive transcription factor with a novel acyl coenzyme A-binding fold." EMBO J 19(19);5167-77. PMID: 11013219

vanAalten00a: van Aalten DM, Knudsen J, DiRusso CC, Kokko T, Wierenga RK (2000). "Crystallization and X-ray diffraction studies of the fatty-acid responsive transcription factor FadR from Escherichia coli." Acta Crystallogr D Biol Crystallogr 2000;56 ( Pt 4);469-71. PMID: 10739923

Xu01: Xu Y, Heath RJ, Li Z, Rock CO, White SW (2001). "The FadR.DNA complex. Transcriptional control of fatty acid metabolism in Escherichia coli." J Biol Chem 276(20);17373-9. PMID: 11279025

Zhang12c: Zhang F, Ouellet M, Batth TS, Adams PD, Petzold CJ, Mukhopadhyay A, Keasling JD (2012). "Enhancing fatty acid production by the expression of the regulatory transcription factor FadR." Metab Eng 14(6);653-60. PMID: 23026122

Other References Related to Gene Regulation

MendozaVargas09: Mendoza-Vargas A, Olvera L, Olvera M, Grande R, Vega-Alvarado L, Taboada B, Jimenez-Jacinto V, Salgado H, Juarez K, Contreras-Moreira B, Huerta AM, Collado-Vides J, Morett E (2009). "Genome-wide identification of transcription start sites, promoters and transcription factor binding sites in E. coli." PLoS One 4(10);e7526. PMID: 19838305


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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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